470P - A phase I study of eribulin and gemcitabine in patients with avanced solid tumours. A study of the Princess Margaret phase II consortium

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
Therapy
Biological Therapy
Presenter Rakesh Goel
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors R. Goel1, S. Lheureux2, S.A. Laurie1, R.A. Halford2, D. Jonker1, E.X. Chen2, D. Keller3, V. Bourada3, L. Wang4, L.A. Doyle5, L. Siu6, A.M. Oza7
  • 1Medicine, The Ottawa Hospital, K1H8L6 - Ottawa/CA
  • 2Drug Development Program, Princess Margaret Cancer Centre, M5G2M9 - Toronto/CA
  • 3Ottawa Hospital Research Institute, The Ottawa Hospital, K1V 1R5 - Ottawa/CA
  • 4Biostatistics, Princess Margaret Cancer Centre, M5G2M9 - Toronto/CA
  • 5Investigational Drug Branch (ctep), National Cancer Institute, 20850 - Bethesda/US
  • 6Drug Development Program, Division Of Medical Oncology And Hematology, Princess Margaret Hospital, M5G2M9 - Toronto/CA
  • 7Drug Development Program, Division Of Medical Oncology And Hematology, Princess Margaret Cancer Centre, M5G 2M9 - Toronto/CA

Abstract

Aim

Gemcitabine, a nucleoside analogue, and eribulin (E7389), an investigational tubulin-based anti-mitotic drug exhibited synergistic cytotoxic effects pre-clinically and were combined in a Phase I dose finding clinical trial.

Methods

A phase I clinical dose-escalation study of these 2 drugs in combination was initiated in patients with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort). Dose escalation was performed in a 3 + 3 design to identify the recommended phase II dose (RPTD). Two additional expansion cohorts consisting of women with gynecologic cancers at the recommended phase II dose (G cohort), and further dose-escalation of chemotherapy-naïve patients (CN cohort), were evaluated.

Results

Forty five patients were treated in 3 cohorts - 21 (CP), 10 (G), and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, 15 of a 28 day cycle (CP) but due to 2/6 DLTs, a less dose-intense schedule with the 2 drugs given days 1 and 8 on a q21day cycle was assessed.

Dose
Dose Level N Schedule E7389 (mg/m2) Gemcitbaine (mg/m2) DLT Toxicity
1 (q28) 6 D1,8,15 q28d 0.7 800 2 Thrombocytopenia
1 (q21) 3 D1,8 q21d 0.7 800
2 3 D1,8 q21d 0.7 1000
3-CP 6 D1,8 q21d 1.0 1000 1 Neutropenia
3-G 10 D1,8 q21d 1.0 1000
4-CP 3 D1.8 q21d 1.4 1000 2 Diarrhea; fatigue
4-CN 7 D1,8 q21d 1.4 1000 1 Elevated transaminases
5-CN 5 D1,8 21d 1.6 1000
6-CN 2 D1,8q21d 1.8 1000 1 Neutropenia

The RPTD was at dose level 3. No other significant hematologic or non-hematologic toxicities were observed with the CP patients. For the CN cohort, additional escalation at dose levels 4, 5, and 6 was attempted, but due to dose limiting neutropenia seen after Cycle 1, DL3 remained RPTD. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN).

Conclusions

The combination of eribulin and gemcitabine was well tolerated with preliminary evidence of activity being seen. Phase II investigation of this regimen should be considered at a dose of 1.0mg/m2 eribulin and 1000 mg/m2 gemcitabine day 1 and 8 q3 weeks. Support by contract HHSN261201100032C/NO1-CM-2011-00032.

Disclosure

All authors have declared no conflicts of interest.