Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer.

Abstract

PURPOSE:

This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.

METHODS:

Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m(2) weekly.

RESULTS:

Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug-drug interactions.

CONCLUSIONS:

Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.

• Authors: Hirofumi Mukai, Norikazu Masuda, Hiroshi Ishiguro, Ayako Mitsuma, Takashi Shibata, Jun Yamamura, Masakazu Toi, Aiko Watabe, Akiko Sarashina, Martina Uttenreuther-Fischer, Yuichi Ando
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 76 Issue 4 Pg. 739-50 (Oct 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 26254023 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Protein Kinase Inhibitors
• Quinazolines
• Afatinib
• Vinblastine
• ErbB Receptors
• Vinorelbine

Topics

• Adult
• Afatinib
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Breast Neoplasms (blood, drug therapy, pathology)
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Monitoring
• ErbB Receptors (antagonists & inhibitors)
• Female
• Humans
• Japan
• Leukopenia (chemically induced)
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, pathology)
• Patient Dropouts
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Quinazolines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Tumor Burden (drug effects)
• Vinblastine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Vinorelbine