Phase II basket trial of olaparib and durvalumab in patients (pts) with isocitrate dehydrogenase (IDH) mutated solid tumors.

Abstract

TPS3167 Background: Somatic IDH mutations are common in low grade gliomas, and rare in other solid tumors with the exception of intrahepatic cholangiocarcinoma (ICA) and certain subtypes of chondrosarcoma. IDH mutations confer a gain-of-function neomorphic activity, such that mutant IDH enzymes preferentially convert αKG to 2-hydroxyglutarate (2HG), resulting in abnormal accumulation of 2HG. 2HG competitively inhibits αKG-dependent dioxygenases, many of which are involved in DNA repair. Preclinical studies show that IDH mutated cancer cells have defective homologous recombination repair and are exquisitely sensitive to poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibition. Methods: This is a single arm phase II basket study (NCT03991832). Pts with IDH mutated solid tumors are divided into three cohorts; A: low-grade glioma; B: cholangiocarinoma; C: all other solid tumors. Pts are treated with olaparib 300 mg twice daily continuously and durvalumab 1500 mg every 4 weeks until progression, intolerable toxicity or consent withdrawal. Radiological assessment is performed after every 2 cycles of study treatments. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, up to 2 lines of systemic therapy for advanced disease, performance status 0 – 2 and adequate organ function. Pts are excluded if they received prior PARP inhibitors and anti-PD-1/PD-L1 antibody. The Simon’s optimal 2-stage design is applied for Cohorts A and B. 10 pts will be enrolled in each of Cohort A and B initially. If 2 or more partial responses (PR) are seen in these 10 pts, additional 19 pts will be enrolled for a total of 29 pts in that cohort. The combination is considered to be of clinical interest for further development if ≥ 6 PRs are seen in each cohort. Cohort C will enroll 20 pts. Archival tumor tissues and serial blood samples will be collected on study. 2HG levels will be measured and correlated with responses. The study was activated in December 2019. 3 pts have been enrolled into Cohort B. Clinical trial information: NCT03991832 .