Abstract CT020: Phase I dose escalation of olaparib (PARP inhibitor) and selumetinib (MEK Inhibitor) combination in solid tumors with Ras pathway alterations

Abstract

Abstract Background: Preclinical data from our team demonstrated that MEK inhibition increases antitumor efficacy of PARP inhibitors in tumors with Ras pathway alterations. We sought to identify dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of olaparib and selumetinib combination in solid tumors with Ras pathway alterations. Methods: Olaparib and selumetinib were given orally twice daily. Dose escalation with three planned dose levels (DL) was performed using the modified toxicity probability interval 2 design with toxicity assessed by CTCAE v4.03. RECIST criteria (v1.1) were used to assess response. Clinical benefit was defined as partial (PR) or complete response, or stable disease for 4 months or longer. Results: 14 patients are evaluable for toxicity in the dose escalation phase, and 12 patients are evaluable for response. Median age was 56.5 years, and 10/14 (71%) patients were female. Median number of prior treatments was 4 (1-9). Of the 14 patients enrolled, 11 had KRAS mutations, 1 amplified KRAS, 1 NRAS mutation and 1 amplified NRAS. The majority of patients had gynecologic cancers. 4 and 3 patients were treated at DL1 and DL2, respectively, and 7 patients at DL3. No DLTs were observed (Table 1). MTD was not reached. DL3 (olaparib 300mg; selumetinib 75mg) was confirmed as the recommended Phase II dose (RP2D). Of 12 evaluable patients, ORR was 17%, and CBR 33%. 2 patients had a PR: 1 patient with KRAS mutant primary peritoneal cancer, and 1 with NRAS mutant ovarian cancer. 2 patients remained on treatment for more than 15 months: 1 with KRAS mutant primary peritoneal cancer (on DL-1), and 1 with KRAS mutant non-small cell lung cancer (DL1). All patients with clinical benefit were BRCA wildtype. Conclusions: The combination of olaparib and selumetinib is well-tolerated at the identified RP2D. This combination also shows promising preliminary anti-tumor activity in patients with mutant RAS. Enrollment to expansion cohorts is ongoing. Table 1Grade 3/4 and Most Common Adverse Events. NOTE: No Grade 4 Events Occurred.Adverse EventGrade 3Any GradeAbdominal pain7%7%Acneiform Rash7%71%Anemia79%Anorexia29%Constipation29%Decreased ejection fraction7%14%Decreased white blood cell count7%36%Diarrhea50%Dizziness29%Dry mouth43%Dry skin29%Dysgeusia36%Edema29%Elevated aspartate aminotransferase7%50%Elevated bilirubin7%7%Elevated CPK7%36%Elevated creatinine29%Fatigue7%64%Hepatic pain7%7%Hypophosphatemia79%Nausea57%Neutropenia7%21%Oral mucositis50%Other skin effects36%Thromboembolic event7%7% Citation Format: Katherine C. Kurnit, Funda Meric-Bernstam, Kenneth Hess, Robert L. Coleman, Priya Bhosale, Katerina Savelieva, Filip Janku, David Hong, Aung Naing, Shubham Pant, Jordi Rodon, Timothy A. Yap, Anil K. Sood, Pamela T. Soliman, David M. Gershenson, Gordon B. Mills, Shannon N. Westin. Phase I dose escalation of olaparib (PARP inhibitor) and selumetinib (MEK Inhibitor) combination in solid tumors with Ras pathway alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT020.