A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor.

Standard treatment for metastatic hormone positive (HR+) breast cancer includes a combination of a CDK4/6 inhibitor and antiestrogen therapy. Despite durable responses, eventual endocrine resistance results in disease progression. The Src/Abl pathway has been shown to mediate endocrine resistance in breast cancer, thus providing a promising target for novel therapies. Bosutinib is a tyrosine kinase inhibitor that targets the Src/Abl pathway, which has been studied in hematologic malignancies. Preclinical data suggests that the addition of bosutinib to a CDK4/6 inhibitor and antiestrogen therapy has the potential to reverse endocrine resistance. This is a phase I, single arm, open-label clinical trial in which we evaluate the combination of palbociclib and fulvestrant with bosutinib in metastatic HR+ breast cancer. Patients with confirmed advanced HR+/HER2- breast cancer who have received no more than three lines of chemotherapy and have progressed on at least one aromatase inhibitor and one CDK4/6 inhibitor will be enrolled. Participants will be given a combination of palbociclib, fulvestrant and bosutinib over 28-day cycles. The primary objective of this study is to assess the safety and tolerability of bosutinib in combination with palbociclib and fulvestrant in the study population. Secondary objectives are to 1) determine the anti-tumor effect of this therapeutic combination by assessing overall response rate (ORR) and clinical benefit rate (CBR) after 6 months of treatment, 2) to determine the clinical pharmacology parameters of bosutinib in this regimen, and 3) to build a tissue repository at Georgetown Lombardi Comprehensive Cancer Center for further translational study.

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Déclaration de conflit d'intérêts

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tina Roy: no competing interests. Elizabeth Barrows: no competing interests. Candace Mainor: declares institutional research support from Pfizer; study drug from Cantex Pharmaceuticals; and institutional research support from BMS. Julie Collins: declares employee status with AstraZeneca. Filipa Lynce: declares consulting/advisory role for AstraZeneca, Pfizer, Merck and Daiichi Sankyo; and institutional research funding from Eisai, AstraZeneca, CytomX, Incyte and Daiichi Sankyo. Claudine Isaacs: declares consulting for Genentech, PUMA, Seagen, AstraZeneca, Novartis, Pfizer, ION, Gilead; Royalties: Wolters Kluwer (UptoDate); McGraw Hill (Goodman and Gillman); Institutional research support from Tesaro/GSK; Seattle Genetics; Pfizer; AZ; BMS; Genentech; Novartis. Paula R Pohlmann: declares consulting for BOLT, Abbvie, CARIS, Puma, Perthera, SEAGEN, Pfizer (uncompensated); Institutional research funding from Pfizer, Genentech; Uncompensated steering committee membership in a SEAGEN global study.