Phase 1b trial of proteasome inhibitor carfilzomib with irinotecan in lung cancer and other irinotecan-sensitive malignancies that have progressed on prior therapy (Onyx IST reference number: CAR-IST-553)

Abstract

Summary Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m2 (given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m2 and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer.

Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer

“…Two of the five cell lines acquired increased sensitivity to IPI compared with their parental counterparts while developing resistance to cisplatin. This result may be consistent with the results of several clinical trials that have shown that proteasome inhibitors are clinically effective in a small but distinct subset of lung cancers, especially platinumpretreated patients with lung cancers [28][29][30][31].…”

“…Proteasome inhibitors and IPIs have prolonged survival of patients with relapsed or refractory multiple myeloma [25][26][27]. In addition, several clinical trials have shown that PIs are clinically effective in a small but distinct subset of lung cancers [28][29][30][31]. Drilon et al reported that 1 out of 16 patients with KRAS G12D-mutant lung adenocarcinoma, who was pretreated with carboplatin and pemetrexed and subsequent gemcitabine, showed remarkable tumor shrinkage after bortezomib treatment in a phase 2 trial [28].…”

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

“…For example, bortezomib showed modest singleagent activity in patients with relapsed or refractory advanced non-small cell lung cancer (36). Objective clinical response for carfilzomib combined with irinotecan had 19% partial response and 6% stable disease in small cell lung cancer in a phase I clinical study (37). However, there is a strong need to improve the antitumor activity of proteasome inhibitors in order to advance them in the clinic for solid tumors.…”

Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer

“…Carfilzomib is a selective proteasome inhibitor being investigated in a number of malignancies including SCLC. The safety of carfilzomib in combination with irinotecan was established in a phase 1 trial [81]. This combination was further evaluated in a phase 2 trial of 62 relapsed SCLC patients.…”