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 C Max 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 LevelDose Level 110 mg Level 225 mg Level 350 mg Level 4100 mg Level 5150 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): 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.

Cohort 1Cohort 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

First Phase 0 - Timelines and what we have achieved

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. Tomaszewski Robert Kinders Ralph E. Parchment Melinda Hollingshead Jiuping Ji Oxana Pickeral Jennifer Low Larry Phillips Alice Chen Tiziano DiPaolo Sherry Yang Yiping Zhang James H. Doroshow Jerry Collins Anthony J Murgo Martin Gutierrez Larry Rubinstein Seth Steinberg Richard Chang Anthony Kim Yvonne Horneffer Lamin Juwara Maryann Yancey Janelle Bingham ABBOTT LABORATORIES NCI’s PHASE 0 TEAM