A Phase II Clinical Trial of CPI-613 in Patients with Relapsed or Refractory Small Cell Lung Carcinoma

Abstract

Background: Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells.

Methods: We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1-3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients.

Results: No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan.

Conclusions: Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.

Fig 1. Flow diagram of study protocol.

Fig 2. Kaplan-Meier curve of overall survival and progression-free survival.

Fig 3. Swimmer’s plot.

Swimmer’s plot of time to progression, time to toxicity causing early discontinuation of study drug, and time to death (overall survival). Three of three patients who progressed on CPI-613 and were subsequently started on topotecan then demonstrated treatment response with survival for 547, 223, and 153 days (dark blue rows).

Fig 4. In vitro assessment of the combination of CPI-613 with topotecan.

DMS-114 and NCI-H69 SCLC cell lines were exposed to the indicated drug for 72 hours and then cell viability was assessed. Combinatorial indices were calculated for the indicated drug combinations. CI = Combinatorial Index, CPI = CPI-613, Tec = Topotecan.