Overview

This is a 28-week, single-arm, open-label phase II clinical trial evaluating the combination of Tirzepatide and remote, supervised, tailored resistance exercise training to achieve weight loss in adult survivors of childhood acute lymphoblastic leukemia (ALL) living with obesity or overweight with comorbidity.

Primary Objective(s):

• To evaluate the effectiveness for weight loss of the combined intervention using once weekly Tirzepatide plus remote, supervised, tailored resistance exercise (three sessions per week) in adult survivors of childhood ALL with obesity or overweight (BMI ≥27 kg/m2) with ≥1 weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). The effectiveness will be estimated as the proportion of evaluable participants who achieve at least 5% weight loss from baseline to week 28.

The study will target a proportion of participants achieving 5% weight loss of 70% and consider fewer than 40% achieving 5% weight loss as unacceptable.

Secondary Objective(s):

• Estimate the proportion of participants who adhere to the 28-week combined intervention. Adherence to Tirzepatide will be defined as receiving at least 70% of prescribed doses. Adherence to resistance exercise will be defined as attending at least 50% of prescribed exercise sessions. Adherence to the combined intervention will be considered if participants complete the study and meet both the Tirzepatide and exercise adherence endpoint. The adherence to each component of the intervention will also be reported.
• Estimate the average percentage weight loss from week 0 to 28 for participants completing the combined 28-week intervention. The study will target a mean weight reduction of 10% and consider \<5% unacceptable.

Eligibility

Inclusion Criteria:

• ≥5 years from diagnosis of acute lymphoblastic leukemia (ALL) treated with chemotherapy only
• ≥2 years from completion of therapy
• Participant has a negative (urine or blood) pregnancy test (if female)

Consistent with the FDA-approval for marketing of Tirzepatide for the treatment of obesity:

• Age ≥18 years at the time of enrollment
• Participant has obesity (BMI \> 30kg/m2) or overweight (BMI \> 27kg/m2) with ≥1 weight related co-morbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease)
  • hypertension: treated or with systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg
  • dyslipidemia: treated or with low-density lipoprotein (LDL) ≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL (1.7 mmol/L), or high-density lipoprotein (HDL) \<40 mg/dL (1.0 mmol/L) for men or HDL\<50 mg/dL (1.3 mmol/L) for women
  • obstructive sleep apnea
  • cardiovascular disease (for example, ischemic cardiovascular disease, New York Heart Association (NYHA) Functional Class I-III heart failure)

Exclusion Criteria:

• Participant has known diabetes or is found at baseline to have laboratory evidence of diabetes including HbA1c ≥ 6.5%
• Participant is using or has used weight management medication in the past 3 months or had recent significant weight loss \> 5kg in the last 3 months Severe renal dysfunction (eGFR \<30 mL/min/1.73 m²)
  • Saxenda® (liraglutide 3.0 mg)
  • Xenical®/Alli® (orlistat)
  • Meridia® (sibutramine)
  • Acutrim® (phenylpropanolamine)
  • Sanorex® (mazindol)
  • Adipex® (phentermine)
  • BELVIQ® (lorcaserin)
  • Qsymia® (phentermine/topiramate combination)
  • Contrave® (naltrexone/bupropion)
  • Compounded or generic incretin mimetic (GLP-1) medication

Note: Use of metformin or any other glucose-lowering medication, whether prescribed for polycystic ovary syndrome or diabetes prevention is not permitted.

• Participant has Multiple Endocrine Neoplasia Type 2 (MEN2) or family history of medullary thyroid cancer
• Participant has severe renal dysfunction (renal-eGFR \<30 mL/min/1.73)
• Participant has history of major cardiovascular event in past 3 months (e.g. acute myocardial infarction, cerebrovascular accident, unstable angina, hospitalization due to congestive heart failure or currently NYHA class IV heart failure symptoms)
• Participant has uncontrolled hypertension during clinic assessment (SBP ≥160 mmHg or DBP ≥100 mmHg) ▪ Participant has known acute or chronic hepatitis or signs and symptoms of other liver disease determined by alanine aminotransferase test (ALT) \> 3 times the upper normal limit
• Participant has known chronic pancreatitis or recent acute pancreatitis (in the past 1 year)
• Participant is pregnant, or within 3 months post-partum, or nursing, or planning to become pregnant
• Participant has clinically significant gastric emptying abnormality or chronically takes medications that affect GI motility (does not include Proton pump inhibitor (PPI) or histamine 2 blockade)
• Participant has a transplanted organ or awaiting a transplant
• Participant has current active cancer or undergoing treatment for active cancer
• Participant has untreated hypothyroidism with thyroid-stimulating hormone (TSH) \> 10 uIU/mL or symptomatic
• Participant has severe mental health disorder (e.g.major depressive disorder, schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) or a history of suicide attempt
• Participant has a patient health questionnaire-8 (PHQ-8) score of 15 or more at screening
• Participant has a history of known drug or alcohol use disorder that in the opinion of the investigator may preclude the participant from following and completing the protocol
• Participant has history of self-reported marijuana use in the past 3 months and unwilling to abstain during the trial.
• Participant is unwilling or unable to perform self-injections of study drug (visually impaired or physically limited) and does not have assistance of a sighted individual/support person who is trained
• Participant has cognitive impairment that, in the opinion of the investigator, would preclude the ability to participate in the intervention including self-injections and virtual study visits
• Participant is Non-English speaking
• Participant has no access to a smartphone with Bluetooth for accelerometer and WiFi availability for exercise sessions
• Participant lives in a state that we cannot ship medication per current St. Jude Pharmacy restrictions