title: Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.
abstract: 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/m2was 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/m2d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.
authors.affiliation: Hospital Universitario Virgen del Rocío, Seville, Spain.|Chair of the Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: University College of London Hospital, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Forster
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
authors.forename: Valentina
authors.initials: V
authors.lastname: Boni
authors.affiliation: Pharma Mar, S.A, Colmenar Viejo, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Szyldergemajn
authors.affiliation: Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Corral
authors.affiliation: University College of London Hospital, London, UK.|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.
authors.forename: Samantha
authors.initials: S
authors.lastname: Turnbull
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cubillo
authors.affiliation: Pharma Mar, S.A, Colmenar Viejo, Madrid, Spain.
authors.forename: Carlos Fernandez
authors.initials: CF
authors.lastname: Teruel
authors.affiliation: Hospital Universitario Virgen del Rocío, Seville, Spain.|Consultant Clinical Oncologist in Can Misses Hospital, Ibiza, Spain.
authors.forename: Iker López
authors.initials: IL
authors.lastname: Calderero
authors.affiliation: Pharma Mar, S.A, Colmenar Viejo, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Siguero
authors.affiliation: Pharma Mar, S.A, Colmenar Viejo, Madrid, Spain.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bohan
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain. Emiliano.Calvo@start.stoh.com.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002243:Carbolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Combination; Gemcitabine; Lurbinectedin; PM01183; Solid tumor