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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. Poly (ADP-Ribose) Polymerase (PARP). Conducted under the FDA’s Exploratory IND Guidance.

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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


Poly adp ribose polymerase parp
Poly (ADP-Ribose) Polymerase (PARP) in Patients With Advanced Malignancies: Results of a Phase 0 Trial


Conducted under the FDA’s Exploratory IND Guidance in Patients With Advanced Malignancies: Results of a Phase 0 Trial

Example 3: Clinical Studies of Mechanism of Action (MOA) Related to Efficacy


Objectives
Objectives in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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
Eligibility Criteria in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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

PBMC Samples in Patients With Advanced Malignancies: Results of a Phase 0 Trial

0, 2, 4, 7, 24 hr

PK Samples

10

Tumor Biopsies

3-6 Hr

Study Schema

ABT-888

  • 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 schema1
Study Schema in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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
Dose Escalation in Patients With Advanced Malignancies: Results of a Phase 0 Trial

3 patients at each dose level

The objective of dose escalation was to investigate a PD end-point, i.e. inhibition of PARP activityand 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.


Trial statistics
Trial Statistics in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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 levelfor the patients, thenthere is 90% power to declare significant inhibition for the dose level, by the binomial distribution.


Trial results to date
Trial Results (To Date) in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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.


Pt 1 in Patients With Advanced Malignancies: Results of a Phase 0 Trial

Pt 2

Pt 3

Pt 4

Pt 6

Pt 7

Pt 8

Pt 10

PAR Inhibition in PBMCs

Cohort 1

Cohort 2

Cohort 3


Par inhibition in tumor biopsies
PAR Inhibition in tumor biopsies in Patients With Advanced Malignancies: Results of a Phase 0 Trial


First phase 0 timelines and what we have achieved
First Phase 0 - Timelines and what we have achieved in Patients With Advanced Malignancies: Results of a Phase 0 Trial


First phase 0 what have we achieved
First Phase 0 - What Have We Achieved? in Patients With Advanced Malignancies: Results of a Phase 0 Trial

  • 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
Acknowledgements in Patients With Advanced Malignancies: Results of a Phase 0 Trial

NCI’s PHASE 0 TEAM

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

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

ABBOTT LABORATORIES

All the present and future patient participants of Phase 0 trials


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