671P - Safety and efficacy of PM060184 plus gemcitabine in advanced solid tumors

Background

PM060184 (PM) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. PM combined with gemcitabine (GEM) showed synergistic antitumor activity in preclinical studies.

Methods

This dose-ranging, phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of PM 10-min infusion plus GEM 30-min infusion, both on Day 1 and 8 in 3-week cycles, in eligible patients (pts) with advanced pretreated solid tumors. Tumors were assessed every 6 weeks until Cycle 4, and every 9 weeks thereafter. Adverse events (AEs) were graded per NCI-CTCAE v.4.

Results

57 pts were enrolled into 8 dose levels (DLs). 74% were females, 74% had ECOG PS1; median age was 62 years; median number of prior lines of therapy was 3 (range, 1-7). Dose-limiting toxicities in Cycle 1 were grade (G) 3 peripheral sensory neuropathy, G3 abdominal pain, G3 intestinal obstruction (at the MTD), and G4 thrombocytopenia (1 pt each). The highest DL (DL8: PM 10.5 mg/m² + GEM 1000 mg/m²) was the MTD. Accrual into DL7 (PM 10.0 mg/m² + GEM 1000 mg/m²) was stopped before it was formally defined as the RD. Most common treatment-related non-hematological AEs at all DLs were fatigue (56%), nausea (55%), diarrhea (31%), decreased appetite and vomiting (27% each). Most of these AEs were G1/2 and none reached G4; most common G3 AEs were fatigue (3 pts), nausea, vomiting and abdominal pain (2 pts each). G3/4 hematological toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. Mean PK parameters for PM at DL7 in Cycle 1 were maximum concentration 665 μg/L, area under curve 430 h*mg/L and half-life 4 h. PK parameters for GEM or dFdU at all DLs were in line with reference values from the literature. 6/46 evaluable pts were responders (overall response rate [ORR]: 13%) and 12/46 pts had stable disease (SD) >4 months (disease control rate: 39%) at all DLs and tumor types. Of note, 2 partial responses and 2 SD >4 months occurred among 13 pts with ovarian cancer.

Conclusions

The combination of PM and GEM is well tolerated. The MTD was PM 10.5 mg/m² + GEM 1000 mg/m². No PK drug-drug interaction was found. While ORR was modest overall, the most encouraging outcome occurred in ovarian cancer pts.

Clinical trial identification

NCT02533674.

Editorial acknowledgement

Legal entity responsible for the study

PharmaMar.

Funding

PharmaMar.

Disclosure

S. Goel: Financial Interests, Institutional, Principal Investigator: PharmaMar. M. Provencio Pulla: Financial Interests, Personal, Advisory Board: BMS, MSD, Bayer, Lilly, Roche, Takeda, Janssen; Non-Financial Interests, Leadership Role, President of Spanish Lung cancer Group: President; Non-Financial Interests, Leadership Role, Insutituto Investigación Sanitaria Puerta de Hierro: Director. M.J. De Miguel Luken: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, BioNTech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. S. Martinez: Financial Interests, Personal, Full or part-time Employment: PharmaMar. C. Kahatt, S. Extremera, S. Fudio, A. Zeaiter: Financial Interests, Personal, Full or part-time Employment: PharmaMar; Financial Interests, Personal, Stocks or ownership: PharmaMar. All other authors have declared no conflicts of interest.