Lung cancer (Amsterdam, Netherlands) · 2026
Evaluating the safety and efficacy of chemotherapy in patients with relapsed small cell lung cancer combined with allopurinol and MycoPhenolate (CLAMP).
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Knapp Brendan, Waqar Saiama N, Ward Jeffrey P, Herzog Brett H, Vellequette Gina, Cotton Aleksis, Turlington Danielle, Plonsky Megan, Wu Ningying, Mann Janelle, Rohatgi Anjali, Govindan Ramaswamy, Devarakonda Siddhartha, Morgensztern Daniel
Аннотация
INTRODUCTION: Relapsed small cell lung cancer (SCLC) upregulates guanosine biosynthesis through inosine monophosphate dehydrogenase enzymes (IMPDH). Pre-clinical data suggests a synergistic effect of IMPDH inhibition with chemotherapy. Mycophenolate mofetil (MMF) inhibits purine synthesis via IMPDH inhibition, and allopurinol inhibits xanthine oxidase, limiting purine salvage. We evaluated the safety and efficacy of irinotecan in combination with MMF and allopurinol in relapsed SCLC.
METHODS: Patients with previously treated SCLC were enrolled, using a 3 + 3 de-escalation design. Irinotecan was administered on days 1 and 8 of a 21-day cycle; MMF and allopurinol were given daily. Doses of irinotecan, MMF, and allopurinol at dose level (DL) 1 were 100 mg/m2, 1 g TID, and 300 mg/day, respectively. Key objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and antitumor activity.
RESULTS: From 3/1/2023 to 8/6/24, 28 patients were screened and 17 were enrolled. Twelve patients (71%) were female, 7 (41%) had brain metastases, and 13 (76%) had a platinum-free interval of <180 days. Median duration of follow up was 7.3 months (range, 1.9-26.6). The most common treatment related adverse events (TRAEs) were anemia and diarrhea, occurring in 12 patients (71%). Grade (G) 3 or higher TRAEs occurred in 12 (71%) patients, with no G5 TRAEs. Five (29%) patients discontinued treatment due to TRAE/intolerance. Two DLTs occurred at DL0 (G3 hypokalemia and diarrhea), and the study was discontinued at DL-1 due to poor tolerance. One (6%) patient had a complete response lasting >18 months, and 6 (35%) patients had a partial response, with an overall response rate of 41%.
CONCLUSION: Despite preliminary evidence of encouraging antitumor activity, the combination of irinotecan, MMF, and allopurinol in patients with relapsed SCLC was associated with increased toxicity. Future studies should explore a more tolerable cytotoxic drug to synergize with inhibitors of purine metabolism.
METHODS: Patients with previously treated SCLC were enrolled, using a 3 + 3 de-escalation design. Irinotecan was administered on days 1 and 8 of a 21-day cycle; MMF and allopurinol were given daily. Doses of irinotecan, MMF, and allopurinol at dose level (DL) 1 were 100 mg/m2, 1 g TID, and 300 mg/day, respectively. Key objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and antitumor activity.
RESULTS: From 3/1/2023 to 8/6/24, 28 patients were screened and 17 were enrolled. Twelve patients (71%) were female, 7 (41%) had brain metastases, and 13 (76%) had a platinum-free interval of <180 days. Median duration of follow up was 7.3 months (range, 1.9-26.6). The most common treatment related adverse events (TRAEs) were anemia and diarrhea, occurring in 12 patients (71%). Grade (G) 3 or higher TRAEs occurred in 12 (71%) patients, with no G5 TRAEs. Five (29%) patients discontinued treatment due to TRAE/intolerance. Two DLTs occurred at DL0 (G3 hypokalemia and diarrhea), and the study was discontinued at DL-1 due to poor tolerance. One (6%) patient had a complete response lasting >18 months, and 6 (35%) patients had a partial response, with an overall response rate of 41%.
CONCLUSION: Despite preliminary evidence of encouraging antitumor activity, the combination of irinotecan, MMF, and allopurinol in patients with relapsed SCLC was associated with increased toxicity. Future studies should explore a more tolerable cytotoxic drug to synergize with inhibitors of purine metabolism.