title: Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies.
abstract: Taxane-gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15-20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700-1000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m cabazitaxel plus 1000 mg/m gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3-4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation.
authors.affiliation: aDivision of Hematology/Oncology, University of New Mexico Cancer Center, Albuquerque, New Mexico bDivision of Hematology-Oncology, Henry-Joyce Cancer Clinic/The Vanderbilt Clinic, Nashville, Tennessee cYale Cancer Center, Yale University, New Haven, Connecticut dFox Chase Cancer Center, Philadelphia, Pennsylvania eDepartment of Medicine, Division of Hematology-Oncology, University of Cincinnati Cancer Institute, Cincinnati, Ohio fSanofi, Bridgewater, New Jersey, USA gSanofi, Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Olugbenga O
authors.initials: OO
authors.lastname: Olowokure
authors.forename: Jian Y
authors.initials: JY
authors.lastname: Yin
authors.forename: Séverine
authors.initials: S
authors.lastname: Doroumian
authors.forename: Liji
authors.initials: L
authors.lastname: Shen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D043823:Taxoids; D003841:Deoxycytidine; C552428:cabazitaxel; D000093542:Gemcitabine