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Pharmacodynamic Response in Phase I Combination Study of Veliparib (ABT-888) and Topotecan in Adults with Refractory Solid Tumors and Lymphomas J. Ji,

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Presentation on theme: "Pharmacodynamic Response in Phase I Combination Study of Veliparib (ABT-888) and Topotecan in Adults with Refractory Solid Tumors and Lymphomas J. Ji,"— Presentation transcript:

1 Pharmacodynamic Response in Phase I Combination Study of Veliparib (ABT-888) and Topotecan in Adults with Refractory Solid Tumors and Lymphomas J. Ji, S. Kummar, A. Chen, Y. Zhang, R. Putvatana, R. J. Kinders, L. Rubinstein, R. E. Parchment, J. E. Tomaszewski, and J. H. Doroshow ASCO 46th Annual Meeting Developmental Therapeutics–Clinical Pharmacology and Immunotherapy June 8, 2010

2 Introduction Poly (ADP-ribose) polymerase (PARP) plays a key role in recognizing DNA damage and facilitating its repair; inhibition of PARP delays this repair. Veliparib (ABT-888), an orally available, small molecule PARP inhibitor, has been shown to increase the efficacy of several cytotoxic agents in preclinical xenograft tumor models. In a proof-of-principle Phase 0 clinical trial conducted at the National Cancer Institute, our validated PAR Immunoassay demonstrated decreased PAR levels in patient tumor and PBMC samples following Veliparib treatment. Kinders et al Clin Cancer Res Kummar et al J Clin Oncol Topoisomerase 1 (TOP1) also plays a key role in DNA damage repair. Topotecan, a TOP1 inhibitor, is an FDA-approved chemotherapeutic agent. Here we investigate the possible effects of Veliparib + topotecan on the DNA damage markers PAR and phosphorylated histone H2AX (gH2AX).

3 Homologous/Non-homologous Recombination
Measuring Pharmacodynamic Response Following Veliparib and Topotecan Treatment Topotecan Veliparib TOP1 PARP PAR Immunoassay gH2AX Immunofluorescence Assay Cell Cycle Checkpoints Double Strand Break Single Strand Break H2AX P H2AX P BRCA1/2 Homologous/Non-homologous Recombination Rad51 ATR Chk1/2 ATM Cell Death Cell Survival

4 Veliparib + Topotecan Phase I Clinical Trial Objectives
Establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination of Veliparib with topotecan in patients with refractory solid tumors and lymphomas. Evaluate the pharmacokinetics of each agent in combination. Determine the effects of the study treatment on the level of PARP inhibition and DNA damage in PBMCs and tumor samples. Dose Level Dose and Days (D) of Administration No. of Patients Topotecan IV (mg/m2/day) Veliparib PO (10 mg BID) 1 1.2 (D-8, D2-5) D1-7 6 -1 0.9 (D-8, D2-5) 3 -2 0.75 (D1-5) D2-5 -3 0.6 (D1-5) 7 -1A D1 only 5 MTD

5 Monitoring Pharmacodynamic Response PAR Immunoassay*
Specimen Collection Specimen Preparation Pharmacodynamic Testing SOP Tumor Frozen Needle Biopsy Collection and Handling SOP Tumor Protein Extraction Tumor Biopsy SOP Poly (ADP-ribose) (PAR) Immunoassay SOP Blood Collection and PBMC Processing SOP PBMC Protein Extraction Blood *

6 Monitoring Pharmacodynamic Response gH2AX Immunofluorescence Assay
Specimen Collection Specimen Preparation Pharmacodynamic Testing SOP Tumor Frozen Needle Biopsy Collection and Handling SOP Tumor Frozen Needle Biopsy Preparation SOP gH2AX IFA for Tumor Biopsy Slides Tumor Biopsy SOP Image Capture and Analysis of Tumor Biopsy Slides from gH2AX IFA SOP PBMC Isolation and Fixation for Cytospin Slides SOP Preparation of Cytospin Slides SOP gH2AX Immunofluorescence Assay for Cytospin Slides Blood SOP Image Capture and Analysis of Cytospin Slides

7 Analysis of PAR and gH2AX in Patient Tumor Biopsies
PAR Immunoassay Paired tumor biopsies analyzed from 3 patients before Veliparib (topotecan alone) and after Veliparib + topotecan combination treatment. There is currently insufficient data to determine if there is a correlation between PAR and gH2AX response in tumors following Veliparib + topotecan treatment. Dose Level Dose Level Dose Level -3 gH2AX Immunofluorescence Assay Dose Level Dose Level -3

8 PAR and gH2AX response in PBMCs at the Veliparib + Topotecan MTD
PAR Immunoassay There is an inverse correlation between PAR and gH2AX response in PBMCs following Veliparib + topotecan combination treatment at dose level -3 (MTD). gH2AX responders are defined as patients with >2-fold increase in %gH2AX nuclear area positive pre-Veliparib treatment. gH2AX Immunofluorescence Assay

9 Veliparib Potentiates Topotecan-Mediated DNA Damage in PBMCs
PAR inhibition of >50% represents a statistically signifcant pharmacodynamic response to Veliparib (arrow). Increased gH2AX levels are associated with PARP inhibition at Dose Level -3 97.8% average PAR reduction in gH2AX responders* 52.3% average PAR reduction in non-responders PBMC specimens 2 h after ABT Topotecan *

10 Conclusions Increased gH2AX levels in PBMCs were associated with PARP inhibition such that gH2AX responders had almost 2-fold more PAR reduction than non-responders. PARP inhibition by Veliparib potentiates topotecan-mediated DNA damage, as measured in PBMCs. Additional tumor biopsy samples are needed to determine if the same effect can be seen in tumor biopsies. Clinical Trial Summary A total of 24 patients with refractory solid tumors and lymphomas were enrolled in the Veliparib + topotecan combination Phase I clinical trial. Significant myelosuppression was observed, necessitating dose reductions and changes in schedule. All of the observed toxicities were expected from topotecan and were managed without complications. The MTD has been established and stable disease has been documented in several patients.

11 Veliparib Early-Phase Clinical Trials: Correlative Studies Using PAR and/or gH2AX Assays
CTEP # Veliparib in Combination With: Clinical Trial Principal Investigator 7981 Topotecan ABT-888 and Topotecan in Treating Patients With Advanced or Refractory Solid Tumors, Lymphoma, or Chronic Lymphocytic Leukemia Kummar 8329 ABT-888 and Topotecan Hydrochloride in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Ovarian Epithelial Cancer or Primary Peritoneal Cancer Menefee 7968 Topotecan, Carboplatin ABT-888 and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders Karp 7967 Carboplatin, Paclitaxel ABT-888, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer Ramalingam 7977 Irinotecan Irinotecan and ABT-888 in Treating Patients With Metastatic or Unresectable Cancer LoRusso 8275 Cyclophosphamide Oral ABT-888 and Cyclophosphamide in Treating Patients With Solid Tumors or Lymphoma That Did Not Respond to Previous Therapy 7998 Cyclophosphamide IV and Doxorubicin ABT-888 and Cyclophosphamide With Versus Without Doxorubicin in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma Tan 8282 Single Agent ABT-888 in Treating Patients With Malignant Solid Tumors That Did Not Respond to Previous Therapy Puhalla 8472 Single Agent and Mitomycin-C Combination ABT-888 With or Without Mitomycin in Treating Patients With Metastatic, Unresectable, or Recurrent Solid Tumors Villalona-Calero

12 Acknowledgements NCI CTEP Veliparib Clinical Trial
Yiping Zhang Ravithat Putvatana William Yutzy Lan Tran Yvonne A. Evrard Karen Gray Tiziano DiPaolo Melanie Simpson Robert J. Kinders Ralph E. Parchment NCI Phase 0 Clinical Trials Team Shivaani Kummar Alice Chen Larry Rubinstein Melinda Hollingshead Anthony Murgo Christophe Redon William Bonner Yves Pommier Jerry Collins Joseph E. Tomaszewski James H. Doroshow NCI CTEP Veliparib Clinical Trial Principal Investigators, Patients, and Teams

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