Inhibition of Poly ADPRibose Polymerase PARP by ABT888 in Patients With Advanced Malignancies: Resul

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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

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Poly (ADP-Ribose) Polymerase (PARP)
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Conducted under the FDAs Exploratory IND Guidance
Example 3 Clinical Studies of Mechanism of
Action (MOA) Related to Efficacy
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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.

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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.

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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

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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.

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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.
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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.

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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.

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PAR Inhibition in PBMCs
Cohort 1
Cohort 2
Cohort 3
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PAR Inhibition in tumor biopsies
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First Phase 0 - Timelines and what we have
achieved
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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.

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Acknowledgements
NCIs 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