CTNI-41 - Phase II and Phase 0 results of ABTC 1801: a multi-arm clinical trial of the PARP inhibitor pamiparib with very low dose metronomic temozolomide in recurrent IDH mutant gliomas

Friday, November 17, 2023

4:35 PM – 4:45 PM PT

Location: Room 109-110

Oral Abstract Presenter(s)

David Schiff

University of Virginia School of Medicine
Charlottesville,, Virginia, United States

Author(s)

Ranjit S. S. Bindra

Department of Therapeutic Radiology, Yale School of Medicine
New Haven, Connecticut, United States
Jing Li

Karmanos Cancer Institute, Wayne State University
Detroit, Michigan, United States
XY

Xiaobu Ye

Johns Hopkins university
Baltimore, Maryland, United States
Benjamin M. Ellingson

UCLA Brain Tumor Imaging Laboratory, Department of Radiological Sciences, University of California Los Angeles
Los Angeles, California, United States
Tobias Walbert

Henry Ford Health
Detroit, Michigan, United States
Jian L. Campian

Mayo Clinic
Rochester, Minnesota, United States
Burt Nabors

Heersink School of Medicine
Birmingham, Alabama, United States
FL

Frank S. Lieberman

University of Pittsburg
Pittsburg, Pennsylvania, United States
BO

Byram Ozer

National Cancer Insitute, National Institutes of Health
Bethesda, Maryland, United States
AD

Arati S. Desai

University of Pennsylvania
Philadelphia, Pennsylvania, United States
AO

Antonio Omuro

Yale University
New Haven, New York, United States
Patrick Y. Wen

Dana-Farber Cancer Institute
Boston, Massachusetts, United States
SD

Serena Desideri

Johns Hopkins
Baltimore, Maryland, United States
ND

Neeraja Danda

Johns Hopkins
Baltimore, Maryland, United States
Stuart A. Grossman

Department of Oncology, Johns Hopkins University School of Medicine
Baltimore, Maryland, United States

Background: Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity.

Methods: The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR).

Results: 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were > 20-fold the in vitro IC50 for PARP inhibition.

Conclusions: While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.