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Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.
- Source :
-
Investigational new drugs [Invest New Drugs] 2017 Apr; Vol. 35 (2), pp. 198-206. Date of Electronic Publication: 2016 Nov 21. - Publication Year :
- 2017
-
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/m <superscript>2</superscript> 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/m <superscript>2</superscript> ); 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/m <superscript>2</superscript> , 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/m <superscript>2</superscript> )/gemcitabine 800 mg/m <superscript>2</superscript> d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.
- Subjects :
- Adult
Aged
Deoxycytidine administration & dosage
Deoxycytidine adverse effects
Deoxycytidine pharmacokinetics
Deoxycytidine therapeutic use
Disease-Free Survival
Female
Humans
Male
Middle Aged
Neoplasms metabolism
Treatment Outcome
Gemcitabine
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 analogs & derivatives
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
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 35
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 27873130
- Full Text :
- https://doi.org/10.1007/s10637-016-0410-3