A Study of a Weight Loss Intervention in People With Endometrial Cancer

Inclusion Criteria:

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

• Obesity (defined as BMI ≥ 30 kg/m2) OR Overweight (defined as BMI ≥ 27 kg/m2) withpresence of ≥1 weight related comorbid condition OR a diagnosis of Type 2 DiabetesMellitus with BMI ≥ 25 kg/m2

• Type 2 Diabetes Mellitus is defined as known history of Type 2 diabetes, HbA1c ≥ 6.5%, fasting blood glucose ≥126 mg/dL on 2 occasions, or random blood glucose ≥ 200mg/dL with signs and symptoms of diabetes mellitus (weight loss, fatigue, polyuria,polydipsia, vision changes)

• Patients with new diagnosis of stage I-III endometrial cancer

• Completed surgery with TH/BSO with no gross residual disease

• Recommended to undergo curative intent adjuvant chemotherapy at MSK with carboplatinand paclitaxel with or without intravaginal radiation OR cisplatin and concurrentradiation followed by carboplatin and paclitaxel. Patients may consent prior to andup to 3 weeks after the first cycle of chemotherapy.

• Patients with the following histologic epithelial cell types are eligible:endometrioid adenocarcinoma, serous adenocarcinoma, carcinosarcoma, undifferentiatedcarcinoma/de-differentiated, clear cell adenocarcinoma, mixed epithelial carcinoma,adenocarcinoma not otherwise specified (N.O.S.), and mucinous adenocarcinoma.

• Patient has adequate organ function, as defined by the following laboratory values:

1. Creatinine clearance (per Cockcroft-Gault formula) ≥30 mL/min

2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × ULN.

3. Total serum bilirubin ≤ 1.5 × ULN except for patients with Gilbert's syndromewho may be included if the total serum bilirubin is ≤3.0 × ULN or directbilirubin ≤ 1.5 × ULN.

• Insurance approval for tirzepatide or semaglutide (alternative) or willingness topay out-of-pocket for tirzepatide or semaglutide (alternative) for duration of studyperiod

• Patients must be capable and willing to learn how to self-inject study drug, asrequired for this protocol (visually impaired persons who are not able to performthe injections must have the assistance of a sighted individual trained to injectstudy drug; persons with physical limitations who are not able to perform theinjections must have the assistance of an individual trained to inject study drug)and administer study drug injection (or receive an injection from a trainedindividual if visually impaired or with physical limitations)

• Not pregnant and not nursing

• English speaking or a family member or caregiver who speaks English and is able toassist with smart phone or tablet based Keenoa app or paper dietary recall handout (if no access to smart phone or tablet).

Exclusion Criteria:

• Known Type 1 diabetes

• Known GAD, Islet Cell, or Zn Transporter 8 antibodies

• History of gastroparesis

• High risk for aspiration

• Active or history of chronic or acute pancreatitis

• History of elevated calcitonin

• Personal or family history of Medullary Thyroid Carcinoma with Multiple EndocrineNeoplasia-2 syndrome

• Patients with a prior surgical, endoscopic, and/or device-based therapy (forexample, mucosal ablation, gastric artery embolization, intragastric balloon andduodenojejunal bypass sleeve) for obesity within the past two years

• Patients with removal of device-based therapy for obesity within the last 6 months

• Current GIP/GLP-1 or GLP-1 receptor agonist use or prior intolerance of GIP/GLP-1 orGLP-1 receptor agonist

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Known intolerance to study drug(s) or any of the excipients.