Comprehensive Multimodal Prehabilitation Alone or With Neoadjuvant Therapy Before Major Cancer Surgery

This is a 2-arm, non-randomized, phase II trial evaluating the efficacy and safety of comprehensive multimodal prehabilitation (CMMP) alone or in combination with planned/off-protocol neoadjuvant therapy (NAT) in high-risk (pre-frail/frail) patients with probable/proven pancreaticobiliary, ovarian, renal, or bladder cancer prior to elective major cancer surgery (EMCS, including pancreatectomy [N=38 in each study arm], cytoreduction [N=12 in each study arm], radical nephrectomy [N=12 in each study arm], or total cystectomy [N=12 in each study arm]; respectively and accounting for a potential 20% dropout rate). The two study arms are independent; within arm (i.e., across cancer and/or procedure types) and between arm comparison will not be performed. The CMMP intervention combines motivational interviewing (MI) with nutritional prehabilitation, inspiratory muscle training, and physical prehabilitation (aerobic exercises and strength/resistance training). Approximately 74 high-risk, male or female patients, 18 years of age or older, will be enrolled in Arm 1 (CMMP alone) and 74 similar patients will be enrolled in Arm 2 (CMMP \& planned NAT).

The primary endpoints are postoperative morbidity-free survival and safety after CMMP. The secondary endpoints are preoperative functional status/fitness; completion of planned preoperative therapy (in Arm 2 only); preoperative/postoperative health-related quality-of -life (HRQOL); and receipt of intended (adjuvant) oncologic therapy (RIOT). Additional secondary endpoints will include postoperative morbidity/healthcare utilization and 2-year overall survival (OS) and disease-free survival (DFS; in patients with proven [histologically confirmed] cancer) after CMMP. The tertiary endpoints are nutritional status and body composition after CMMP.

Exploratory analyses using baseline/pre-CMMP and post-CMMP peripheral blood samples, as well as baseline/pre-CMMP (clinical diagnostic biopsy) and post-CMMP (EMCS specimen) tumor samples will include (but not be limited to) correlates of response to CMMP including as peripheral immune modulation, as well as (in patients with proven cancer) changes to the tumor microenvironment (TME: vasculature, hypoxia, and immune cell infiltration) and pathologic response (in Arm 1 patients who did not receive NAT prior to study entry).

Patients in Arm 1 (CMMP alone) will receive (at least 3) weekly cycles of CMMP between study registration and Preoperative Reassessment. Patients in Arm 2 (CMMP \& planned NAT) will receive (at least 3) weekly cycles of CMMP during receipt of planned/off-protocol NAT between study registration and Preoperative Reassessment. Patients will be provided with ready access to videos explaining the subcomponents of the CMMP intervention. Throughout the CMMP intervention, weekly automated assessments of adherence to the CMMP intervention and assessments for AEs/SAEs will be conducted electronically (via text/email using a text-enabled Research Electronic Data Capture [REDCap] database/system) and/or by study staff (in-person or by email/telephone).

At the Preoperative Reassessment, impact of the CMMP intervention on relevant intermediate endpoints will be evaluated, including, nutritional status, body composition (muscle mass), respiratory muscle function, muscular (grip) strength, functional capacity, functional status/fitness, HRQOL, and ECOG performance status.

After the Preoperative Reassessment, patients will proceed to planned/off protocol EMCS < 67 days after start of last cycle of CMMP. Patients who undergo EMCS and meet eligibility criteria at Second Registration will continue in the study and complete a series postoperative assessments, including assessments of postoperative mortality/morbidity, healthcare utilization, and HRQOL through postoperative day 90, as well as vital and (in patients with proven cancer) disease status assessments up to 2 years after First Registration.

Preoperative and postoperative peripheral blood and tumor tissue samples will be collected and used to conduct correlative studies exploring potential mechanism(s) of oncologic benefit of CMMP, including but to limited to changes in the peripheral immune milieu and (in patients with proven cancer) TME. Collection of blood specimens (PBMC, plasma, serum) will be performed at baseline (after First Registration) and at the Preoperative Reassessment; these specimens will be compared to assess peripheral immune modulation after CMMP. In patients with proven cancer, tumor tissue (in the form of slides) obtained as part of the patient's standard care (i.e., diagnostic biopsy) will be collected after First Registration and used to assess the pretreatment (baseline). Tumor tissue will also be collected at the time of EMCS (surgical resection specimen); these specimens will be compared to assess for changes in TME after the CMMP (and in patients in Arm 1 who did not received NAT prior to First Registration, as pathologic response to CMMP [alone]).

The investigators hypothesize that the CMMP intervention will be feasible and safe; improve preoperative nutritional status, muscle mass, and functional status/fitness; improve postoperative morbidity-free survival; improve perioperative HRQO; results in high rates of receipt of NAT and RIOT; and reduce postoperative PPCs and health care utilization. The investigators hypothesize that the CMMP intervention will result in peripheral immune mobilization and activation. In patients with proven cancer, the investigators further hypothesize that it will also result in improved tumor vasculature, reduced tumor hypoxia, and improved immune cell infiltration; and (even when used without NAT) potentially result in a pathologic response.