||5R01CA235711-04 Interpret this number
||Sloan-Kettering Inst Can Research
||Phase 1a/1b Trial of Exercise Treatment in Hormone Receptor-Positive Metastatic Breast Cancer
Nearly half of patients receiving first line therapy for hormone receptor (HR)-positive metastatic breast cancer
(MBC) do not respond to treatment, and virtually all develop treatment resistance. Efficacious but low cost
strategies that can be chronically administered with minimal toxicity are urgently required. Structured aerobic
exercise therapy (hereafter exercise) is one such candidate approach. However, most exercise-oncology
studies to date have been conducted in early-stage cancers to test the impact of exercise on symptom control
outcomes (e.g., fatigue, pain). To develop exercise as an anticancer strategy, early phase studies are required
to determine the appropriate exercise dose for further testing – this is a mandatory prerequisite in drug
development but one largely ignored in the development of exercise as a treatment strategy. The overall
objective of this grant is to identify the optimal dose of exercise in patients with HR-positive MBC. Prior
observational and preclinical evidence provide promising hypothesis-generating data of an association
between exercise and improved prognosis. The next step in the development of exercise as an anti-cancer
intervention is to identify the optimal dose for testing in randomized control trials (RCTs). Our group recently
reported a vanguard clinical trial (R21 CA133186) showing, for the first time, the feasibility, safety, and
promising benefit of a conservative exercise prescription in MBC patients with good performance status
receiving 1st or 2nd-line therapy. Based on this strong scientific rationale, our specific aims are (1) to identify the
maximum feasible dose (MFD) of exercise in a phase 1a dose-finding study, and (2) to further assess
tolerability and biological / clinical activity in a phase 1b dose-expansion cohort. In Aim 1, 40 postmenopausal
women receiving first-line therapy for HR-positive MBC will be allocated to one of five exercise doses which will
consist of supervised individualized treadmill walking 3 to 5 days/week, at 50% to 85% exercise capacity for
landmark 24 weeks. In Aim 2, 40 postmenopausal MBC patients will receive the MFD of exercise or one dose
level below the MFD. The primary endpoint is tolerability. Secondary endpoints are biological and clinical
activity. Biological activity will be assessed by change in tumor burden, quantified by circulating tumor DNA
(ctDNA) in serially obtained liquid biopsies. Clinical activity will be assessed by radiographic tumor response,
progression free survival, and quality of life measures. We hypothesize that a tolerable dose of exercise will be
identified and that this dose will have antitumor activity characterized by reductions in tumor burden (ctDNA)
and improvements in clinical response compared to historical data. This contribution is significant because it
will inform the recommended phase 2 dose of exercise for testing in definitive RCTs. This proposal is
innovative because it adapts rigorous standards from oncology drug development and incorporates novel liquid
biopsy technology (e.g., ctDNA), thereby setting a new standard for exercise oncology research and practice.
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