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DCTD Division of Cancer Treatment and Diagnosis
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 MeetingDevelopmental 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. 2008. Clin Cancer Res• Kummar et al. 2009. 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 (H2AX).
3
Measuring Pharmacodynamic Response Following Veliparib and Topotecan Treatment
H2AXP
H2AXP
BRCA1/2BRCA1/2
Dou
ble
Stra
nd B
reak
Rad51Rad51
Cell Death
Single Strand Break
Homologous/Non-homologous Recombination
PARPPARP
Cell SurvivalATR
ATM
Cell Cycle Checkpoints
TOP1TOP1
PAR Immunoassay
PAR Immunoassay
H2AX Immunofluorescence
Assay
H2AX Immunofluorescence
Assay
Topotecan Veliparib
Chk1/2
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 AdministrationNo. of
PatientsTopotecan 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) D1-7 3
-2 0.75 (D1-5) D2-5 3
-3 0.6 (D1-5) D2-5 7
-1A 0.75 (D1-5) D1 only 5
MTD
5
Specimen Collection Specimen Preparation Pharmacodynamic Testing
Tumor Biopsy
0.0
5.0
10.0
15.0
20.0
25.0
30.0
Untreated 0.03 0.3 1 3
Topotecan Concentration (uM)
PAR Standard Curve 022507-1
1000000
10000000
100000000
10 100 1000 10000
PAR Std (pg/ml)
RL
U
PAR std(pg/ml)
SOP340503 Blood Collection and PBMC Processing
SOP340507 Tumor Frozen Needle Biopsy Collection and Handling
SOP340520 Tumor Protein Extraction
SOP340506 PBMC Protein ExtractionBlood
SOP340505 Poly (ADP-ribose) (PAR) Immunoassay
*http://dctd.cancer.gov/ResearchResources/ResearchResources-biomarkers.htm
Monitoring Pharmacodynamic ResponsePAR Immunoassay*
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Monitoring Pharmacodynamic ResponseH2AX Immunofluorescence Assay
SOP340523 H2AX IFA for Tumor Biopsy Slides
SOP340504 Preparation of Cytospin Slides
SOP340522 Tumor Frozen Needle Biopsy Preparation
SOP340524 H2AX Immunofluorescence Assay for Cytospin Slides
SOP340533 Image Capture and Analysis of Tumor Biopsy Slides from H2AX IFA
SOP340514 PBMC Isolation and Fixation for Cytospin Slides
SOP340507 Tumor Frozen Needle Biopsy Collection and Handling
SOP340525 Image Capture and Analysis of Cytospin Slides
Tumor Biopsy
Blood
Specimen Collection Specimen Preparation Pharmacodynamic Testing
7
PAR Immunoassay
H2AX Immunofluorescence Assay
Analysis of PAR and H2AX in Patient Tumor Biopsies
•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 H2AX response in tumors following Veliparib + topotecan treatment.
Dose Level 1 Dose Level -1 Dose Level -3
Dose Level -1 Dose Level -3
8
H2AX Immunofluorescence Assay
PAR and H2AX response in PBMCs at the Veliparib + Topotecan MTD
•There is an inverse correlation between PAR and H2AX response in PBMCs following Veliparib + topotecan combination treatment at dose level -3 (MTD).
•H2AX responders are defined as patients with >2-fold increase in %H2AX nuclear area positive pre-Veliparib treatment.
PAR Immunoassay
9
Veliparib Potentiates Topotecan-Mediated DNA Damage in PBMCs
• PAR inhibition of >50% represents a statistically signifcant pharmacodynamic response to Veliparib (arrow).
• Increased H2AX levels are associated with PARP inhibition at Dose Level -3
97.8% average PAR reduction in H2AX responders*
52.3% average PAR reduction in non-responders
PBMC specimens 2 h after ABT-888 + Topotecan
*
*
*
10
Conclusions
• Increased H2AX levels in PBMCs were associated with PARP inhibition such that H2AX 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 H2AX Assays
CTEP #Veliparib in Combination With:
Clinical TrialPrincipal Investigator
7981 Topotecan ABT-888 and Topotecan in Treating Patients With Advanced or Refractory Solid Tumors, Lymphoma, or Chronic Lymphocytic Leukemia Kummar
8329 TopotecanABT-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, CarboplatinABT-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, PaclitaxelABT-888, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer Ramalingam
7977 IrinotecanIrinotecan and ABT-888 in Treating Patients With Metastatic or Unresectable Cancer LoRusso
8275 Cyclophosphamide OralABT-888 and Cyclophosphamide in Treating Patients With Solid Tumors or Lymphoma That Did Not Respond to Previous Therapy Kummar
7998Cyclophosphamide 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 AgentABT-888 in Treating Patients With Malignant Solid Tumors That Did Not Respond to Previous Therapy Puhalla
8472Single 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
Yiping ZhangRavithat PutvatanaWilliam YutzyLan TranYvonne A. EvrardKaren Gray Tiziano DiPaoloMelanie SimpsonRobert J. KindersRalph E. ParchmentNCI Phase 0 Clinical Trials Team
Shivaani KummarAlice ChenLarry RubinsteinMelinda HollingsheadAnthony MurgoChristophe RedonWilliam BonnerYves PommierJerry CollinsJoseph E. TomaszewskiJames H. Doroshow
NCI CTEP Veliparib Clinical Trial Principal Investigators, Patients, and Teams
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