ABSTRACT Advances in screening and adjuvant therapy have significantly improved disease outcomes in primary (early-stage) cancer, however 30% still experience relapse despite curative treatment. Recurrent (metastatic) disease is currently incurable. Thus, effective strategies to prevent disease recurrence in those patients at highest risk are of major clinical importance. Exercise therapy is a well-tolerated strategy that may also hold significant promise to control MRD in breast, prostate, and colorectal cancer. Observational studies show that self-reported exercise is associated with 20% to 60% reductions in the risk of relapse in primary breast, prostate, and colorectal cancer. Moreover, these observations extend to patients with high-risk (e.g., stage 3, node positive) disease. In preclinical support of these data, we have demonstrated exercise significantly inhibits primary tumor growth in aggressive mouse models of breast, colorectal, and prostate cancer. Finally, we have translated the development of exercise interventions to the clinic with numerous prospective trials demonstrating exercise training is safe, well- tolerated, and exhibits significant pharmacodynamic (PD) activity as illustrated by favorable alterations in the circulating availability of multiple growth factors and hormones as well as inflammatory-immune effectors known to affect cancer cell proliferation and survival in breast, prostate, and colorectal cancer. Collectively, the encouraging data strongly support further clinical investigation of whether exercise has adjuvant therapy benefit in patients with primary solid tumors. We will conduct a phase 1a/1b study of exercise in primary cancer patients at high-risk of disease relapse. We will leverage analysis of circulating tumor DNA (ctDNA) to: (1) identify those at high-risk of relapse, and (2) monitor therapeutic response to exercise. This grant has two specific aims: (1) Aim 1: Phase 1a Dose- Finding and (2) Aim 2: Phase 1b Dose Expansion.