Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study

• Published in: British journal of cancer Vol. 111; no. 11; pp. 2058 - 2066
• Main Authors: Isakoff, S J, Wang, D, Campone, M, Calles, A, Leip, E, Turnbull, K, Bardy-Bouxin, N, Duvillié, L, Calvo, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-11-2014; Nature Publishing Group
• Subjects: 631/154/436/108; 692/699/67/1059/99; Adult; Aged; Aged, 80 and over; Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Capecitabine; Clinical Study; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Drug Resistance; Epidemiology; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - analogs & derivatives; Humans; Kinases; Male; Maximum Tolerated Dose; Medical research; Medical sciences; Metastasis; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - pathology; Nitriles - administration & dosage; Nitriles - adverse effects; Oncology; Prostate; Quinolines - administration & dosage; Quinolines - adverse effects; R&D; Research & development; Tumors; France; United States > US; capecitabine; phase 1; metastatic cancer; neoplasms; safety; bosutinib; Antineoplastic agent; Solid tumor; Tyrosine kinase inhibitor; Capecitabine; Fluoropyrimidine derivatives; Metastasis; Prodrug; Malignant tumor; Bosutinib; Increasing dose; Cancerology; Phase I trial; Advanced stage; Solid phase; Pyrimidine nucleoside; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.508

Background:
This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine.
Methods:
Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down’ design to determine the toxicity contour of the combination.
Results:
Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m
−2
twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (
n
=1); grade 3 pruritus/rash and increased alanine aminotransferase (
n
=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients.
Conclusions:
In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed.