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

September 5, 2007

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 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 endpoint, i.e., inhibition of PARP activity, and not to determine the maximum tolerated dose (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)

14 patients enrolled on study, 11 are evaluable

3 patients (10 mg); 3 patients (25 mg); 8 patients (50 mg- 3 NE: tumor biopsy negative for PAR levels at baseline (1), 1 pt withdrew prior to receiving drug due to personal reasons, 1 pt currently being evaluated)

Age (range): 49-74 years

Diagnoses: carcinoid (1), colorectal cancer (3), small cell lung cancer (1), low grade lymphomas (3), CTCL (3), adenocarcinoma of the external auditory canal (1), SCC head and neck (1), melanoma (1)

Patients monitored by serial bloodwork, EKGs, physical exams

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0.21 uM target

Mean Plasma Concentration of ABT-888 Following a Single Oral Dose

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PAR Inhibition in PBMCs

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PAR Inhibition in Tumor Biopsies 3-6 Hours Post Dose

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PAR Inhibition in PBMC and Tumor Biopsies 24 Hours Post 50-mg Dose

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PAR levels in PBMC samples from Patient 12 (levels in Patient 13

below defined minimum for continued sampling)

PAR levels in tumor biopsy samples from Patients 12 and 13

First Phase 0 - Timelines and What We Have Achieved

Jan-06 Apr-06 Jul-06 Oct-06 Jan-07 Apr-07 Jul-07 Oct-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 I Combination Trials

(August 2007)X-lND submitted to FDA (May 12, 2006)

3rd Cohort Completed (July 10, 2007)

Met Study Objectives(Oct 25, 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 I combination studies.

The Next Speaker is:

Dr. Steve Larson