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CONFIDENTIAL INFORMATION OF DELMAR PHARMACEUTICALS, INC. ©2015 DelMar Pharmaceuticals
VAL-083: GBM
Historical Review &
Strategy for Product Development
CONFIDENTIAL – Updated February 2015
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©2015 DelMar Pharmaceuticals
Contents
1. EXECUTIVE SUMMARY ........................................................................................................... 2
2. Introduction ................................................................................................................................ 3
3. VAL-083 Background ................................................................................................................ 3
4. Glioblastoma Multiforme (GBM) ................................................................................................ 5
5. Alkylating Agent Chemotherapy in the Treatment of GBM ....................................................... 8
6. VAL-083 in GBM: ..................................................................................................................... 10
6.1. VAL-083: Overcoming MGMT Resistance ................................................................... 10
6.2. VAL-083 in GBM: Activity Against Cancer Stem Cells (CSCs) in vitro......................... 11
6.3. VAL-083 in GBM: Activity in Combination with Radiation Therapy .............................. 14
6.4. VAL-083 in GBM: Activity in vivo .................................................................................. 15
6.5. VAL-083 in GBM: Historical Human Clinical Experience ............................................. 16
6.6. VAL-083: Summary of Published Historical Safety & Toxicity Data ............................. 21
6.7. VAL-083: DelMar Pharmaceuticals Current Refractory GBM Clinical Trial .................. 23
6.8. VAL-083: Clinical Pharmacokinetics (PK) and Bio-distribution .................................... 25
6.9. VAL-083: Manufacturing ............................................................................................... 26
6.10. VAL-083: Intellectual Property ...................................................................................... 27
7. Market Opportunity .................................................................................................................. 28
8. DelMar Pharmaceutical’s VAL-083 Development & Commercialization Strategy for GBM ... 29
9. Immunotherapy & GBM: Potential integration with VAL-083 ................................................. 32
10. References .............................................................................................................................. 35
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1. EXECUTIVE SUMMARY
Glioblastoma multiforme (GBM) affects approximately 15,000 patients annually in
the United States;
The global market for GBM therapy currently exceeds $1.3 billion annually, with an
opportunity for significant growth;
In spite of recent advances in cancer therapy, prognosis for GBM patients remains
poor. Most patients fail to respond to today’s standard of care and treatment
options for refractory or relapsed patients are limited;
VAL-083 is a first-in-class alkylating agent with a unique bi-functional DNA cross-
linking mechanism that is distinct from other agents used in the treatment of
GBM;
In historical NCI-sponsored clinical trials VAL-083 demonstrated promising anti-
tumor activity in the treatment of hematologic malignancies and a range of solid
tumors, including brain cancer;
VAL-083 is well tolerated with a favorable safety profile in comparison to other
cytotoxic agents with the only reported dose limiting toxicity of
myelosuppression, which reverses spontaneously following treatment;
VAL-083 readily crosses the blood-brain barrier and has been shown to
preferentially accumulate in brain tumor tissue;
VAL-083 demonstrates more potent activity against GBM cells in comparison to
today’s standard of care and can overcome MGMT-mediated chemo-resistance;
VAL-083 is also active against cancer stem cells, suggesting the potential to
surpass the current standard-of-care in the treatment of GBM;
VAL-083 has been granted orphan drug protection for the treatment of gliomas in
the United States and Europe; and is the subject of three newly issued US patents
and one international patent; and
DelMar Pharmaceuticals is positioned to advance VAL-083 into Phase II/III
registration directed clinical trials as a potential new treatment for GBM patients
who have failed other available treatments during 2015.
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2. Introduction
DelMar Pharmaceuticals, Inc. is investigating VAL-083 (dianhydrogalactitol) in Phase I/II clinical trials in
the United States as a potential treatment for refractory glioblastoma multiforme (clinicaltrials.gov
identifier: NCT01478178). VAL-083 has been granted orphan drug status for the treatment of glioma in
the United States and European Union.
Glioblastoma multiforme (“GBM”) is the most common and most aggressive form of brain cancer,
affecting approximately 15,000 patients annually in the United States. Annual incidence of GBM is
approximately 3 per 100,000-population globally. Renewed attention was drawn to this form of brain
cancer when Senator Ted Kennedy was diagnosed and ultimately died from it.
Without treatment median survival following GBM diagnosis is usually less than six months. Only modest
advancements in the treatment of GBM have occurred in the past 25 years and no contemporary GBM
treatments are curative. Median survival from diagnosis with current standard-of-care is well under two
years.
Upon initial diagnosis, standard treatment consists of maximal surgical resection, radiotherapy, and
concomitant and adjuvant chemotherapy with temozolomide (Temodar®
or “TMZ”). Median time to
recurrence after standard chemo-radiation therapy is 6.9 months. Avastin is used as palliative second-
line therapy, but does not increase survival. Patients with refractory or resistant GBM have limited
therapeutic options.
Novel chemotherapies, particularly those with novel cytotoxic mechanisms of action to overcome chemo
resistance would offer important new treatment options for both newly-diagnosed and recurrent GBM.
VAL-083 is a first-in-class alkylating agent with a unique bi-functional DNA cross-linking mechanism
targeting the N7 position of guanine. This mechanism is distinct from other alkylating agents used in the
treatment of GBM.
In historical studies sponsored by the United States National Cancer Institute (“NCI”), VAL-083 exhibited
clinical activity against a range of tumor types including CNS tumors, solid tumors, and hematologic
malignancies. VAL-083 demonstrated promise in the treatment of GBM both as a single-agent and in
combination regimens in NCI-sponsored clinical trials. VAL-083 is approved in China for the treatment of
chronic myelogenous leukemia (“CML”) and lung cancer (Approval No. Guoyao Zhunzi H45021133;
manufactured by Guangxi Wuzhou Pharmaceutical (Group) Co. Ltd.)
DelMar believes that VAL-083’s unique mechanism of action, in association with newly developed data
positions the drug as a valuable therapy for GBM patients who have failed or are unlikely to respond to
other chemotherapeutic interventions.
VAL-083 is initially being positioned as a new treatment for refractory GBM – a significant unmet medical
need. DelMar’s data also supports VAL-083 as a potentially superior alternative to TMZ – the current
front-line chemotherapy in the treatment of newly diagnosed GBM – representing a potential multi-billion
dollar market opportunity.
3. VAL-083 Background
VAL-083 is DelMar Pharmaceuticals’ development identifier given to 1,2:5,6-dianhydrogalactitol
(dianhydrodulcitol, DAG, NSC-132313), a chemotherapeutic agent that was investigated in NCI-
sponsored research and human clinical trials as a treatment for cancer starting in the late 1970s.
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NCI-sponsored clinical studies suggested promising anti-tumor activity in with VAL-083 in the treatment of
hematologic malignancies and a range of solid tumors, including brain tumors. Antitumor activity has
been observed in clinical trials following both intravenous and oral administration.
Research was eventually not pursued in the United States due to an increased focus on targeted biologic
therapies during the early 1990s. VAL-083 was subsequently approved in China for the treatment of
chronic myeloid leukemia and lung cancer.1
VAL-083 is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks
targeting N7 of guanine.
VAL-083 Molecular Structure
Molecular Formula
C6H10O4
Molecular Weight
146.14
CAS Registry Number
23261-20-3
The functional groups and cytotoxic mechanism associated with VAL-083 differ from other alkylating
chemotherapeutic agents, such as the platinum-based compounds, nitrosoureas or temozolomide.
The principal mechanism of action is attributed to alkylation via the epoxide groups, which form cross-
links at the N-7 position of guanine leading to double-strand DNA breaks.2 The prevalence of guanine-
rich CpG islands in DNA, particularly within the promoters of genes, provides substantial regions of where
guanine residues are in close proximity for targeting by VAL-083 cross-links.
VAL-083 exhibits a favorable safety profile in human clinical trials. Dose limiting toxicity in humans is
myelosuppression, which has been shown to reverse spontaneously following treatment. Alopecia is not
associated with VAL-083 therapy; gastrointestinal toxicity is limited and no significant target organ
damage has been reported in the literature.3 Cumulative toxicity with long-term treatment has not been
reported.
VAL-083 crosses the blood-brain-barrier (BBB) and preferentially accumulates in tumor tissue4,
suggesting VAL-083 may be a therapeutic option for patients with brain metastasis as well as primary
brain tumors.
1Chinese Product Label for VAL-083 2Institoris et al., Chem.-BioL Interactions (1981) 3Vogel et al., Cancer Treat Rep. (1976) 4Eckhardt et al., Cancer Treat Rep. 61:841-47(1977)
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VAL-083 has demonstrated efficacy in cyclophosphamide, BCNU and phenylanine mustard resistant cell
lines and no evidence of cross-resistance has been encountered in published clinical studies. DelMar
Pharmaceuticals also has demonstrated that VAL-083 anti-cancer activity is independent of prominent
repair and resistance mechanisms such as O6-methylguanine methyltransferase (MGMT)
5, and that the
drug is active against temozolomide and platinum-resistant cell lines in vitro and in vivo. Further, the
combination of VAL-083 + other alkylating agents demonstrates more than additive or potentially
synergistic tumor killing effects.
Historical NCI-sponsored clinical trials in GBM achieved promising results with limited toxicity using a
dosing regimen of 25mg/m2/day for five days every five weeks.
In light of extensive safety data and promising efficacy against GBM in historical NCI-sponsored clinical
trials and data supporting that VAL-083’s unique cytotoxic mechanism can overcome chemo-resistance to
currently approved chemotherapies, DelMar Pharmaceuticals initiated a new Phase I/II clinical study to
establish the maximum tolerated dose (“MTD”) in refractory GBM patients using an optimized dosing
scheme.
The goal of DelMar’s current clinical trial is to determine an appropriate dose for advancement into Phase
II/III registration-directed trials in the United States in order to seek FDA approval as new therapy for the
treatment of refractory GBM.
4. Glioblastoma Multiforme (GBM)
Epidemiology
Worldwide, there are an estimated 240,000 new cases of brain and central nervous system (“CNS”)
tumors each year.
Gliomas are a type of CNS tumor that arises from glial cells in the brain or spine. Glial cells are the cells
surrounding nerves. Their primary function is to provide support and protection for neurons in the CNS.
Gliomas are classified by whether they are low-grade (I or II) — slow or relatively slow growing, or high-
grade (III or IV) – malignant, with fast growth and spread into normal brain tissue.
Glioblastoma multiforme (GBM), also known as Grade IV astrocytoma, is the most common and the most
lethal, of these tumors. The World Health Organization estimates that new cases of GBM occur in
approximately 2-3 per 100,000 people each year. In the US, approximately 15,000 people are diagnosed
with GBM annually.
GBM progresses quickly and patients deteriorate rapidly. Common symptoms include headaches,
seizures, nausea, weakness, paralysis and personality or cognitive changes such as loss of speech or
difficulty in thinking clearly.
The majority of patients do not survive for more than two years following diagnosis, and the median
survival in newly diagnosed patients with best available treatments is 14.6 months. Nearly all patients
diagnosed with GBM will relapse following first-line treatment, with a 1-year survival rate of approximately
25% following failure of front-line therapy, with average 5-year survival rate less than 3%.
5Dunn et al., AACR 2012 Annual Meeting.
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Standard of Care in the Treatment of GBM
Standard treatment following diagnosis includes surgical resection to remove as much of the tumor as possible
(debulking) followed by radiotherapy with concomitant and adjuvant chemotherapy with Temodar®
(temozolomide, “TMZ”).
Unfortunately, in almost all cases, GBM will recur and progress following treatment (known as recurrent
disease). Recurrent tumors may be treated with repeated surgical resection and/or additional
chemotherapy. Avastin® (bevacizumab – an anti-VEGF antibody) is approved as a single agent for
patients with recurrent GBM following prior therapy as an alternative to corticosteroids to relieve disease
symptoms in the US, Canada, Australia and Japan.
Temodar®
Following surgery, the current standard front-line therapy for GBM is Temodar® (TMZ). TMZ is a
nonfunctional alkylating agent that produces methylation of DNA, predominantly on the O6 and N
7
positions of guanine; however, its cytotoxic activity is limited to O6 alkylation.
TMZ was originally approved by the US Food and Drug Administration (FDA) in in 1999 for the treatment
of relapsed refractory anaplastic astrocytoma. The label was expanded in 2005 to include GBM in
combination with radiation therapy (“XRT”).
Treatment of newly diagnosed GBM patients with TMZ+XRT showed a statistically significant
improvement in overall survival compared to XRT alone, with median survival increased by 2.5 months in
the TMZ+XRT arm of the study.6
6Temodar Label
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Avastin®
Avastin (bevacizumab) was approved as a single agent for GBM patients with progressive disease
following prior therapy in the United States (2009) and Canada (2010). Avastin is a recombinant
humanized monoclonal IgG antibody that inhibits the biologic activity of human vascular endothelial
growth factor (“VEGF”) leading to reduced micro vascular growth and inhibition of metastatic disease
progression in other solid tumors.
Approval of Avastin for refractory GBM was based on an independent review of an 85 patient Genentech-
sponsored Phase II clinical trial, the results of which were supported by and a separate, independently-
conducted 56 patient NCI-sponsored study.7 Objective responses were assessed using the Macdonald
criteria which defines a complete response as disappearance of all legions and a partial response as a
>50% reduction in the sum of the product diameters (“SPD”) of any lesions that are >10mm at baseline.
Table 4.1: Efficacy Summary; Basis for Approval of Avastin in refractory GBM
Study Sponsor Genentech NCI
# subjects (n) 85 56
Objective Response Rate 28.2% CR=1 (1.2%);
PR = 23 (27.1%)
19.6% CR = 0;
PR=11 (19.6%)
Median Duration of Response 5.6 months 3.9 months
In the Genentech sponsored study, 46.4% of the patients treated with Avastin as a single-agent therapy
experienced a severe adverse event (Grade 3), life threatening or disabling (Grade 4) and death (Grade
5), with three (2.4%) patient deaths related to Avastin therapy.
Avastin carries a “black-box warning” related to severe, sometimes fatal, side effects related to
gastrointestinal perforations, wound healing complications and hemorrhage. There are no data
demonstrating an improvement in disease-related symptoms or increased survival in refractory GBM with
Avastin.8
Avastin was subsequently studied in two Phase III placebo-controlled trials in newly diagnosed GBM. No
survival benefit was observed in the Avastin treated arms. Avastin was, however, associated with a
higher rate of toxicities, including hypertension, bleeding, deep vein thrombosis, pulmonary embolism,
and gastrointestinal perforation. Patients on Avastin therapy also experienced increase rates of symptom
burden and neurocognitive decline, as well as decreased quality of life, compared to those on placebo.
Based on these data, the FDA and key opinion leaders stated that Avastin should not be used in the
treatment of newly diagnosed GBM.9
7 ODAC Briefing Book for Avastin – Genentech Inc. (2009) 8 Avastin Label 9 Gilbert, et al. N Engl J Med (2014)
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5. Alkylating Agent Chemotherapy in the Treatment of GBM
DNA, or deoxyribonucleic acid, is the hereditary material in humans. The information in DNA is stored as
a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). DNA
bases pair up with each other -- A with T and C with G -- to form units called “base pairs”. Each base is
also attached to a deoxyribose sugar molecule and a phosphate molecule, which are arranged in a
double-helix. The structure of the double helix is somewhat like a twisted ladder, with the base pairs
forming the ladder’s rungs.
An important property of DNA is that it can replicate, or make copies of itself in a process known as
mitosis. Each strand of DNA in the double helix can serve as a template for duplicating the sequence of
bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA
present in the original cell. When a mistake is made in the copying of DNA due to toxins, sunlight (UV)
damage or radiation, the cell is instructed to “die” via a process known as apoptosis. However, cells with
DNA errors sometimes escape the body’s natural defense mechanisms resulting in DNA mutations and
the formation of cancer.
Alkylating agents are among the oldest type of cancer chemotherapies in use today. Alkylating agents
bind to DNA to causing damage to cancer cells. Their anti-tumor mechanism is via alkylation of DNA
resulting in base-pair mismatch or strand-mediated cross links between base pairs. The DNA damage
caused by alkylating agents mimics naturally occurring errors, resulting in apoptosis and tumor cell death.
Temozolomide (TMZ) and the nitrosoureas (BCNU - carmustine; CCNU – lomustine, ACNU - nimustine)
are alkylating agents that readily cross the blood-brain-barrier (BBB) and are used in the treatment of
central nervous system (CNS) cancers, including GBM.
The primary cytotoxic mechanism of TMZ and the nitrosoureas is via alkylation of the O6 position of the
DNA base residue, guanine. TMZ treatment causes DNA damage mainly by methylation at the O6
position of guanine resulting in guanine-thymine base pair mismatches during replication. Nitrosoureas
mediate their cytotoxic effect by ethylation at the O6 position of guanine which produces a cross-link to
cytosine residues resulting in double-strand DNA breaks during mitosis.
Prior to the approval of Temodar, the treatment paradigm for GBM included combination therapy of XRT
plus procarbazine and vincristine with either lomustine (CCNU) or carmustine (BCNU), known as PCV
and BVD, respectively. According to the literature, the median length of survival for XRT+TMZ versus
XRT+PCV and XRT+BVD is not significantly different at approximately 14-16 months.
Jim Wells MD Anderson Cancer Center
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TMZ is widely used in preference to the nitrosoureas based on the convenience of its oral dosage
formulation and lower toxicity.10
The current standard of care for GBM is safe maximal surgical resection
followed by radiotherapy and concurrent TMZ followed by adjuvant (maintenance therapy) with TMZ
alone.
Alkylating agents have been shown to act synergistically with radiation to promote enhanced tumor killing
through alkylation-mediated radiation damage; however, this benefit is limited to effective cytotoxic
alkylation and not maintained in situations of chemo resistance.11
Resistance to alkylating agents is generally mediated by base mismatch repair or excision repair
enzymes, which rapidly repair the chemotherapy damage caused to a tumor cell’s DNA thereby enabling
tumor survival and growth.
MGMT Repair Meditated Chemo-resistance
Chemo-resistance to O6 alkylating agents is mediated predominantly by the naturally occurring O
6-DNA
methylguanine methyl-transferase (“MGMT”) enzyme which repairs O6-guanine lesions. MGMT reverses
the formation of chemotherapy-derived DNA adducts at the O6 position of guanine preventing the
formation of lethal base-pair mismatch and DNA cross-links. This repair mechanism in turn prevents
apoptosis and allows tumor survival and growth.
The expression of MGMT can be monitored in tumor cells by measuring the level of methylation in the
promotor region of the MGMT gene. Highly methylated promotors down-regulate the transcription of the
MGMT gene leading to low expression of the MGMT repair enzyme. Unfortunately, most GBM patients
have unmethylated MGMT promotors and high MGMT expression.
Consistent with the importance of its repair activity, high expression of MGMT is strongly correlated with
poor patient outcomes. Several clinical studies have established that MGMT is an important prognostic
indicator of response to TMZ and patient survival.12
10 Neider et al. Reviews on Recent Clinical Trials (2006) 11 Rivera et al. Neuro. Oncol. (2010) 12 Hegi et al. N Eng. J Med (2005)
Hegi et al NEJM,
2005
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Likewise, GBM tumor cells lacking MGMT expression are significantly more sensitive to the cytotoxic
effects of TMZ than are cells that have high MGMT activity in vitro.
GBM cell line U251 T98G
MGMT expression Low High
TMZ resistance Low High
Dunn et al., AACR 2012 MGMT repair is the single, most important factor responsible for resistance to chemotherapy in the
treatment of GBM. Patients with high expression of MGMT (approximately 2/3 of GBM patients) rarely
survive longer than 2 years.13
6. VAL-083 in GBM:
6.1. VAL-083: Overcoming MGMT Resistance
VAL-083 is an alkylating agent which readily crosses the blood brain barrier. Its primary cytotoxic
mechanism, epoxide derived DNA cross-links at the N7 position of guanine, is distinct from TMZ or the
nitrosoureas.
DelMar’s research demonstrates that VAL-083’s N7 targeting mechanism retains cytotoxic activity
independent of MGMT expression in vitro. The prevalence of guanine-rich CpG islands in DNA,
particularly within the promoters of genes, provides substantial regions of where guanine residues are in
close proximity for targeting by VAL-083 cross-links. For example, the CpG island within
the MGMT promoter region itself contains nearly 100 CpG dinucleotide sites providing substantial
targeting opportunity for VAL-083.14
VAL-083 has more potent activity against brain tumor cells in comparison to TMZ and overcome
resistance associated with MGMT suggesting the potential to surpass the current standard-of-care in the
treatment of GBM.15
13 Hegi et al., N Engl J. Med (2005)(352):997-1003 14 Nakagawachi et al., Oncogene (2003) 22, 8835–8844 15 Dunn et al., AACR Annual Meeting (2012)
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6.2. VAL-083 in GBM: Activity against Cancer Stem Cells (CSCs) in vitro
It has been hypothesized that tumor relapses are driven by brain tumor initiating cells (‘BTICs”) otherwise
known as cancer stem cells (“CSCs”) which escaped or are resistant to initial therapy. This may because
of how a particular chemotherapy targets more differentiated (mature) tumor cells while sparing the
subpopulation of stem-like cells.16
The same hypothesis therefore predicts that only therapies that
efficiently eliminate CSCs would induce long-term tumor responses and eliminate disease recurrence.
Additional support for the differentiated profile of VAL-083 and TMZ comes from the results of studies with
CSCs. GBM CSCs display strong resistance to TMZ, even where MGMT expression is low; however,
DelMar Pharmaceuticals data demonstrates that GBM CSCs are susceptible to VAL-082 independent of
MGMT expression.
DelMar examined VAL-083 and TMZ in neurosphere growth assays. Neurospheres are clusters of
suspected neural stem cells, of which a small fraction are considered secondary neurospheres with
demonstrated cancer-like renewal properties (CSCs). 5 μM VAL-083 effectively depleted all secondary
neurospheres with minimal effect on normal human neural stem cells. In contrast, TMZ was ineffective
against primary and secondary neurospheres.
Notably, where temozolomide had no activity against BITCs, the combination of VAL-083 + temozolomide
was more effective than VAL-083 alone. This suggests the potential for future treatment with VAL-
083+TMZ combination chemotherapy.
16 Beier et al., Molecular Cancer (2011)
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Additional studies with CSCs were undertaken in collaboration with researchers at the University of
California, San Francisco and DelMar. Studies were performed to understand VAL-083’s activity in GBM
CSCs compared to Temodar.17
A panel of primary cancer stem cells (CSC) and their paired primary non-stem (non-CSC) cultures were
characterized for MGMT expression.
Each CSC and non-CSC pair was subsequently exposed to DMSO (control), VAL-083 or temozolomide
and analyzed for cell cycle profile and viability.
Cell cycle progression proceeds from G1 to S to G2 through M (mitosis = cell division) and back to G1.
The G1 phase is a growth portion of the cell cycle and the majority of a cell culture would be expected to
be in the G1 phase at any given time. Agents that interfere with DNA replication or repair, such as VAL-
083 or TMZ, will block cell cycle progression and block cells from moving through mitosis and back into
G1 phase.
Treatment with VAL-083 led to a greater degree of cell cycle arrest as indicated by fewer cells in the G1 phase (indicated by the blue portion of each column).
17 Fouse, et al., Neuro-Oncology (2014)
MGMT western blot analysis of protein extracts from 4 pairs of CSC and non-CSC cultures derived from primary GBM tissue
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Over 40% of the CSCs treated with DMSO control of TMZ are in G1 phase at doses of
5µm, representing a normal cell cycle distribution for viable tumor cells at doses similar to
those achieved clinically in the treatment of glioblastoma.
In contrast, than 10% are in G1 phase after a dose of 5µM with VAL-083, indicating that
progression back into G1 phase has been blocked causing cell cycle arrest and
apoptosis.
Higher doses resulted in cell-cycle arrest for both compounds; however, doses exceeding
CNS tissue exposure higher than 10µM of TMZ or VAL-083 are generally not achievable
in a clinical setting due to toxicity.
In summary, DelMar’s data supports that:
Response to VAL-083 was not dependent on culture type. Both and non-CSC cell
cultures exhibit sensitivity to VAL-083.
VAL-083 killed tumor cells at clinically relevant doses in all CSC and non-CSC cultures
tested independent of MGMT expression.
All CSCs were resistant to TMZ and in non-CSC cultures where MGMT is highly
expressed.
These data suggests that VAL-083 has the potential to surpass TMZ outcomes in the treatment of
GBM.
Cells were treated with either increasing doses of TMZ (5, 50 100 and 200 μM) or VAL-083 (1, 5, 25 and 100 μM) and cell cycle analysis was performed 4 days post treatment. MGMT-expressing and all CSC cultures (A, B, D) were all resistant to TMZ at clinically relevant doses; however, VAL-083 was active against all cell cultures tested even at low (single µM) doses.
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GBM Cancer Cell GBM Cancer Stem Cell
MGMT
Status HIGH
TMZ:
VAL-083:
TMZ:
VAL-083:
LOW TMZ:
VAL-083:
TMZ:
VAL-083:
6.3. VAL-083 in GBM: Activity in Combination with Radiation Therapy
Alkylating agents have been shown to act synergistically with radiation to promote tumor cell killing
through alkylation-mediated radiotherapy enhancement. This benefit with TMZ is specific to those GBMs
that have undetectable MGMT expression, while unmethylated MGMT tumors can actually progress
during radiation treatment.18
To examine this further, MGMT expressing GBM tumor cells and MGMT expressing GBM tumor stem
cells were treated with either TMZ at high doses (50µM) or VAL-083 at a clinically relevant dose of (5µM)
either with or without 2Gy of radiation and compared to untreated control (nul in the graphs below).
As expected, temozolomide exhibited no activity against MGMT expressing GBM tumor cells in
comparison to control with or without radiation. However, VAL-083 was active against both MGMT
expressing GBM tumor cells and MGMT expressing GBM tumor stem cells.
18 Rivera et al. Neuro. Oncol (2010)
Cell viability analysis at day 6 post treatment for the paired CSC and non-CSC MGMT-expressing 7996
cultures.
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VAL-083 at 5uM doses resulted in near-100% tumor cell kill; therefore, radiation had no added benefit.
Notably however, when VAL-083 was added to CSC cultures at low micromolar doses (1, 2.5 µM) with or
without 2Gy radiation, VAL-083 acted as a radio-sensitizer against CSC’s in all cultures tested.
In summary, the addition of radiation to low doses of VAL-083 to both MGMT and non-MGMT expressing
GBM tumor stem cells demonstrates an expected radio-sensitizing effect.
Because VAL-083’s radio-sensitizing effect is seen in MGMT-expressing GBM that are resistant to TMZ +
radiation, VAL-083 has the potential to replace TMZ as the chemotherapy of choice in chemo-radiation
treatment of newly diagnosed GBM.
6.4. VAL-083 in GBM: Activity in vivo
VAL-083 demonstrated clinical activity against GBM as a single agent and in combination with BCNU in
historical NCI-sponsored studies. Further VAL-083 increased the life span of both BCNU-sensitive and -
resistant tumor-bearing mice.19
The absence of cross-resistance is explained by the different kinds of
DNA damage caused by the two alkylating agents and the presumably different defense mechanisms
developed by cells against these lesions.
19 Institoris et al. Cancer Chemother Pharmacol. (1989)
Cell cycle profile analysis at day 4 post treatment and cell viability analysis at day 6 post treatment for two different patient-derived CSC cultures treated with VAL-083 with or without irradiation (2Gy). 7996 (graph A&B) and 8565 (graph C&D).
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Published observations of VAL-083 activity in animal models are consistent with in vitro reports. VAL-083
is active against a range of tumor types, and demonstrates a lack of cross-resistance maintaining activity
where other chemotherapies fail. For example, in a brain tumor model where BCNU achieved only 4 -
16% survival at 120 days, the combination of VAL-083 with BCNU was curative in 85 - 100% of animals
at 120 days.20
Likewise, tumors from patients resistant to cyclophosphamide were sensitive to VAL-083 in
vitro and in mouse models.21
To further examine the comparative effects of VAL-083 and TMZ, DelMar established a mouse model of
GBM in collaboration with the British Columbia Cancer Agency (BCCA). Female Rag2 mice bearing
intracranial human GBM xenograft tumors of U251 (TMZ-sensitive) or BT74 (TMZ-resistant) origin were
treated with TMZ or VAL-083.
Animals were treated with a dose of 30 mg/kg of TMZ or three different doses of VAL-083 ranging from 3
mg/kg to 5 mg/kg. Disease progression is evaluated by overall survival, clinical observations and body
weight measurements.
As expected, animals bearing intracranial U251 (TMZ-sensitive) tumors were sensitive to both TMZ and
VAL-083. Treatment with either compound resulted in a statistically significant survival benefit. Studies
with BT74 (TMZ-resistant) tumors are ongoing.
6.5. VAL-083 in GBM: Historical Human Clinical Experience
VAL-083 was investigated in a number of clinical trials in the United States and Europe during the 1970s
both as a stand-alone therapy and in combination with other chemotherapeutic regimens.
There are five published peer reviewed Phase II studies of VAL-083 for the treatment of brain tumors. In
general, these studies confirm an objective response of 40% or greater with respect to survival and time
to progression, which is comparable to currently approved therapies.
In summary,
VAL-083 was shown to be active against brain tumors, including GBM, in multiple
Phase II human clinical trials;
VAL-083 was well-tolerated by patients; dose limiting toxicity is
thrombocytopenia, which has been shown to resolve spontaneously following
treatment; and
VAL-083 showed no cross resistance to nitrosoureas (e.g. BCNU), a
topoisomerase II inhibitor, or a RNA/DNA anti-metabolites in the published
studies.
An overview of each randomized and open-label study design and the results are provided in Table 6.5.1
and 6.5.2, respectively. Brief narratives of each are provided below the table and the full publications
referenced and available for further review. VAL-083 is referred to as “DAG” or “dianhydrogalactitol” in
the reference publications.
20 Levin et al., Cancer Chemotherapy and Pharmacology (1982) 21 Helson et al., Cancer Treat Rep. (1980)
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Table 6.5.1 VAL-083 Randomized Clinical Study in Brain Tumors
Ref Enroll
Eval.
Design
Control
Drug Dose and Regimen Diagnosis
Inclusion
Results
Eagan
197922
(Mayo Clinic
Rochester,
MN)
43
42
Open-label
Randomized
2x2
Parallel
4 arms
VAL-083: iv push 25mg/m2/d x 5 d,
every 5 wk/ yr 1; every 10 wk/ yr 2
Cont Radiation: 5,000 rads in 25
fractions in 5w
Split Radiation: 2,500 rads in 10
fractions, 3 wk rest, then 2,500 rads
in 10 fractions
Carmustine: after VAL-083 failure:
iv 70 mg/m2/d x 3 d every 8 wk
Supratentorial
astrocytomas
grades 3-4
Median Survival:
Rad only: 8.8 Mo.
VAL-083+Rad: 16.8 Mo.
Eagan et al., 1979: VAL-083 Potentiates Radiation Therapy
In a prospective, randomized VAL-083 brain tumor study (Eagan et al., 1979), subjects with supratentorial
astrocytomas, grades 3 and 4, were randomized to one of four treatment arms after surgical resection.
Two of the treatment arms only received whole-brain irradiation (XRT), either continuous or split-dose
XRT treatment whereas the other two treatment arms had the same two XRT treatments with concomitant
VAL-083 therapy. Upon treatment failure (defined by tumor progression determined by worsening
neurological results and computerized transaxial tomographic scans) the XRT -only treated subjects
would then be treated with VAL-083 and the XRT + VAL-083-treated subjects (including the previous XRT
-only treatment failures) would then be treated with BCNU (a nitrosourea). The carmustine treatment
was intravenous 70 mg/m2/day for three days every eight weeks.
22 Eagan et al., JAMA (1979)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Continuous XRT
Continuous XRT + DAG
Split XRT
Split XRT + DAG
fail
fail
fail
fail
VAL-083 fail fail BCNU No longer
in study
fail BCNU No longer
in study
fail BCNU No longer
in study
VAL-083 fail fail BCNU No longer
in study
Figure 1 – Schema of Eagan Study Design
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A total of 42 subjects received therapy as follows:
1) 10 subjects continuous XRT only - 5,000 rads in 25 fractions over five weeks
2) 10 subjects split XRT only - 2,500 rads in ten fractions, three week rest period
followed by 2,500 rads in ten fractions
3) 11 subjects continuous XRT plus VAL-083
4) 11 subjects split XRT plus VAL-083
The VAL-083 chemotherapy consisted of an intravenous push of 25 mg/m2/day for five sequential days,
equivalent to 125 mg/m2
total dose per course, every five weeks in year 1 and every ten weeks in year
two.
There was statistically significant superiority of the median survival of the radiation + VAL-083 treated
subjects versus radiation alone (radiation + VAL-083 – 16.8 months, radiation-only – 8.8 months;
P=0.02).
Essentially, the median survival was doubled by VAL-083 treatment over radiation treatment alone.
These data support anti-GBM activity similar to or better than TMZ.
Treatment of GBM temozolomide
(Phase III Stupp 2005) VAL-083
( Phase II Eagan 1979)
Median Overall Survival RT + Chemo
58 weeks 67 weeks
OS Benefit of adding Chemo: RT & Chemo vs. XRT Only
2.5 months (p<0.01)
8.4 months (p=0.02)
Sample (n=) Randomization
573 1:1
42 1:1
The comparison to TMZ must be considered in the context of the period of the study (1979 vs. 2005).
Undoubtedly, improvements in surgical technique and XRT delivery (e.g. gamma knife) would have
improved survival in the XRT-alone arm. However, an examination of the VAL-083 + XRT data in the
context of 2005-delivered surgery and radiation still demonstrates benefit vs. XRT-alone.
Importantly, the authors noted that the median survival of 16.8 months in the XRT + VAL-083 treated
subjects was longer than what was published in the scientific literature for XRT + nitrosourea treated
subjects during the same era.
XRT + VAL-083 Nitrosourea therapy
BCNU CCNU ACNU
Median survival (months) 16.8 12.5 13.0 8.8
Benefit vs. XRT alone 8.4 2.5 1.2 n/a
These comparison data support superior anti-GBM activity for VAL-083’s N7 DNA cross-linking
mechanism versus nitrosoureas O6 alkylating activity.
VAL-083 was well tolerated by patients, with dose limiting toxicity (DLT) defined by myelosuppression.
Time to nadir WBC or platelet counts was typically 3 - 4 weeks after the start of each course (range 1½ to
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5 weeks). The typical low WBC count was 2,000 – 3,000/mm3 and for platelets was 100,000/mm
3 (range
50,000 – 130,000/mm3). Some evidence of cumulative myelosuppression was reported: The proportion
of subjects experiencing below normal WBC counts rose from 38% after the first course of treatment up to
82% after the sixth course of treatment, though only 50% of subjects (11 of 22) received their sixth course
of VAL-083 treatment. Other than myelosuppression, VAL-083 treatment only resulted in occasional mild
nausea and vomiting.
Of the 20 subjects in the two radiation-only arms, 18 completed their course of radiation therapy and 21 of
the 22 radiation + VAL-083 subjects received their planned therapy. Of the 20 radiation-only treated
subjects, three received VAL-083 upon tumor progression, one of which experienced tumor regression
(but died after two courses of an infection), another one of the three later received BCNU but did not
respond. Of the 22 XRT + VAL-083 treated subjects, 11 received BCNU upon tumor progression and 2 of
these 11 experienced tumor regression. For the VAL-083-treated subjects, the average number of VAL-
083 courses was six, which would encompass 30 weeks of VAL-083 treatment.
Furthermore, several VAL-083-treated subjects experienced tumor regressions after carmustine treatment
suggesting that the tumors are not cross-resistant to VAL-083 and carmustine. Lack of cross-resistance
between VAL-083 and nitrosoureas has also been reported in preclinical studies.
These observations support the hypothesis that VAL-083 will be a valuable in the treatment of TMZ-failed
GBM because nitrosoureas and TMZ attack the same position on DNA and exhibit cross-resistance.
Table 6.5.2 VAL-083 Open-Label Clinical Studies in Brain Tumors
Ref Enroll
Eval.
Design
Control
Drug Dose and Regimen Diagnosis
Inclusion
Results
Espana 197823
(NCI )
17
14
Open-
label
Single-
arm
VAL-083: 1 hr iv, 130mg/m2/d x 5 d,
every 3wks
XRT: 6,000 rads
Astrocytoma
grades 3-4
Median Survival: 7.1 Mo.
Eagan 198124
(Mayo Clinic)
30
30
Open-
label
Parallel
two-arms
2-drug regimen:
VAL-083 + VP-16
3-drug regimen:
VAL-083 + VP-16 + TZT
Supratentorial
primary brain
tumors
recurrent
after XRT
2-drug Tumor Reg: 40%
3-drug Tumor Reg: 33%
2-drug Med. Surv: 9.8mo.
3-drug Med. Surv: 8.8mo.
Weinblatt198125
(LA Children’s
Hospital)
12
7
Open-
label
Single-
arm
VAL-083: 37.5 or 50 mg/m2 twice a
week
primary brain
tumors all with
prior XRT and
chemotherapy
Med. Prog.: 3.7mo.
Eagan 198226
(Mayo Clinic)
49
43
Open-
label
Single-
arm
Combination chemotherapy of VAL-083
and BCNU every 5-7 wk in year 1 and
every 10-12 wk in year 2
VAL-083: 70 mg/m2 iv over 5 min
BCNU: 90 mg/m2 iv over 45-60 min
primary brain
tumors
with no prior
nitrosourea
Med. Surv: 7.4 Mo.
Med. Prog: 3.6 Mo
47% tumor reg.
37% stab. Dis.
23 Espana et al. Cancer Treatment Reports (1978) 24 Eagan et al. Oncology (1982) 25 Wenblatt et al. Cancer Treatment Reports. (1981) 26 Eagan et al. Cancer Treatment Reports (1982)
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Espana et al. 1978 Phase II study of VAL-083 in malignant glioma
In this open-label, single-arm, uncontrolled study, 17 subjects with astrocytomas, grades 3 and 4, were
treated with VAL-083 subsequent to surgical resection and concurrent with radiation treatment. Four
subjects also had prior chemotherapy treatment with semustine (meCCNU) and VM-26. Subjects were
given a single 1 hour intravenous infusion of VAL-083, 150 mg/m2/d every 21 days.
Depending on severity of myelosuppression or adverse events, or lack thereof, subjects either had their
doses reduced to 130 mg/m2/d or increased to 170 mg/m
2/d. Three of the subjects were not evaluable
due to either only receiving single doses or being lost to follow-up.
The median duration of survival was 7.1 months from start of VAL-083-treatment and 18 months (range 1
- 52) from diagnosis (surgery). Leukopenia was the most common adverse event in 8 (57%) subjects and
thrombocytopenia in 6 (43%) with nadirs being observed about two weeks after treatment (range 2-3
weeks) after treatment.
Notably, three patients who failed to respond to treatment the nitrosourea meCCNU did responded to
VAL-083. These observations support a lack of cross resistance between VAL-083’s N7 DNA cross-
linking mechanism and the nitrosoureas O6 alkylating activity.
Eagan et al. 1981 Phase II studies of VAL-083 in combination chemotherapy
In an open-label, parallel-group study in subjects with supratentorial brain tumors recurrent after XRT
were treated with experimental therapy:
VAL-083 (NSC 1478178; DAG): Novel N7 DNA cross-linking agent
o i.v. 20mg/m2 for five days every 5-6 weeks
VP-16 (NSC 141540): Semi-synthetic epipodophylotoxin derivative o i.v. 75mg/m
2 on days 1, 3 and 5
Triazinate (NSC 139105; TZT) is a triazine folate antagonist similar to methotrexate o i.v. 75mg/m
2 on days 1 and 3.
Patients were given either a two drug regimen of “VAL-083 + VP-16 (“DV”) or a three drug regimen of
VAL-083 + VP-16 + TZT (“DVT”). A total of 30 subjects were treated, 15 in each arm with similar
demographics.
Tumor regressions were noted in 40% of patients treated with the DV regimen and 33% of patients
treated with the DVT regimen. Myelosuppression was the most frequent toxicity encountered. The
authors note that the 37% overall regression rate for VAL-083-based combination therapy suggest that
VAL-083 is probably effective against primary brain tumors.
Weinblatt et al. 1981 VAL-083 in the treatment of children with brain tumors
Twelve (12) pediatric subjects (mean age 9.3 ± 3.6 years, range 4 to 15 years) with recurrent or
progressive primary brain tumors were treated with VAL-083 in an open-label, single-arm, uncontrolled
study.
Subjects had been heavily pre-treated treated with multiple brain tumor therapies including XRT (12/12),
surgical resection (10/12), CCNU (11/12), vincristine (12/12), procarbazine (11/12), cyclophosphamide
(1/12) and cisplatin (1/12).
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VAL-083 was administered at 37.5 or 50 mg/m2 twice a week and modified as needed based on
hematologic toxicity (myelosuppression).
Seven (7) subjects experienced disease progression after 3.7 ± 2.0 months (range 1.5 – 7 months). The
remaining five (5) subjects were asymptomatic with no evidence of disease, representing a response rate
of 45%.
Eagan et al. 1982 Combination VAL-083 + BCNU
43 patients (mean age 48 years, range 22 - 74) with primary brain tumors with no prior chemotherapy or
XRT therapy were treated with a combination of VAL-083 and BCNU in an open-label, single arm study
uncontrolled study.
Of the 43 subjects, 32 (74%) were diagnosed with astrocytomas with grades 1 (2, 5%), 2 (13, 30%), 3
(14, 33) and 4 (3, 7%). The remaining subjects had unbiopsied glioma (10, 23%) and one subject with an
oligodendroglioma grade 2. One subject had prior aziridine benzoquinone and three subjects had prior
radiation therapy within 8 weeks due for disease progression.
BCNU was administered at a dose of 90 mg/m2 i.v. over 45-60 minutes; VAL-083 was administered at a
dose of 70 mg/m2 i.v. over 5 minutes every 5-7 weeks in year 1 and every 10-12 weeks in year 2. Drug
doses were modified to maintain sufficient counts above nadirs for white blood cells ≥2750/mm3 and
platelets ≥95,000/mm3.
Results were as follows:
Tumor Regression 20 (47%)
Stable Disease 16 (37%)
Disease progression 7 (16%)
Notably, 57% (8 of 14) of subjects with Grade 3 astrocytomas experienced tumor regression.
Based on a comparison to previously published brain tumor regression response for a BCNU only study,
the authors calculated the contribution of VAL-083 to provide a tumor regression rate of 21% representing
nearly half of the overall 47% tumor regression response rate.
Median survival correlated positively with subjects experiencing tumor regression living the longest with a
median survival of 12.7 months; for subjects with stable disease median survival was 5.2 months; and for
those with immediate progression only 1.9 months.
VAL-083 related toxicity was minor: Nausea and vomiting were mild and infrequent and hematologic
toxicity was noted. The proportion of subjects experiencing leucopenia was 30% (wbc count nadir
<4000/mm3) or thrombocytopenia was 28% (platelet count nadir <100,000/mm
3).
6.6. VAL-083: Summary of Published Historical Safety & Toxicity Data
VAL-083 appears to be a well-tolerated chemotherapeutic agent with definite antitumor activity in
humans. An extensive clinical safety data base exists for VAL-083 in the United States and in China. A
review of the Chinese literature and US Phase I and Phase II US data support the safety profile of VAL-
083.
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Toxicity in NCI-sponsored Phase I studies of patients with unresectable or metastatic cancer was mainly
hematologic, with thrombocytopenia being more common than leukopenia.27
Additional toxicities noted include nephrotoxicity, fatigue, and alopecia, but these were not reported to be
severe. No cumulative renal, hepatic, central nervous system, cardiac or pulmonary toxicity was
observed. Toxicities in the combination studies were generally more frequent and severe, and more
intense administration (weekly, rather than monthly) also increased toxicities. Any observed
gastrointestinal toxicity included nausea and vomiting and was generally mild to moderate.
The main dose-limiting toxicity related to the administration of VAL-083 observed in the NCI-sponsored
clinical studies overall was myelosuppression, with a higher frequency and severity observed in patients
with significant prior therapies. .
Thrombocytopenia was generally reported as the dose-limiting factor. Recovery of platelet counts to the
normal range occurred spontaneously following the course within a reasonable time frame allowing for
multiple courses of treatment. General leukopenic toxicities could likely be further managed by modern
concomitant medications such as Neupogen™ or growth factors.
Summary of VAL-083 Safety Studies
Ref Dose Schedule Dose Limiting Toxicity
Single-Agent Safety Studies
Espana, 1978 150mg/m2 Single dose tolerated
Eagan, 1976 (n=50) 2-40 mg/m2/d x5 days every 5 weeks Myelosuppression
Hass, 1976 (n=37) 2-31 mg/m2/d x5 or 10 days every 5 weeks Myelosuppression
Vogel, 1976 (n=28) 2-80 mg/m2/d Once per week Myelosuppression
Chinese product insert 25-40 mg/m2/d x5 days every 2 weeks Myelosuppression
Combination Safety Studies
Creagan, 1979 (n=8) VAL-083: 60-70 mg/m2/d
BCNU: 80-90 mg/m2/d
Myelosuppression
Creagan, 1987 (n=9) VAL-083: 60-70 mg/m
2/d
VP-16-213: 60-80 mg/m2/d
CDDP 20 mg/m2/d
4 week cycle:
VAL-083: once per day
VP-16-213 x 3 days
CDDP x 3 day
Myelosuppression
A variety of dose regimens were used with VAL-083 to treat cancer patients with cancer. The most
common regimen was 25-30 mg/m2/day every 5 days, with re-treatment every 2 to 5 weeks. DLT was
myelosuppression with toxic effects noted in reduced white blood cell (WBC) and platelet counts.
Anemia, nausea and vomiting were usually mild to moderate. No renal, hepatic, central nervous system,
cardiac, or pulmonary toxicity was identified.
For example, A dose of 50 mg/m2/day x 5 days every two weeks was used in a study of children with
leukemia, and patients with refractory cancers were treated with a VAL-083 dosing regimen of 50 mg/m2
twice a week for 4 weeks, then twice weekly for 2 weeks and every 6 weeks for maintenance of
refractory cancers.28
According to the Chinese product label, the recommended dosing regimen for the
treatment of solid tumors is 40mg per day over a 5 day course, followed by 2 weeks intermission between
courses.
27 Eagan et al., Journal of the National Cancer Institute. (1976) 28 Finklestein et al., Cancer Treat Rep. (1985)
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A regimen of 25 mg/m2/day every 5 days, with re-treatment every 5 weeks resulted in nadir (low point of
blood cell counts) of platelets = 88,000/ mm3 (thrombocytopenia) and WBC = 2,100/mm
3 (lymphopenia).
29
A dose of 40mg/m2/day for five days in combination with other chemotherapy resulted in a median platelet
nadir of 31,000/mm3 and WBC nadir of 2,300/mm
3.30
In general, nadir occurred within three weeks and
returned to normal within 7 days.
VAL-083 was also well tolerated in combination with XRT or other alkylating agents. The study by
Espana (1978), patients with malignant glioma were given VAL-083 at a dose of 150 mg/m2 i.v. at 21-day
intervals in conjunction with XRT, and in Eagan 1982, patients received 70 mg/m2 VAL-083 i.v. in
combination with 90 mg/m2 BCNU, with repeat cycles of treatment every 5 – 7 weeks. In both of these
studies, toxicities were not a major concern. No patients were discontinued from drug due to toxicity, and
there were no drug-related deaths.
6.7. VAL-083: DelMar Pharmaceuticals Current Refractory GBM Clinical Trial
In DelMar Pharmaceutical’s current US Phase I/II clinical trial, Dose escalation is being undertaken to
establish a safe, “modernized” dosing regimen for glioblastoma patients who have been pre-treated with
standard XRT + TMZ and have also received or are ineligible for Avastin®. There is currently no available
approved therapy for these patients and their prognosis is poor.
The DelMar “modernized” dosing regimen uses a cycle of treatment on the first three days of every three
weeks. The DelMar dosing regimen is designed to deliver more VAL-083 to the tumor in comparison to
historical NCI-sponsored studies, which employed a dosing regimen of the first five days of every five
weeks.
As noted below, DelMar has achieved doses of VAL-083 that are significantly higher than prior NCI doses
in terms of single-dose, overall cycle exposure, and dose intensity.
DOSING REGIMEN & STUDY
SINGLE DOSE
Acute Regimen (single cycle)
Comparative Cumulative Dose
(@ 35 days)
Dose Density (dose per
week) Status
NCI GBM historical regimen
(Eagan et al.) daily x 5 q 5wks (cycle = 35 days)
25 mg/m2 x5 days = 125 mg/m
2 125 mg/m
2 25mg/m
2/wk
Historical Studies: Myelosuppression
observed
DelMar VAL-083 regimen
daily x 3 q 3wks (cycle = 21 days)
30 mg/m2
x3 days =
90 mg/m2 180 mg/m
2 30mg/m
2/wk No DLT
40 mg/m2 120 mg/m
2 240 mg/m
2 40mg/m
2/wk No DLT
50 mg/m2 150 mg/m
2 300 mg/m
2 50mg/m
2/wk DLT observed
60 mg/m2 180 mg/m
2 360 mg/m
2 60mg/m
2/wk planned
The protocol is designed to determine MTD, with the assumption that early doses are sub-therapeutic;
however, patients are monitored for tumor response by MRI (RANO criteria). One of three GBM patients
in cohort 7 (40mg/m2) and one of three GBM patients in cohort 6 (30 mg/m
2) exhibited stable disease
after one or two cycles of treatment. In earlier cohorts, we reported that two patients exhibited a
response (stable disease or partial response) with a maximum response of 28 cycles (84 weeks) and
improved clinical signs prior to discontinuing due to adverse events unrelated to the study.
29 Eagan et al. JAMA (1979) 30 Eagan et al. Cancer Treat Rep. (1981)
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No serious adverse events related to study drug or dose limiting toxicity (DLT) were encountered at doses
up to 40mg/m2/day x 3 days. NCI-CTCAE Grade 1 lymphopenia (LLN to >3,000/L) and
thrombocytopenia (platelet counts LLN to >75,000/L) at doses above 20mg/m2/day x 3 days were
observed at doses at doses up to 40mg/m2.
A 50mg/m2 cohort is ongoing:
The first patient completed the required 35 day follow-up period without observation of a DLT.
The second patient in the cohort experienced myelosuppressive DLT as defined by grade four
thrombocytopenia (low platelet counts). The patient's symptoms resolved rapidly and
spontaneously returned to normal without concomitant medication or transfusion. These
observations are consistent with VAL-083-related toxicities and resolution reported in the
scientific literature.
The third patient in the cohort is currently completing the 35-day follow-up period. The patient
experienced grade three thrombocytopenia, which resolved rapidly and spontaneously.
Summary of hematologic-related safety data observed to date in the DelMar clinical trial to date 15-Feb/2015
Cohort Dose &
Hematologic Toxicity Grade
1 Grade
2 Grade
3 Grade
4 Grade
5 Total
1 - 4
up to 10 mg/m2
LYMPHOPENIA 0 0 0 0 0 0
THROMBOCYTOPENIA 0 0 0 0 0 0
5
20 mg/m2
LYMPHOPENIA 1 0 0 0 0 1
THROMBOCYTOPENIA 0 0 0 0 0 0
6
30 mg/m2
LYMPHOPENIA 0 0 0 0 0 0
THROMBOCYTOPENIA 1 0 0 0 0 1
7
40 mg/m2
LYMPHOPENIA 1 0 0 0 0 1
THROMBOCYTOPENIA 0 0 0 0 0 0
8
50 mg/m2 -
Ongoing
LYMPHOPENIA 0 1 2 0 0 3
THROMBOCYTOPENIA 0 0 2 1 0 3
If no DLT is observed in the third patient within the 35-day follow-up period, the protocol stipulates that an
additional three patients will be added at the 50mg.m2 dose. If a DLT is observed with any of these
patients, the highest previous dose – 40mg/m2 – will be proposed as the maximum tolerated dose (MTD)
for advancement to registration directed trials. However, if no further DLT is observed at 50mg/m2, dose
escalation to may proceed to 60mg/m2 in accordance with the protocol. However, if significant trends
toward a DLT are observed dose escalation may be stopped and 50mg/m2 proposed the MTD for
advancement to registration directed trials. This decision will be based on data from the 50mg/m2 cohort.
Once MTD is determined, the protocol dictates that an additional 14 patients at that dose to gather more
information about safety and activity. DelMar anticipates requesting a guidance meeting with FDA during
the 14-patient expansion phase of the current trial. The purpose of the meeting will be to discuss the
Phase II/III registration trial design.
The Phase II/III registration trial design is anticipated to involve approximately 100 patients with
radiographic response and overall survival as the primary endpoints. Final trial design will be determined
based on input from DelMar’s clinical advisors and the FDA.
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6.8. VAL-083: Clinical Pharmacokinetics (PK) and Bio-distribution
The current clinical formulation of VAL-083 is for intravenous use. The drug is orally bioavailable and has
demonstrated clinical activity following oral administration.31
VAL-083 readily enters the CNS and crosses
the BBB.
Historical Human Clinical PK Experience
In humans, intravenously administered doses of 50mg/m2 given as a 1-hour infusion, produced peak
plasma concentrations of 1.9 to 5.6µg/ml.32
Elimination of VAL-083 is biphasic with an alpha half-life of
3.9 minutes and a beta half-life of ~5 hours. Overall, the primary route of elimination is metabolism to a
series of highly polar metabolites, which are excreted in the urine.
Plasma half-life as stated in the published literature is short, about 1-2 hours. The drug appears to reach
steady state rapidly in the plasma. At high doses plasma concentrations and AUC increase only slightly
with dose escalation; for example, the AUC changed only from 32.7±11.2 to 39.4±9.5 when the dose was
raised from 690 to 1050 mg/m2.33
Human Pharmacokinetics: Historical Human Clinical Experience (*=single dose 50mg VAL-083)
Plasma Cerebral Spinal Fluid
t½ Tmax Cmax* AUC* Protein Binding t½ Tmax Cmax AUC Protein Binding
2.05 hr
(1-4hr) 1-2hr 3.6µg/ml 22µg/h-ml 20-30%
20 hr
(3-24) 2 hr
negligible
It has been established that VAL-083 enters the CSF rapidly, peaking at 1-2 hrs and is slowly eliminated,
with a half-life of 20 hrs (vs. 1-2 hrs in plasma). Rapid entry into the CNS is characterized by a
concentration in the CSF of 40-50% of plasma levels at simultaneous time points.34
Published preclinical and clinical research demonstrates that VAL-083 is selective for tumor tissue, with
up to 28-fold higher accumulation in CNS tumor tissue.35
Current Clinical Observations
Pharmacokinetic observations from DelMar Pharmaceuticals’ current clinical study in the United States
are consistent with literature-based plasma PK data. Data from cohorts 1-7 demonstrate dose-dependent
linear systemic exposure with a short plasma 1-2 h terminal half-life; Cmax in cohort 7 (40 mg/m2) ranged
from 1130 to 739 ng/mL (7.7 to 5.1 µM).
These data are well correlated with the PK profile published in the scientific literature (Eagan et al 1982)
as shown in the following figure:
31 DeJageer et al., Eur. J Cancer (1989) 32 Eagan et al., Oncology (1982) 33 Kerpe-Fronius et al., Cancer Chemother Pharmacol (1986) 34Horváth et al., Eur J Cancer Clin Oncol. (1986) 35Eckhardt et al. Cancer Treat Rep. (1977)
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By extrapolating CNS exposure based on information in the published literature, DelMar has calculated
that observed plasma concentrations obtained to date are predicted to exceed in CNS tissue
concentrations effective against glioma cell lines in vitro.
Dose and Dosing Day of
Each Cycle
Current Trial
Plasma Cmax
(μg/mL)1
Estimated Maximum
Tumor Concentration in
Brain 2,3
IC50 in
GBM Cell
Lines
(μg/g tissue) μM* μM
40mg/m2 Day-1 0.781 0.344 2.36
2.5-5.0 40mg/m2 Day-2 0.781 0.503 3.45
40mg/m2 Day-3 0.781 0.563 3.86
6.9. VAL-083: Manufacturing
VAL-083, which is also known as “Weimutrin” or “Dianhydrodulcitol” in the Chinese market, is approved in
China for the treatment of CML and lung cancer.
VAL-083 is supplied as pure drug product for reconstitution exclusively by Guangxi Wuzhou
Pharmaceutical (Group) Co. Ltd., a wholly owned subsidiary of Zhongheng Group, a publicly listed
company in China (SHG: 600252). VAL-083 is not commercially available outside of China. Guangxi
Wuzhou Pharmaceuticals currently holds the only license from the SFDA for the manufacture of VAL-083
for Injection in China (Approval No. Guoyao Zhunzi H45021133) and is compliant with Ministry of Health
(MoH) Decree No.79 for the manufacture of an injectable pharmaceutical.
DelMar Pharmaceuticals is collaborating with Guangxi Wuzhou Pharmaceuticals to implement FDA-
acceptable cGMP practices into manufacture of the active pharmaceutical ingredient (API) and finished
drug product (DP).
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For current clinical studies in the United States, DelMar has acquired the finished drug product from the
Chinese manufacturer, for release under Good Manufacturing Practice (“GMP”) in the United States
based on an internally developed analytical methods and expanded specifications.
DelMar has established a collaboration with Guangxi Wuzhou Pharmaceuticals for the supply of VAL-083.
Under the terms of the agreement, the companies are collaborating support activities related to qualifying
Guangxi Wuzhou Pharmaceuticals as a commercial supplier under FDA and EMEA GMP regulations.
Guangxi Wuzhou Pharmaceuticals is funding these activities under DelMar’s supervision. Upon FDA
certification, Guangxi Wuzhou Pharmaceuticals will be the exclusive commercial supplier of VAL-083.
DelMar has also established a back-up supply relationship with a GMP-certified contract manufacturer
based in North America.
6.10. VAL-083: Intellectual Property
VAL-083 has been granted orphan drug status for the treatment of gliomas in the United States and the
European Union, which provides VAL-083 with 7 and 10 years of market exclusivity following approval,
respectively. DelMar Pharmaceuticals intends to seek data and orphan drug protections in other
international jurisdictions where it is available. This strategy extends to new indications in China where
new indications established under a Category 1 or Category 2 SFDA approval obtain a 5 year safety
review period, exclusive of patent protections which may exist on the product.
In addition to Orphan Drug protection, DelMar employs a strategy for obtaining new patent claims to
protect the intellectual property associated with the development of ‘old’ drugs for modern indications has
been validated by companies such as Celgene, Cephalon, Chemgenex and Salmedix. In general, this
strategy includes new patent filings claiming:
The use of the drug in new patient populations, such as those failing modern biologic
therapies which had not yet been invented at the time of the drug’s original study;
Novel label claims, such as modernized dosing administration to improve efficacy and
reduce toxicity;
Improvements to the manufacturing process;
New analytical methods required for product approval under “Current Good
Manufacturing Practice” (cGMP) guidelines;
Identification and control of the chemical composition of the active pharmaceutical
ingredient and the final drug product; and
Composition of matter claims for new chemical entities or analogues to VAL-083 in the
“surrounding” or related chemical space.
To date, three new United States patents and one international patent have been issued for VAL-083
have issued to DelMar Pharmaceuticals and provide patent protection at least through 2030.
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7. Market Opportunity
GBM is a rapidly progressive and almost universally fatal brain tumor that affects approximately 15,000
new individuals each year in the US,36
with similar incidence globally.
Surgical intervention followed by TMZ and XRT is generally the first course of treatment for newly
diagnosed GBM. Avastin is the current second-line therapy targeted for the approximately 60% of
patients who fail chemo-radiation.
Peak global sales of Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales
have decreased to $708 million since the drug came off patent in major markets including Europe and the
US during 2013. Yearly, GBM revenue for Avastin is approximately $170 million, mainly from the US
market. Therefore, the global GBM market is approximately $1.3 billion, but this could expand quickly
based on the entrance of innovative new drugs such as immuno-oncology products and VAL-083.
U.S. Market Opportunity in Refractory GBM
Approximately 4,800 (48%) of new GBM patients will fail both Temodar and Avastin in the United States.
No alternative therapy with a demonstrated third-line treatment benefit has been approved for these
patients to date. There is an extremely urgent unmet need for a salvage therapy to address the needs of
refractory patients; however, other innovative therapies such as immuno-oncology products are generally
targeted to newly diagnosed patients. Therefore, VAL-083 has the potential to capture substantial
marketshare in the salvage patient population, which is estimated at approximately 7,000 patients per
year in the United States.
New GBM diagnoses 15,000 Recurrence after surgery 100%Recurrence after chemoradiation 60%Avastin Failure Rate 80%
Salvage patient population 7,200
Temodar is currently reimbursed at $5,600 per month, although it’s worth noting that the drug recently lost
patent protection. New oncology drugs, including Avastin, are priced significantly higher than Temodar.
VAL-083 has the potential to achieve a much higher reimbursement rate than Temodar using a modern
model for oncology pricing and assuming that it demonstrates a compelling benefit for refractory patients.
With estimated treatment duration of 6 months for the nearly 7,000 refractory patients, the total
opportunity for VAL-083 in the third-line setting is an estimated to be between $200 million and 400
million.
36 Ostrom, Q.T. et al., Neuro-Oncology (2014)
Pricing paradigm
Like Temodar $5,000/mo
Like Avastin $10,000/mo
USA Revenue Oppty $216 million/yr
USA Revenue Oppty $432 million/yr
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Global Opportunity in Newly Diagnosed GBM
VAL-083 has been shown to be a potentiator of XRT in preclinical and clinical studies; to be active
independent of MGMT promoter methylation; and active against CSCs with outcomes comparable or
superior to other alkylating agents in the treatment of GBM.
This represents a compelling profile for VAL-083 as a potential alternative to TMZ in the standard front-
line chemo-radiation + maintenance therapy protocol. A reimbursable MGMT-based prognostic assay for
GBM that could be used as a companion diagnostic to identify patients unlikely to respond to TMZ VAL-
083 is already in common practice.
Peak global sales of Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales
have decreased to $708 million since the drug came off patent in major markets including Europe and the
US during 2013.
If VAL-083 gains market share in front-line therapy either as an alternative to temozolomide or in
combination with novel immune-oncology agents peak sales could be expected to exceed several billion
annually in the treatment of GBM.
8. DelMar Pharmaceutical’s VAL-083 Development & Commercialization Strategy for GBM
Glioblastoma Multiforme (GBM) is a devastating disease affecting 3 – 5 per 100,000 individuals. Nearly
all patients will experience relapse following first-line treatment. Currently, there are no approved
treatments demonstrating a proven survival benefit for recurrent GBM patients and the 1-year survival
rate is approximately 25% following failure of front-line treatment.
Refractory GBM
DelMar plans to develop VAL-083 initially as single-agent therapy in patients with recurrent GBM who are
resistant to or ineligible for bevacizumab therapy (Avastin) under the auspices of the orphan drug act in
the United States.
The rationale for initially focusing on refractory disease includes opportunity for rapid clinical
advancement through fast-track or breakthrough therapy designation due to unmet medical need; a
relatively small and cost effective open-label registration trial design; ability to market a product with small
sales force; and an attractive reimbursement paradigm.
DelMar initiated a Phase I/II dose-escalation study to establish the MTD for VAL-083 using an optimized
dosing regimen for patients that have experienced relapse following pre-treatment with XRT, TMZ and
Avastin. The dose-escalation portion of the study is currently being undertaken at three centers in the
United States. The purpose of the study is to determine a dose for advancement into Phase II/III
registration-directed clinical trials in the United States.
Based on current progress, it is anticipated that an MTD for advancement into Phase II/III registration-
directed trials will be determined in the first half of 2015. Upon determination of MTD, DelMar will:
Enroll and additional 14-subjects to gather further information about the safety, tolerability
and anti-tumor activity of VAL-083 at the MTD;
Expand the number of clinical sites to accelerate enrollment;
Seek a guidance meeting with FDA to confirm the design for the Phase II/III registration-
directed clinical trial.
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DelMar anticipates requesting a guidance meeting with FDA during the 14-patient expansion phase of the
current trial. The purpose of the meeting will be to discuss the Phase II/III registration trial design.
The Phase II/III registration trial design is anticipated to involve approximately 100 patients with
radiographic response and overall survival as the primary endpoints. Final trial design will be determined
based on input from DelMar’s clinical advisors and the FDA.
DelMar anticipates significantly expanding the number of sites during the registration trial. DelMar will
use commercially reasonable efforts to include any academic or tertiary medical center that is significantly
involved in the treatment of post-Avastin GBM patients. The company anticipates the trial may
encompass 20-25 centers in the United States and Canada.
The budget for the registration-directed clinical trial is anticipated to be approximately US$85,000 per
patient, including CRO costs and corporate overhead. Therefore the total budget for the Phase II/III
registration-directed trial is expected to approximate US$8.5 million.
Subject to satisfactory enrollment, DelMar anticipates that the Phase II/III registration-directed trial could
be fully enrolled within 12 months of initiation, with approximately six months of follow-up. This potentially
positions NDA filing for late 2016 or early 2017, with commercial launch in the first half of 2017.
timel ine (rev) 2015
MTD Q1 Q2 Q3 Q4 FILE NDA
Find MTD
14 pt Expanion
Begin Reg Tria l
Q1 2017
Refractory GBM patients in the United States and Canada are generally treated at relative small number
of academic medical centers. DelMar anticipates that the primary refractory GBM physician prescriber
base will largely overlap those centers involved in its Phase II/III registration-directed clinical trial. This
will allow DelMar to establish a strong pre-commercial relationship with its potential customer base.
The focused academic medical center customer base could potentially be serviced with a small contract
or in-house sales force. DelMar will seek to retain commercial rights to VAL-083 for the treatment of
refractory GBM at academic medical centers in the context of potential future pharmaceutical
partnerships, which may be consummated for the development of VAL-083.
Front-line GBM
Juxtaposing the promise of historical clinical data in the treatment of GBM, with the modern scientific
profile of VAL-083, DelMar believes that VAL-083 has the potential to replace TMZ as the chemotherapy
of choice in chemo-radiation treatment of newly diagnosed GBM.
The global GBM market is approximately $1.3 billion, but this could expand quickly based on the entrance
of innovative new drugs such as immuno-oncology products and VAL-083. Peak global sales of
Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales have decreased to
$708 million since the drug came off patent in major markets including Europe and the US during 2013.
Once MTD is established for refractory disease, DelMar plans to leverage its modernized dosing regimen
for development as a potential new therapy for newly diagnosed GBM for patients who are unlikely to
respond to TMZ.
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An assay for detection of MGMT activity in tumor tissue is commercially available from Sigma Aldrich
(Sigma Product No. MD0100) and other manufacturers. The assay test is certified under CLIA (Clinical
Laboratory Improvement Amendments) and currently used in standard practice as a prognostic indicator
of GBM outcomes, and reimbursed by several insurance carriers. This assay can also be used as a
companion diagnostic to identify patients unlikely to respond to TMZ for purposes of patient selection in
future clinical trials.
DelMar anticipates that a global Phase II/III clinical trial in newly diagnosed GBM patients could be
initiated following a short dose-confirming lead-in trial with XRT + VAL-083. It is anticipated that the trial
would compare outcomes of VAL-083 to TMZ following the standard Stupp regimen (and potentially
including an XRT only arm).
Phase II/III Front Line GBM Trial Design
Based on recent trials and high-level statistical analysis, it is estimated that a Phase II/III registration trial
for front line GBM would require randomization of 500 – 600 patients and an investment of at least $40
million. A Phase II – III adaptive design could potentially be developed to permit step-wise investment to
an early statistical endpoint.
Newly diagnosed GBM is generally treated by community oncologists, which will require a significant
global sales and marketing infrastructure. Based on the costs and infrastructure involved in the
development and commercialization of a front-line GBM therapy, DelMar anticipates seeking partnerships
with global pharmaceutical companies for the development of VAL-083 in newly diagnosed GBM.
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9. Immunotherapy & GBM: Potential integration with VAL-083
Recently, there have been intensified research efforts studying immunotherapy as an effective adjunct or
alternative to the current treatment paradigm in GBM.
Modest efficacy and variable immunogenicity have been observed in early-stage clinical trials.
Immunotherapy may offer a promising approach to complement and enhance the current chemo-radiation
regimen.
Immunotherapy centers on the principal that the host immune system may destroy tumor cells if immune
effector function is appropriately augmented. There are three basic strategies underlying immunotherapy:
(1) Immune modulating cytokine therapy, (2) passive therapy and (3) active immune therapy including
cancer vaccines.
Cytokine therapy takes advantage of specific immune mediators such as interleukins. While
some success has been achieved in early studies, the immune effects of cytokine therapy are
non-specific often leading to extensive systemic toxicities.37
Clinical results in tumor regression
have been disappointing, which may be due to the multiplicity mechanisms of tumor immune
evasion in the tumor microenvironment. These specific mediators, such as checkpoint
interactions, have themselves become targets of interest for therapeutic intervention.
Immune checkpoint inhibitors are aimed at overcoming a tumor’s mechanism for evading the
immune system through a locally immunosuppressive microenvironment. Immune checkpoint
inhibitors are gaining considerable attention as a strategy for eliminating poorly immunogenic
tumors. It is important to note, however, that the systemic autoimmune toxicities associated with
checkpoint blockade are significant, including severe colitis and pituitary inflammation.
Nevertheless, clinical results in melanoma and other tumors are encouraging and justify
investigation in GBM.
Cancer vaccines have emerged recently in clinical studies with recent advances being achieved
in prostate cancer and advanced melanoma. Dendritic (DC) cell vaccines may be capable of
inducing systemic immunity; however, a significant limitation of this approach is the necessity of
direct physical interaction of DC and tumor antigens, which are protected in the
immunosuppressive tumor microenvironment.38
Therefore a number of techniques to expose
DCs to tumor antigens either ex vivo or in vivo have been developed.
Historically, chemotherapy and immunotherapy have often been regarded as independent or agnostic
treatment modalities; however, recent studies demonstrate the potential benefit of combining these
modalities.
Synergy between cancer immunotherapies, including cancer vaccines, and conventional chemotherapy
have demonstrated potential both in laboratory studies and in early clinical trials demonstrate that
immunotherapy may have potential as a future adjunct to standard of care in multi-modal treatment
paradigms.39
37 Dunn et al., Nat. Immunol ( 2002) 38 Yang et al.,. (2002) 39 Patel et al., Cancers (2014)
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ICT-107 is a dendritic cell-based vaccine targeting multiple tumor-associated antigens for glioblastoma.
A randomized, double-blind, placebo-controlled phase II study of the safety and efficacy of ICT-107 in
patients with newly diagnosed glioblastoma multiforme following resection and chemo-radiation (with
TMZ) failed to meet its Phase II endpoints; however, retrospective analysis suggests potential benefit in
MGMT methylated patients as an adjuvant to TMZ.
ICT-107 Retrospective Analysis Presented at SNO 2014
Median PFS (AvB) Median OS (AvB)
Methylated (low-MGMT)
Statistically Significant benefit p = 0.004
Analysis ongoing
Unmethylated (high-MGMT)
No Statistical Benefit p = 0.364
No statistical benefit p = 0.223
CDX-110 is an EGFRvIII vaccine that is currently undergoing clinical trials both in newly diagnosed
GBM patients in combination with standard TMZ therapy and in refractory disease.
The variant III mutation of the epidermal growth factor receptor (EGVRvIII) is commonly observed in
human tumors and promotes cell proliferation and inhibits apoptosis. EGVRvIII vaccines therefore
represent a potential alternative or adjunct to standard therapy.
Recent results in the refractory trial demonstrated potential in TMZ refractory patients in combination
with Avastin®; however, patients who were refractory to Avastin® did not benefit from CDX-110. A
Phase III trial in newly diagnosed patients in combination with TMZ is ongoing.
Notably, an effective chemotherapy is a key component of these approaches. Traditional chemo-
radiation has been shown to have synergistic effects when used in combination with immunotherapy
providing for potential benefit in a multi-modal chemo-immunotherapy approach.
Some forms of chemotherapy-induced cell death can be highly immunogenic. Apoptosis in particular may
serve to alter the local tumor microenvironment to disrupt pathways of immune tolerance and suppression
and sensitize tumor cells to immunotherapy.
Upregulating the expression of tumor antigens can augment cross-priming of the tumor-specific t-cell
response, thereby increasing tumor antigen presentation or decreasing the expression of immune
checkpoint molecules.40,41
Likewise, immunotherapies may also be used as pro-inflammatory chemo-sensitizing agents that render
drug-resistant tumors more amenable to standard therapeutic options.42
However, while the benefit of chemo-immunotherapy has been observed, the interaction between
chemotherapy and the immune system is complex and could be antagonistic in some cases Many
standard-dose chemotherapy regimens actually suppress the anti-tumor immune response by directly
decreasing lymphocytes or inhibiting lymphocyte functions. As such, an immunosuppressive
40 Casares, N. et al., J Exp Med. (2005) 41 Emens LA., et al., Curr Opin Mol Ther (2001) 42 Liu et al., Expert Rev Vaccines. (2006)
Surgery
A: TMZ + XRT + ICT107
B: TMZ + XRT + placebo
Randomi-
zation
2
1
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©2015 DelMar Pharmaceuticals
chemotherapy could hinder immunotherapy response either by inducing lymphopenia or contributing to
lymphocyte dysfunction and truncating immune-based outcomes.
VAL-083 and Immunotherapy
It is important that a chemotherapy regimen does not alter the tumor micro-environment in a way that
inhibits immunotherapy.
Clinical observations with VAL-083 support limited neutropenia or lymphopenia, and, therefore, VAL-083
is unlikely to have a negative impact on immunotherapeutic activity immune response through immune
suppression via neutrophil or t-cells depletion.
Of course, a key component of any chemo-immunotherapy regimen is an active chemotherapy. This
further highlights the need for a novel chemotherapeutic agent that can overcome MGMT-mediated
chemo-resistance in GBM. VAL-083 represents this type of agent.
While a number of immunotherapeutic approaches are currently being investigated for the treatment of
GBM, none have yet to receive regulatory approval.
As one or more of these approaches evolve, DelMar Pharmaceuticals believes that VAL-083 represents
an ideal agent of choice for strategically integrating potential immune-based therapies with chemotherapy
treatment in a multi-modal chemo-immunotherapy regimen.
Such approaches could represent area of safely and effectively harnessing the immune system in the
treatment of GBM and provide much needed improvements in quality of life and survival.
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10. References (alphabetical list)
10.1 Avastin Label
10.2 Beier et al.,Chemoresistance of glioblastoma cancer cells – Much more complex than expected. Molecular Cancer 2011:(10)128
10.3 Casares, N. et al., Caspase-dependent immunogenicity of doxorubicin-induced cell death. J Exp Med. 2005:(202)1691-1701
10.4 Chinese Product Label: VAL-083
10.5 Chiuten et al., Clinical Trials with the Hexitol derivatives in the U.S. Cancer. 1981:(47)442-451.
10.6 DeJageer et al., Dianhydrogalactitol (NSC-132313): Phase II study in solid tumors: A Report of the E.O.R.T.C. Early Clnical Trial Cooperative Group. Eur. J Cancer 1989 Jul:15(7):971-974.
10.7 Dunn et al Cancer Immunoediting: From immuno- surveillance to tumor escape. Nat. Immunol. 2002:(3)991–998
10.8 Dunn et al., VAL083, a novel N7 alkylating agent, surpasses temozolomide activity and inhibits cancer stem cells providing a new potential treatment option for glioblastoma multiforme. American Association of Cancer Research 2012 Annual Meeting. Permanent Abstract No. 811
10.9 Eagan et al., Phase II study of the combination of dianhydrogalactitol, doxorubicin, and cisplatin (DAP) in patients with advanced squamous cell lung cancer. Cancer Treat Rep. 1981(65)517-9
10.10 Eagan et al., Brief Communication: Phase I Study of a Five-Day Intermittent Schedule for 1,2:5,6-dianhydrogalactitol (NSC-132313). Journal of the National Cancer Institute. 1976:56(1)179-181
10.11 Eagan et al., Phase II Studies of Dianhydrogalactitol-Based Combination Chemotherapy for Recurrent Brain Tumors. Oncology. 1982:(38)4-6
10.12 Eagan et al., Platinum-based polychemotherapy versus 1,2:5,6-dianhydrogalactitol in advanced non-small cell lung cancer. Cancer Treat Rep 1977:61:1339
10.13 Eagan et al., Combination Carmustine (BCNU) and Dianhydrogalactitol in the Treatment of Primary Brain Tumors Recurring After Irradiation. Cancer Treatment Reports. 1982:66(8):1647-1649
10.14 Eagan et al., Dianhydrogalactitol and Radiation Therapy Treatment of Supratentorial Glioma. JAMA
1979:241(19):2046-2050
10.15 Eckhardt et al., Uptake of Labeled Dianhydrogalactitol into Human Gliomas and Nervous Tissue. Cancer
Treat Rep. 1977:61:841-847.
10.16 Emens LA., et al., Chemotherapy: friend or foe to cancer vaccines? Curr Opin Mol Ther 3:77-84(2001)
10.17 Espana et al., Phase II Study of Dianhydrogalactitol in Malignant Glioma. Cancer Treatment Reports. 1978:62(8):1199-1200.
10.18 Finklestein JZ, et al., Phase II trial of dianhydrogalactitol in the treatment of children with refractory childhood malignancies: a report from the Children's Cancer Study Group. Cancer Treat Rep. 1985 Nov;69(11):1331-3.
10.19 Fouse, S.D. et al., 2014. VAL-083 is a novel N7 alkylating agent that inhibits the growth of glioma stem and non-stem cultures, including temozolomide-resistant lines. Neuro-Oncology, 15(suppl 5) v83.
10.20 Gilbert, et al., N Engl J Med 2014; 370:699-708
10.21 Guangxi Zhuang Autonomous Region, Pharmaceutical Research Institute: Anti-tumor Activity and Toxicity Experiment of Dianhydroducitol, Pharm . Tech. Infl., Vol. 12 (1977).
10.22 Hegi et al., MGMT gene silencing and benefit from temozolomide in glioblastoma N Engl J. Med (2005)(352):997-1003
10.23 Helson et al., Dianhydrogalactitol and neural tumors: an in vitro, in vivo preclinical evaluation. Cancer
Treat Rep. 1980;64(12):1287-94
10.24 Hematology Department, Guangxi Medical Research Institute. Short-Term Effect of 1,2:5,6-Dianhydrodulcitol on 21 Chronic Myeloid Leukemia Patients
10.25 Horváth et al., Pharmacokinetics and metabolism of dianhydrogalactitol DAG in patients: a comparison with the human disposition of dibromodulcitol DBD. Eur J Cancer Clin Oncol. 1986 Feb;22(2):163-71.
CONFIDENTIAL – Updated February 2015
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©2015 DelMar Pharmaceuticals
10.26 Huang Zhung Qien. Effect of 1,2:5,6-Dianhydroducitol on 12 Chronic Myeloid Leukemia Patients. First Affiliated Hospital of Chongqing Medical University.
10.27 Institoris et al., In vivo study on alkylation site in dna by the bifunctional dianhydrogalactitol, Chem.-BioL
Interactions, 35 (1981) 207—216
10.28 Institoris et al.,Absence of cross-resistance between two alkylating agents: BCNU vs bifunctional galactitol. Cancer Chemother Pharmacol. 1989;24(5):311-3.
10.29 Johnson et al., End Points and United States Food and Drug Administration Approval of Oncology Drugs. Journal of clinical Oncology. 2003:21(7):1404-1411
10.30 Kerpe-Fronius et al., Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent administration of an alkylating agent, diactyldianhdrogalactitol. Cancer Chemother Pharmacol. 1986;16(3):264-8.
10.31 Levin et al., Chemotherapeutic approaches to brain tumors. Experimental observations with dianhydrogalactitol and dibromodulcitol Cancer Chemotherapy and Pharmacology. 1982; 8(1):125-31
10.32 Liu et al., Sensitization of malignant glioma to chemotherapy through dendritic cell vaccination. Expert Rev Vaccines. 2006 Apr;5(2):233-47.
10.33 Nakagawachi et al., Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer Oncogene 2003;22(55):8835-44
10.34 Neider et al., Combined Modality Treatment of Glioblastoma Multiforme: The Role of Temozolomide. Reviews on Recent Clinical Trials (2006):1:43-51.
10.35 Nemeth et al., Pharmacologic and antitumor effects of 1,2:5,6-dianhydrogalactitol (NSC-132313). Cancer Chemother Rep. 1972:56:593-602.
10.36 ODAC Briefing Book for Avastin – Genentech Inc. 25 Feb 2009
10.37 Ostrom, Q.T. et al.,, 2014. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncology, 14(Suppl 5), v1-v49.
10.38 Patel et al.,. The future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy. Cancers 2014(6) 1953-85
10.39 Rivera et al., MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro. Oncol. 2010(12)116–121
10.40 Schabel et al., Patterns of resistance and therapeutic synergism among alkylating agents. Fundamentals in Cancer Chemotherapy. 1978:23:200-215.
10.41 Stehman et al., Phase II trial of Galactitol 1,2:5,6-Dianhydro (NSC 132313) in the Treatment of Advanced Gynecologic Malignancies: A Gynecologic Oncology Group Study. Gynecologic Oncology 1983:15:381-
390
10.42 Temodar Label
10.43 Vogel et al., Phase I trial of DAG administered IV in a weekly schedule. Cancer Treat Rep. 1976 Jul; 60(7):895-901. PMID: 795538
10.44 Wenblatt et al., Dianhydrogalactitol in the Treatment of Children with Primary Brain Tumors. Cancer Treatment Reports. 1981:65(9-10):923-924.
10.45 Yamauchi et al., Carmustine-Resistance Cancer Cells are sensitized to Temozolomide as a Result of Enhanced Mismatch Repair during the Development of Carmustine Resistance. Mol. Pharmacol. 2008:74:82-91
10.46 Yang et al., Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: Implications for the use of dendritic cells for therapy of gliomas. Cancer Res. 2002(62)2583–2591