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Invest New Drugs. 2017 Apr;35(2):198-206. doi: 10.1007/s10637-016-0410-3. Epub 2016 Nov 21.

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.

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Hospital Universitario Virgen del Rocío, Seville, Spain.
Chair of the Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
University College of London Hospital, London, UK.
START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
Pharma Mar, S.A, Colmenar Viejo, Madrid, Spain.
Clinical Research Fellow and SpR in Medical Oncology, Leeds Immunotherapy Team (LIT) at the Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Consultant Clinical Oncologist in Can Misses Hospital, Ibiza, Spain.
START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.


Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.


Combination; Gemcitabine; Lurbinectedin; PM01183; Solid tumor

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