PROACT AYA: Preventing Overweight/Obesity-Associated Cardiotoxicity With Tirzepatide In Adolescent And Young Adult Cancer Survivors - A Phase 2 Single-Arm, Single-Center Feasibility Study

Primary Objectives:

To evaluate the feasibility of administering Tirz in overweight or obese AYA sarcoma patients during the first year after anthracycline therapy.

Feasibility will be assessed as a composite of recruitment, retention, and treatment adherence, and will be considered if all the following criteria are achieved:

• Enrollment: ≥40% of eligible patients offered participation to enroll.
• Visit completion: ≥70% of enrolled participants complete ≥70% of scheduled study visits through end of year one (≥5 out of 6 visits).
• Treatment adherence: ≥70% of participants receive ≥70% of planned Tirz doses (measured using participant-reported medication logs/diaries and clinician-verified dose administration records).

If any criterion is not met, contributing factors (e.g., ineligibility, refusal, operational barriers) will be documented to guide future trial design.

To evaluate the safety and tolerability of Tirz in AYA sarcoma patients. Safety will be characterized by the incidence, type, and severity of treatment-related adverse events, graded according to CTCAE v6.0.

Secondary Objectives:

To determine the incidence of subclinical cardiotoxicity following Tirz treatment.

Subclinical cardiotoxicity will be defined as the presence of any of the following:

• ≥10% absolute decline in LVEF
• LVEF <50%
• ≥12% relative reduction in GLS
• ≥20% relative decline in septal or lateral e' velocity
• ≥10% relative decline in LVPWT/EDD ratio

Changes will be assessed upon completion of Tirz treatment compared to baseline.

To evaluate changes in cardiac structure and function associated with Tirz therapy.

Specifically, to assess changes from baseline to after completion of Tirz in:

• Left ventricular ejection fraction (LVEF)
• Global longitudinal strain (GLS)
• Left ventricular posterior wall thickness/end-diastolic diameter ratio (LVPWT/EDD)
• Left ventricular diastolic function (septal and lateral e' velocities)
• Myocardial performance index
• Right ventricular systolic function (TAPSE)

To assess changes in body composition, dietary habits and physical function/activity.

Specifically, to assess changes after completion of Tirz in:

• CT-derived body composition metrics, including skeletal muscle and adiposity area and density (at baseline, pre-Tirz and post-Tirz)
• Anthropometric measures including BMI and waist-to-hip ratio (at baseline, pre-Tirz and postTirz)
• Dietary habits, assessed using a brief questionnaire evaluating overall dietary patterns and quality (pre-Tirz and post-Tirz)
• Physical activity, assessed using a brief questionnaire capturing frequency, intensity, and duration of habitual activity (pre-Tirz and post-Tirz)
• Physical function metrics including:
• 30-second sit-to-stand test: number of stands completed (pre-Tirz and post-Tirz)
• 30-second arm curl test: number of biceps curls completed using standardized weights (8 lb for men, 5 lb for women; both right and left arms) (pre-Tirz and postTirz)

To characterize metabolic and cardiac biomarker responses to Tirz.

Specifically, to assess changes from pre- to post-Tirz in:

• Lipid profile (total cholesterol, LDL, HDL, triglycerides)
• Hemoglobin A1c
• NT-proBNP
• Circulating microRNAs (miR-1, miR-499) and inflammatory cytokines (IL-1α, IL-1β, IL-6) as potential early markers of cardiac or skeletal muscle injury