Exploring the Role of Nab-paclitaxel (ABRAXANE®) as a

Radiation Sensitizer

Newer Dimensions in Radiation Therapy Presented at National Conference AROI Nov 2012

Dr. Lokesh Viswanath M.DProfessor, Dept of Radiation Oncology

Kidwai Memorial Institute of Oncology, Bangalore

Radiation Sensitizer Agents possessing significant ability to augment the

effect of radiation– Super / sub-additive effect– Little or non-toxic at doses used– Minimal cytotoxic – Selective or preferential to tumor cf normal tissue– Counter act – determinants of radio-resistance > altering

the cancer cells radio-sensitivity– Cell survival curve – steeper slope (eliminate shoulder or

change the slope) • Shoulder – repair of radiation damage• Tail – resistance to CT agents

– Lesser systemic toxicity – Minimal or manageable enhancement of Radiation

toxicity

Paclitaxel Approval - U.S FDA • Paclitaxel for treatment

– ovarian cancer : December 29, 1992– breast cancer : April 15, 1994.

• approved - semi-synthetic form Docetaxel in -1995 • January 7, 2005:

– Abraxane™, a trademark of American BioScience, Inc unique fast track approval for MBC

• Oct 2012 for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

• 2012, Paclitaxel poliglumex– Orphan drug status for Treatment of GBM

Paclitaxel • a potent cytotoxic agent • mechanism of action – interferes with mitotic spindle function – block the cell in the G2/M phase of the cell cycle – ↑ apoptosis and tumor reoxygenation also may occur • binds to & stabilizes microtubules - loss of microtubule

dynamics > impair the mitotic spindle• preventing microtubule depolymerization

Preclinical Models• Classic radiobiological concept: Cell Cycle dependent Radio-

sensitivity

• Radio-sensitizing effect of Paclitaxel is dependent on – Duration of exposure– Drug concentration

• Contribution of P53 to Paclitaxel dependent Cyto-toxicity – Mutant P53 is more sensitive to Paclitaxel

• Theoretically Paclitaxel and RT act as non cross resistant agent– RT is effective in wild type P53– Paclitaxel in mutant P53

Taxanes• Paclitaxel (Px) Highly hydrophobic (water insoluble)

• To enable Parentral Administration– Solvent : • Paclitaxel : – Polyethylated Castor Oil (Cremphor EL)– Ethanol – as vehicle

• Docetaxel– Polysorbate 80 – Ethanol

– Toxicities: (direct – 80% )• Hypersensitivity reactions • Prolonged & irreversible pripheral neuropathy (demyelination

& Axonal degeneration)

Polyethylated Castor Oil - Cremphor EL • Disadvantages of Cremphor EL – in conventional Paclitaxel

– Entrapp paclitaxel in cremophor micelles at clinically relevant concentrations : limit ing > Px bioavailability & antitumour activity

– inhibits Px binding with endothelial cell and albumin > inhibition of gp60-caveolar mediated transport

– Prevent distribution of Px outside the circulation & into tissue > ↓ tumour Px concentration and low volume distribution - ↑ exposure of Px to Bone marrow - ↑ Hematological toxicity

– Cremphor EL – inhibits P glycoprotein in Hematopoietic progenitor cells

– Inhibition of hepatic elimination– Axonal degeneration, demyelination, irreversible sensory neuropathy– leach plasticizers

Cremophor paclitaxelCremophor paclitaxel : : Large Micelles Observed in Plasma Large Micelles Observed in Plasma

Control plasma Plasma + Taxol

LargeMicelle

Hamad and Moghimi, Expert Opin. Drug Deliv. (2008) 5(2):205-219

Rat – peripheral nerve

• Control: Saline • Test: – Cremophor Treated– Several degenerated Axons

Need for Innovation

• potential quantum benefits of miniaturization – Richard Feynman 1959

• Manipulation of atoms, molecules, and materials to form structures on the scale of nanometres (billionths of a metre).

• Particles having sizes less than 0.1m (100nm)– 1st : <100nm– 2nd : <10nm

Nanoparticle Technology

Abraxane® : ABI -007• Albumin bound Nano particle• To improve Drug delivery and PK– American BioScience, Inc., Santa Monica,

California. – BIOCON (India)

• A novel – 130 nanometer particle – 1/10th - platelet, – 1/20th - smallest blood vessels – 1/40th - RBC)

• Protosphere™ technology : – convert insoluble drugs into soluble nanoparticles – Enhanced drug delivery

• 1st anticancer agent (Paclitaxel) – incorporate albumin technology

• Albumin – unique– A natural carrier of lipophylic molecules – Preferential drug delivery: Albumin receptor medicated drug

transport across endothelial cells (ABI- 007 4.5 fold ↑ in paclitaxel transport)

• Cremophor-free: ↓ Hypersensitivity & Nerve damage

- Half life of Abraxane is 27 hours for the dose of (260mg/m2)

Abraxane® : ABI -007

Therapeutic efficacy & TI of ABI 007 (Abraxane)

Trans endothelial transport of albumin is mediated by gp60 (albondin) receptor and activation of caveolin 1•Endothelial binding ↑9.9 x •Endothelial Trans-cytosis ↑4.2x •↑ Endothelial binding ABI007 - ↑ anti-angiogenic activity•↑ anti-tumour activity - ↑ enhanced intratumoral delivery

•AbI007 PK - plasma Clearance & Volume distribution – 50% higher

• Tumor Inhibition Paclitaxel AUC at equal doses is 33% higher for ABI007

• > 50% higher dose administration is feasible

SAPRC Expression

• SPARC – Tumour secreted glycoprotein – 43kDa– High binding affinity to albumin– Modulates cell & extracellular matrix interaction– Key regulator of Cell proliferation, survival & migration

• SPARC ^up-regulation in Cancer cells• SPARC – albumin interaction– Facilitate accumulation of albumin in Tumour– Increase intracellular Paclitaxel – ^ effectiveness of

nab Paclitaxel

Abraxane

Solvent based Paclitaxel

0 hr

0 hr

24 hr

Abraxane Stablility : Abraxane Stablility : Microscopic assessment at 5 mg/mL, 40 Microscopic assessment at 5 mg/mL, 40 C:C:

Unstable: aggregate ↓ drug delivery

Cremphor base Paclitaxel - as Radiation Sensitizer

• Review of literature• CRT experiences in the last 2 decades - what

have we learnt ?

Ca Cervix – CR rates when RT is combine with various Radiation Sensitizers

• RT alone 71%• RT + CDDP 87%• RT + CDDP + Paclitaxel 90%• RT + Carbo + Docetaxel 97%

Taxanes are Good Radiation SensitizersTrade off : Taxnes - Acute G3Toxicities

• GI ~ 58%• Hemat ~ 40%• Poor Compliance ~ 20 % Discontinued

• Compliance with Abraxane – 96% (as scheduled)

Ca Cervix RT + Paclitaxel (as Radiation Sensitizer)

Which Scheduling may be better with RTOnce in 3 weeks PXSchedule

Weekly Px Schedule

CR - rates (Complete Response Rate)

70% 88-91 %

Hematological toxicity Gr3

61% 11%

2ys DFS 82%

3yr DFS 82% 70%

2yr OS 93%

3yr OS 86.6% 65%

what we have learnt so far ?

Abraxane (ABI 001) – in Metastatic Breast Cancer

Abraxane: Phase – I Trial

• MTD: 300mg/m2

• 70% higher than convetional 175mg/m2

• No - severe Hypersensitivity reaction• No – premedication• Administration time: 30 min v/s 90 min

regular paclitaxel• Pharmacokinetics: max AUC time curve : dose

135 – 300 mg.m2

Abraxane: Phase – II Trial

• Metastatic breast cancer• 300mg/m2

ORR TTPAll : 48% 26.6 weeksABI-007 as 1st Line : 64% 63.6 weeks

Findings suggested: Abraxane – may offer important advantages over standard paclitaxel

Nab Paclitaxel ABI-007 Abraxane

• In vitro ABI-007 Cremphore Paclitaxel– LD 50 47mg/kg/d 13.4mg/kgd– MTD 30 13.4

• Every 3 wk – ABX – MTD 300mg/m2

• Response Rate 42% 27% (Equi Toxic Doses) 260mg/m2 175mg/m2

Ca Breast : Safety profile of ABI007ABI007260mg/m2

CREMPHOR BASED PACLITAXEL175mg/m2

Tumour Response rates

33% 19% P 0.001

TT progression 23 wk 16.9 wk P 0.006

Gr 4 Neutropenia 9% 22% P 0.001

Sensory neuropathy 10% Temporary 2% P 0.001

250mg/m232% (Gr3) axona

MBC – weekly nab Paclitaxel

median OS (mo)

• Weekly Nab Paclitaxel 150mg/m2 qw 3/4 - 33.8• Nab Paclitaxel 300mg/m2 q3w - 27.7• Docetaxel 100mg/m2 qw 3/4 - 26.6

Form H&N Ca TAX studies we know that Docetaxel is better that Paclitaxel

Weekly Abraxane Schedule is Equivalent to Docetaxel

MTD - in Weekly schedule

Exploring What Doses of Abraxane needs to be used for Concurrent Chemoradiation

• Paclitaxel 50mg/m2/wk when combined with CDDP 30-60mg/m2

• Abraxane : 100mg/m2/wk In heavily pre- treated subjects

Combination : is CDDP or Carbo Better ?ORR

CDDP + Paclitaxel 29% (Ca Cx recurrence)

Carbo + Paclitaxel 53% CDDP+5Fu+Abraxane 100% (H&N) CR -53%

Weekly CDDP v/s Weekly Carbo v/s once in 3 weeks schedule

• For Indian setting use of RT + Radiation Sensitizer - Weekly CDDP 40mg/m2 with Abraxane 75mg/m2 (50 -100) may be suitable , without enhanced RT toxicities

• Giving a taxane with radiation at the present time is, however, investigational.

Newer dimension's in Radiation sensitization – Abraxane ABI-007

Radiation-modulating effects of ABRAXANE ABI 007

in tumor and normal tissues Pre Clinical Study: Mice - syngeneic ovarian or mammary Ca

• nab-paclitaxel produced supra-additive effects when given before radiation

• Nab-paclitaxel significantly increased radiocurability by reducing the dose yielding 50% tumor cure (TCD50) from 54.3 to 35.2 Gy.

• ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. Phase I/II trials have also been conducted in other solid tumours, including squamous cell cancer of the head and neck, and pelvis.

Tisheret et al (2012), A Phase I/II Trial of Concurrent Abraxane in Combination With Carboplatin and Intensity Modulated Radiation Therapy (IMRT) in Locally Advanced Squamous Cancer of the Head and Neck

Rationale: favorable biodistrubition of Abraxane may allow loco-regional treatment without increasing normal tissue toxicity

LASCCHN - Abraxane CRT

• Phase I – Dose escalation study• n=28• Median f/u 25 mo• Nab paclitaxel + Carbo + IMRT • Abraxane – 50mg/m2 • G3 Gysphagia, mucositis & dermaitiis – 85%• No DLT observed• Control rates ~ 82%

L. A. Nedzi et al (2010). Phase I Study Of Nab-paclitaxel, Cisplatin And Cetuximab With Concurrent Radiation Therapy For Local-regionally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)

• n=11• The maximum tolerated dose of weekly nab-paclitaxel given

concurrently with cisplatinum, cetuximab and 70 Gy continuous course radiotherapy for loco-regionally advanced HNSCC is 20mg/m2

Phase I Trial of ABI-007 (Abraxane) Plus Cisplatin Plus 5-Fluorouracil (APF) as Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Patients With Locally Advanced Squamous Cell Cancers of the Head and Neck (HNSCC)

– Drug: • ABI-007 Dose escalation beginning with ABI-007 75 mg/m2 day 1

+ day 8, • Cisplatin 100 mg/m2 day 1, • 5-FU 1000 mg/m2/d continuous infusion x 96 hours on day 1-4, • for 3 weeks x 3 cycles.• Followed by Concurrent weekly Carboplatin (AUC 1.5) with

radiotherapy for 7 weeks..

H&N : Induction CT + CRT OS PFS 2YRS

TAX 232: Induction + RT alone PF ~35% 2YRS

TPF ~45%

TAX 324: Induction + CRT PF 55% 42% 2YRS

TPF 67% 54%

ACPF+CRT 84% 65% 2YRS

Abraxane: 100mg/m2/wkC225-250 Mg/m2/wkCDDP-75mgm2 x 3wk5FU-750m/m2 dy1-5 x 3wk

Paclitaxel poliglumex

• 2012 FDA - Orphan drug status for Treatment of GBM

• Phase II : Paclitaxel P (50mg/m2) + TMZ + RT• N=25 (GBM-15), Median f/u 10.2 mo• CR-24%, PR-16%, SD-40%• PFS – 76%• GBM PFS – 66.7% (Stupp 53.9%)• AE: G3 Neutopenia – 4%, Thrombocytopenia -24%

Weekly Nanoparticle Albumin-Bound Paclitaxel (Abraxane) + Weekly Cetuximab + Radiation Therapy (IMRT, Intensity-Modulated Radiation Therapy) in Patients With Stage III-IVB Head and Neck Squamous Cell Carcinoma (HNSCC)– To establish recommended dose of weekly (Abraxane®)

given concurrently with weekly cetuximab + definitive radiation therapy (IMRT) for patients with HNSCC.

– Memorial Sloan-Kettering Cancer Center– Completion Date 08/01/2012

Current Ongoing Trials - Other Disease Sites for Chemo-radiation with Abraxane

• Ca Pancreas – Stastically significant improved responses reported

• Ca Oesophagus• Gastric Ca • Unresectable Metastatic Ca Prostate:

Abraxane Plus Hormonal Therapy • human Grade III astrocytoma cell line

Abraxane as Radiation sensitizer

Other proposed Schedules:•A minimum of 3 hr prior exposure – G2/M block – lasting 24 hrs•Use 1/3 the weekly dose, 3 times/week – maintains G2/M block

•ABRAXANE• 75 - 150 mg/m2 weekly IV over 30 min, x3 q4w

Summary• Nab Paclitaxel Abraxane (ABI 007) – is one of the latest nanoparticle

molecule to be used as a Radiation sensitizer • The results of the recently completed clinical trials are eagerly awaited• Preliminary reports are encouraging • The response rates and toxicity profile of ABI 007 - potential use as

Radiation sensitizer in various Clinical setting in years to come• A Platin combination seems to be essential to achieve escalated

responses • Clinical Trials in Indian setting are being encouraged:

– we are in the process of designing Chemo-radiation schedule in various clinical settings

– The study design shall be relevant to our patients profile , radiation toxicity tolerances and supportive care available.

Thank you