497P - Dose-Escalation Phase I Study of Cabazitaxel (CBZ) + Gemcitabine (GEM) in Patients (PTS) with Metastatic or Unresectable Advanced Solid Malignancy

Abstract

ABSTRACT Rationale Gem + taxane combinations have shown activity in some advanced cancers. Cbz (a novel taxane) + prednisone (P) improved overall survival vs mitoxantrone + P in pts with metastatic castration-resistant prostate cancer previously treated with docetaxel (de Bono 2010). Methods A Phase I study (NCT01001221) was conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + Gem (parts 1a and 1b) and to evaluate antitumour activity at the MTD (part 2). Pts with histologically or cytologically confirmed metastatic or unresectable solid tumours without existing standard treatment were eligible. Cohorts of 3–6 pts were treated with Cbz (15–20 mg/m2 1-h infusion) followed by Gem (700–1000 mg/m2) on d1 and Gem alone on d8 (part 1a). The administration sequence on d1 was then reversed (part 1b), based on preliminary PK data. Results Of the 12 pts in part 1a, 5 pts were treated at Cbz 20 mg/m2 + Gem 1000 mg/m2 dose level (DL 20/1000), 5 pts at DL 15/900 and 2 pts at DL 15/700. In part 1b, all 6 pts were treated at the lowest DL (700/15) allowed. At all DLs, ≥ 2 pts experienced a DLT, regardless of administration sequence. DLTs were febrile neutropenia (FN) (4 pts), Grade (Gr) 4 neutropenia (2 pts), Gr 4 thrombocytopenia (2 pts) and Gr 3 AST increase (1 pt). No MTD was established and part 2 was not performed. All pts experienced at least 1 treatment-emergent AE (TEAE); the most frequent all grade non-haematological TEAEs were fatigue 66.7%, decreased appetite 50.0%, diarrhoea 44.4%, nausea 38.9% and weight decrease 33.3%. Gr 3–4 haematological toxicities included neutropenia 66.7%, thrombocytopenia 33.3% and FN 22.2%. Nine pts continued study treatment and received 6–22 cycles; 3 pts had a partial response (melanoma, prostate small cell and appendiceal tumours), while 8 pts experienced stable disease. PK analysis did not reveal a drug–drug interaction between Cbz and Gem. Conclusion The MTD of Cbz + Gem could not be established due to DLTs. Antitumour activity was observed and drug administration sequence did not affect the toxicity profile. Further investigation of alternative dosing regimens is warranted in an effort to establish a tolerable combination. Disclosure P.M. LoRusso: Has received research funding from Sanofi. J. Yin: Is a Sanofi employee and owns Sanofi stocks and shares. S. Doroumian: Is a Sanofi employee (pharmacokineticist) and owns Sanofi stocks and shares. X. Zhi: Is a Sanofi employee (statistician) and owns Sanofi stocks and shares. A.J. Olszanski: Research funding - Sanofi supplies support for the conduct of the study. All other authors have declared no conflicts of interest.