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 Anti-Cancer Agents & Biologic 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.