inhibition of poly (adp-ribose) polymerase (parp) by abt-888 in patients with advanced malignancies:...
TRANSCRIPT
Inhibition of Poly (ADP-Ribose) Polymerase (PARP) by ABT-888 in
Patients With Advanced Malignancies: Results of a Phase 0 Trial
Inhibition of Poly (ADP-Ribose) Polymerase (PARP) by ABT-888 in
Patients With Advanced Malignancies: Results of a Phase 0 Trial
Shivaani Kummar, MD
National Cancer Institute
June 3, 2007
Shivaani Kummar, MD
National Cancer Institute
June 3, 2007
Poly (ADP-Ribose) Polymerase (PARP)
Conducted under the FDA’s Exploratory IND Guidance
Example 3: Clinical Studies of Mechanism of Action (MOA) Related to Efficacy
Objectives Primary:
Determine a non-toxic dose range at which ABT-888 inhibits PARP in tumor samples and in peripheral blood mononuclear cells (PBMCs) .
Determine the pharmacokinetics of ABT-888.
Determine the time course of PARP inhibition in PBMCs by ABT-888.
Secondary:
Determine the safety of administering one dose of ABT-888.
Eligibility Criteria
Participants with solid tumors must have advanced disease refractory to at least one line of standard therapy or for which no standard therapy is available.
Participants with CLL or lymphoma may be enrolled if they have disease for which standard therapy is currently not indicated or disease that has failed at least one line of standard therapy.
Any prior therapy must have been completed ≥ 2 weeks prior to protocol enrollment.
Adequate organ function.
Study Schema
ABT-888
Tumor Biopsies
3-6 Hr
PBMC Samples
0, 2, 4, 7, 24 hr
PK Samples 10
Tumor biopsies planned:
Significant PARP inhibition in PBMCs from at least 1 of the 3 participants at a given dose level, OR
Plasma CMax of 210 nM was achieved in at least 1 participant
Study Schema
The level of PARP expression in both tumor and PBMCs was determined using an ELISA assay prior to proceeding with drug administration and further sampling.
The required minimum level of PAR expression was defined as 31 pg PAR per mL of PBMC extract (allows for demonstration of a 50% reduction in PARP activity) prior to proceeding with sampling for PD studies.
All participants received drug and had sampling for PK studies.
Dose Escalation
3 patients at each dose level
The objective of dose escalation was to investigate a PD end-point, i.e. inhibition of PARP activity and not to determine the MTD.
Dose escalation continued with the goal to achieve significant PARP inhibition in tumor samples in 3 out of 3 participants at 2 dose levels.
Dose Level Dose
Level 1 10 mg
Level 2 25 mg
Level 3 50 mg
Level 4 100 mg
Level 5 150 mg
Trial Statistics
Endpoints are PARP inhibition in tumor tissue and in PBMCs. For either endpoint:
Significant PARP inhibition for a dose level is defined as 2-fold reduction in PAR level for at least 2 patients out of the 3 accrued
If there is 80% likelihood of 2-fold reduction in PAR level for the patients, then there is 90% power to declare significant inhibition for the
dose level, by the binomial distribution.
Trial Results (To Date)
10 patients enrolled on study, 8 are evaluable
3 patients (10 mg); 3 patients (25 mg); 4 patients (50 mg- 2 NE: tumor biopsy negative for PAR levels at baseline (1), 1 pt withdrew prior to receiving drug due to personal reasons)
Age (range): 49-70 years
Diagnoses: Carcinoid (1), Colorectal cancer (3), small cell lung cancer (1), low grade lymphomas (3), CTCL (1), adenocarcinoma of the external auditory canal (1).
Patients monitored by serial bloodwork, EKGs, physical exams.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 5 10 15 20 25
Time (hr)
Pla
sm
a C
on
cen
tra
tio
n (
uM
)
10 mg dose
25 mg dose
50 mg dose
0.21 uM target
Average (n = 3) Plasma Concentration of ABT-888 Following a Single Oral Dose
0
20
40
60
80
100
120
Pe
rce
nt
of
Ba
se
lin
e
Baseline
2 hrs4 hrs
7 hrs24 hrs
0
20
40
60
80
100
120
Pe
rce
nt
of
Ba
se
lin
e
Baseline
2 hrs4 hrs
7 hrs24 hrs
0
20
40
60
80
100
120
Pe
rce
nt
of
Ba
se
lin
e
Baseline
2 hrs4 hrs
7 hrs24 hrs
Cohort 1 Cohort 2
Cohort 3
Pt 10
Pt 2
Pt 3
Pt 4
Pt 6
Pt 7
Pt 8
Pt 1
PAR Inhibition in PBMCs
PAR Inhibition in tumor biopsies
0
20
40
60
80
100
120
Pe
rce
nt
of
Ba
se
line
Baseline
Post-Dose
Pt 4
Pt 5
Pt 6
Pt 07
Pt 10
First Phase 0 - Timelines and what we have achieved
Jan-06 Apr-06 Jul-06 Oct-06 Jan-07 Apr-07 Jul-07
First Patient in Clinic (Jun 27, 2006)
Concept Approval (Dec 1, 2005)
X-lND accepted by FDA (June 15, 2006)
1st Cohort Completed (July 25, 2006)
2nd Cohort Completed (Oct 25. 2006)
Phase 1 Combination Trials
X-lND submitted to FDA (May 12, 2006)
First Phase 0 - What Have We Achieved?
Established that ABT-888 inhibits the target of interest at clinically achievable concentrations.
Established target assay feasibility in human samples after qualification in animal models. Assay validated in preclinical models using clinical procedures.
Developed SOPs for human tissue acquisition, handling and processing.
Performed real-time PK and PD analyses (results received within 72 hours of obtaining sample).
PK and PD data, including timing of tumor and PBMC sampling, available well before planned Phase 1 combination studies.
Acknowledgements
All the present and future patient participants of Phase 0 trials
Joseph E. TomaszewskiRobert KindersRalph E. ParchmentMelinda HollingsheadJiuping JiOxana PickeralJennifer LowLarry PhillipsAlice ChenTiziano DiPaoloSherry YangYiping Zhang
James H. DoroshowJerry CollinsAnthony J MurgoMartin GutierrezLarry RubinsteinSeth SteinbergRichard ChangAnthony KimYvonne HornefferLamin JuwaraMaryann YanceyJanelle Bingham
ABBOTT LABORATORIES
NCI’s PHASE 0 TEAM