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

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

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/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.

Keywords: Combination; Gemcitabine; Lurbinectedin; PM01183; Solid tumor.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / adverse effects
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Carbolines* / administration & dosage
  • Carbolines* / adverse effects
  • Carbolines* / pharmacokinetics
  • Carbolines* / therapeutic use
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / therapeutic use
  • Disease-Free Survival
  • Female
  • Heterocyclic Compounds, 4 or More Rings* / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings* / adverse effects
  • Heterocyclic Compounds, 4 or More Rings* / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings* / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Carbolines
  • Heterocyclic Compounds, 4 or More Rings
  • PM 01183
  • Deoxycytidine
  • gemcitabine