A randomized phase II trial of fulvestrant with or without Ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive HER2 negative breast cancer

Brief description of study

This is a phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate fulvestrant +/- ribociclib in patients with HR+HER2- breast cancer who have previously progressed on an aromatase inhibitor (AI) plus CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Progression free survival is the primary endpoint. The trial will determine whether there is clinical benefit to continuing CDK4/6 inhibition beyond progression. Patients can be screened and registered at two different time points: Registration Scenario #1: Before receiving any CDK4/6 inhibitor or Scenario #2: At the time of disease progression while being treated with a CDK4/6 inhibitor (ribociclib or palbociclib or abemaciclib)+ AI In scenario #1, the study will provide patients with ribociclib + letrozole, but patients will not be randomized until they demonstrate objective evidence of disease progression on treatment. If the patient has previously received letrozole, an alternative AI can be prescribed but will not be provided by the study, i.e. administered as standard of care (ribociclib and letrozole will still be provided by the study). Patients are allowed to have received 4 consecutive weeks of an aromatase inhibitor prior to protocol registration for scenario 1. In scenario #2, patients will be randomized after registration. At randomization, patients will be assigned to one of the two arms in a 1:1 ratio: 1) Fulvestrant + ribociclib or 2) Fulvestrant + placebo. Fulvestrant will be given as a 500 mg dose intramuscularly (IM) every 2 weeks for 3 times (loading dose) and then every 4 weeks, as per standard of care. The investigational drug ribociclib will be given as 600 mg daily, 3 weeks on/1 week off. Placebo will be administered on the same schedule. For all patients, ribociclib/placebo will be supplied by the study. Fulvestrant will be given, as standard of care. Accrual Target: N= 132 patients. Patients will be accrued from 9 academic medical centers in the US, with a goal of completing accrual in two years. We will ensure that neither registration scenario contains > 60% (N=80) of total study accrual. Patients will receive treatment on study until disease progression, unacceptable toxicity, or death or withdrawal from study based on patient choice or treating physician’s discretion. Every effort will be made to follow patients for primary and secondary outcomes regardless of treatment discontinuation for any reason. Crossover is not built into the study.




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