Endometrial Intraepithelial Neoplasia, Grade 1 Endometrial Endometrioid Carcinoma, Metabolic Comorbidities
Conditions
Keywords
Tirzepatide, LNG-IUD
Brief summary
This single-arm study will evaluate the feasibility, safety, and preliminary efficacy of tirzepatide in combination with standard levonorgestrel intrauterine device (LNG-IUD) therapy in patients with endometrial intraepithelial neoplasia (EIN) or grade 1 endometrioid endometrial carcinoma with co-existing obesity and metabolic risk factors. Participants will receive tirzepatide once weekly while continuing standard clinical management with an LNG-IUD. Treatment decisions will remain at the discretion of the treating physician. The primary objective is to evaluate pathologic response at approximately 6 months. Secondary objectives include changes in metabolic parameters, assessing the incidence and severity of adverse events of tirzepatide and LNG-IUD therapy, quality of life assessment, change in weight, and change in BMI.
Detailed description
Endometrial cancer is one of the most common gynecologic malignancies in the United States, with an increasing incidence rate. Obesity has been identified as a major risk factor for endometrial carcinogenesis and is prevalent among patients with endometrial intraepithelial neoplasia (EIN) and early-stage endometrial cancer. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA), can cause meaningful weight loss and improvement in metabolic parameters. Levonorgestrel intrauterine device (LNG-IUD) therapy is a standard hormonal treatment for local EIN and grade 1 endometrioid endometrial carcinoma. This single-arm, single-center investigator-initiated study will evaluate the feasibility, safety, and preliminary efficacy of combining tirzepatide with standard LNG-IUD treatment in patients with EIN or grade 1 endometrioid endometrial carcinoma with co-existing obesity and metabolic risk factors. Eligible participants will be enrolled after initial histological confirmation of either EIN or grade 1 endometrioid endometrial carcinoma. Clinical management will remain at the discretion of the treating physician.
Interventions
DRUGTirzepatide
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA) that can promote weight loss and improve metabolic parameters in patients with obesity.
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive tirzepatide in combination with standard clinical management with an LNG-IUD. Treatment decisions will remain at the discretion of the treating clinical team.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion 1. Age ≥ 18 years 2. Histologically confirmed endometrial intraepithelial neoplasia (EIN) or grade 1 endometrioid EC 3. BMI ≥ 30 kg/m2 4. Presence of at least one obesity-associated metabolic comorbidity, including: a. Hypertension defined as: i. Documented diagnosis of hypertension, regardless of treatment status, documented in the medical records, or ii. Participants receiving antihypertensive therapy, or iii. BP ≥ 130/80 mmHg over 3 independent measurements, or iv. Single BP ≥ 160/100 mmHg b. Hyperlipidemia defined as: i. Documented diagnosis of hyperlipidemia, regardless of treatment status, documented in the medical record, or ii. Participants receiving lipid-lowering therapy, or iii. Triglycerides \> 200 mg/dL, or iv. LDL Cholesterol \> 130 mg/dL c. Type 2 Diabetes defined as: i. Documented diagnosis of Type 2 diabetes mellitus, regardless of treatment status, documented in the medical record, or ii. Receiving glucose-lowering therapy, or iii. Impaired glucose tolerance (Hgb A1c \> 6.0%) d. Diagnosed with sleep apnea 5. For participants diagnosed with grade 1 endometrioid endometrial carcinoma: clinical stage 1A disease with MRI-confirmed myometrial invasion \< 50% and no evidence of metastatic disease 6. For participants with EIN: no evidence of extrauterine disease based on clinically appropriate evaluation 7. Ability to provide informed consent and comply with study procedures and follow-up Exclusion 1. Mismatch repair-deficient (MMRd) tumors 2. p53-abnormal tumors 3. Known hypersensitivity or contraindication to either: 1. Tirzepatide, or 2. LNG-IUD 4. Prior LNG-IUD in place at the time of EIN or endometrial cancer diagnosis 5. Current systemic progestin therapy 6. Current treatment with tirzepatide or another GLP-1 receptor agonist/GLP-1-GIP receptor agonist, or prior treatment with these agents within 1 month before study enrollment 7. Type 1 diabetes or a history of pancreatitis, medullary thyroid carcinoma, or Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 8. Pregnancy, breastfeeding, or intention to become pregnant during the study treatment 9. Concurrent malignancy requiring active treatment (except non-melanoma skin cancer) 10. Any medical, psychiatric, or social condition, that in the opinion of the investigator, would interfere with study participation or safety 11. Participants with diabetic eye disease, including non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema 12. Severe renal impairment, defined as eGFR \< 30 mL/min/1.73m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Response at 6 months from Cycle 1 Day 1 | At the end Cycle 6 Day 28 (Approximately 6 months from Cycle 1 Day 1with each cycle approximately 28 days) | Pathologic response will be assessed at Cycle 6 Day 28, approximately 6 months after Cycle 1 Day 1, using available clinical pathology specimens, as clinically indicated. For participants undergoing definitive surgical management, pathologic response may be assessed using the hysterectomy specimen. For participants not undergoing hysterectomy, pathologic response may be assessed using an endometrial biopsy or dilation and curettage (D\&C). Pathologic response will be categorized as complete response, partial response, stable disease, or progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in metabolic parameters | At Baseline, Cycle 4 Day 1, and Cycle 6 Day 28 (each cycle is approximately 28 days) | Hemoglobin A1c and Lipid Profile |
| Assessing the Incidence and Severity of Adverse Events of Tirzepatide and LNG-IUD therapy | Through study completion, an average of 9 months | Assess the incidence and severity of adverse events during study treatment, including adverse events considered related to tirzepatide or LNG-IUD therapy, graded according to CTCAE version 5.0 where applicable. |
| Quality of Life Assessment Utilizing Study 36-Item Short Form Health Survey (SF-36) Quality of Life Score | Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 28, and 3 months from Cycle 6 Day 28 | Quality of life will be assessed using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). This survey form is a questionnaire, and participants will answer 3-point and 5-point Likert Scale questions as well as yes or no questions. This survey does not provide an aggregated score as it is opinion based. If the survey shows that a patient's quality of life is being impacted due to study treatment, appropriate action will be taken at the discretion of the treating physician. |
| Change in Weight | For a total of 6 months from Baseline to Cycle 6 Day 28. Weight will be collected at Baseline, Cycle 4 Day 1, Cycle 6 Day 28, and 3 months from Cycle 6 Day 28 (each cycle is approximately 28 days) | Participants weight will be collected for approximately 6 months to assess change in weight while using Tirzepatide. |
| Change in BMI | For a total of 6 months from Baseline to Cycle 6 Day 28. Weight will be collected at Baseline, Cycle 4 Day 1, Cycle 6 Day 28, and 3 months from Cycle 6 Day 28 (each cycle is approximately 28 days) | Participants BMI will be collected for approximately 6 months to assess changes in BMI while utilizing Tirzepatide |
Countries
United States
Contacts
CONTACTCrystal Sowers
PRINCIPAL_INVESTIGATORShaina Bruce, MD
Penn State Cancer Institute
Outcome results
None listed