Abemaciclib and Letrozole with or without Metformin, Zotatifin, or Gedatolisib for the Treatment of Patients with Recurrent, Metastatic or Resistant Endometrial and Low Grade Ovarian Cancer, the RESOLVE Trial

Inclusion Criteria

• Participants must have cytologically or histologically confirmed endometrial cancer that is recurrent or metastatic and/or resistant to standard therapies, or for which no standard therapy is available. Participants enrolled in the second stage of Cohort 1A, or into Cohorts 3, 4, 6, or 7 must have histologically confirmed either i) endometrioid endometrial cancer or ii) endometrial carcinosarcoma with endometrioid epithelial component
• COHORT 5: Participants must have histologically confirmed diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum; original diagnosis of de novo low-grade serous carcinoma or original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma. Participants whose tumors contain both low-grade serous carcinoma and high-grade serous carcinoma are not eligible
• Participants must have estrogen receptor (ER)-positive disease, defined as >= 1 percent of tumor cell nuclei being immunoreactive by immunohistochemistry (IHC). If multiple analyses have been performed, judgment should be based on the most recent biopsy or pathology specimen analyzed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. For Cohort 5, participants are eligible regardless of ER positive or negative status
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin ≥ 9.0 g/dL (grade ≤ 2) maintained for ≥ 2 weeks from any prior transfusion
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN). Patients with Gilbert's syndrome with a total bilirubin of =< 2.0 times ULN and direct bilirubin within normal limits are permitted
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
• Creatinine =< 1.5 x institutional ULN, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels > 1.5 x institutional ULN
• The effects of the study agents on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of study agent. Contraceptive methods may include an intrauterine device (IUD) or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. A negative serum pregnancy test is required for study entry from women of childbearing potential.
• Ability to understand and the willingness to sign a written informed consent document
• Ability to swallow and retain oral medication
• Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤ 1. Participants with grade ≤ 2 chemotherapy-induced neuropathy, any grade alopecia, amenorrhea, or other toxicities not considered a safety risk for the patient as per investigator's discretion are eligible. Participants with prior grade 2 endocrine toxicities (hypothyroidism, adrenal insufficiency, etc) from checkpoint inhibitor therapy that are well managed with hormone supplementation are allowed
• Participants can have received an unlimited number of prior therapies
• Participants must have archival tissue available for analysis in the form of a formalin-fixed paraffin embedded (FFPE) block or unstained slides * Note: confirmation of availability of archival tissue is the only requirement for eligibility, archival tissue does not need to be received by the study team prior to enrollment
• COHORTS 4, 5, 6 and 7: Patients must not have remaining ovarian function to be included. Women who have ovarian function are eligible but must be placed on hormonal suppression
• COHORTS 6 AND 7: Participants must have hemoglobin A1c (HbA1c) ≤ 6.4% and fasting plasma glucose (FPG) ≤ 140 mg/dL
• COHORT 6 and 7: Patients must have wildtype TP53 as assessed either by immunohistochemistry or any CLIA-certified next-generation sequencing assay
• COHORT 7: Patients must have received prior CDK4/6 inhibitor therapy and developed disease progression as deemed by the investigator. Patients who have stopped CDK4/6 inhibitor therapy because of intolerance are ineligible. Patients previously enrolled on 18-301 (Cohorts 1, 1A, 2, or 3) are permitted to re-enroll

Exclusion Criteria

• Participants who have had chemotherapy, immune therapy, other investigational therapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study medication. Previous hormonal therapy, including prior letrozole, is allowed and there is no required washout period for hormonal therapy
• Participants who have had tyrosine kinase inhibitor (TKI) therapy within 5 half-lives of study entry
• Participants who have had radiation therapy within 2 weeks of the first dose of study medication
• Participants who have received previous treatment with CDK4/6 inhibitors, including but not limited to previous abemaciclib therapy. For cohorts 4 and 5, prior treatment with CDK4/6 inhibitors is allowed in up to 50% of participants for each cohort ( ≤ 8 participants in the first stage and ≤ 17 total in both stages for each cohort [if the study goes to second stage]) For Cohort 7, patients must have received prior treatment with CDK4/6 inhibitors as stated above * NOTE: For participants for whom prior treatment with CDK4/6 inhibitors is permitted, patients who have been enrolled on previous 18-301 cohorts (Cohorts 1, 1A, 2, or 3) may be re-enrolled onto Cohorts 4 or 7
• Participants who have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea malabsorption syndrome, or small bowel resection)
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents that the participant will be administered
• Participants who at the time of study enrollment are known to require concomitant therapy with moderate or strong CYP3A4 inducers, or strong inhibitors of CYP3A4. Due to potential drug interactions, concomitant use of these medications is not permitted for the duration of treatment on trial. Participants are eligible for study entry if an appropriate substitution is made prior to the first dose of study medication
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active bacterial infection (requiring IV antibiotics at time of initiating study treatment), fungal infection, detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea), or psychiatric illness/social situations that would limit compliance with study requirements
• Use of known QT-prolonging drugs during screening or expected requirement for use during study therapy
• Participants with personal histories or evidence of cardiovascular risk including any of the following: acute coronary syndromes (i.e. myocardial infarction or angina), coronary angioplasty, syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, or stenting within 6 months prior to study enrollment
• Pregnant women are excluded from this study because the study agents are anti-cancer agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding must be discontinued if the mother is treated on trial
• Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 5 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ
• Known human immunodeficiency virus (HIV)-positive participants are ineligible because of the increased risk of lethal infections when treated with marrow-suppressive therapy
• Participants with a history of uncontrolled hypertension despite optimal medical management, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg
• COHORT 3: Participants who are currently receiving metformin therapy (if enrolling to Cohort 3)
• COHORTS 4 and 5: Participants with a history of bleeding diathesis, gastrointestinal bleeding, or other prior significant bleeding event and are at increased risk of stroke or gastrointestinal bleeding (including but not limited to patients with cirrhosis, portal hypertension, untreated gastroesophageal varices, etc.)
• COHORTS 4 and 5: Participants who at the time of study enrollment are requiring anticoagulation or receiving therapy that interferes with platelet function (including but not limited to ibuprofen, aspirin, and other non-steroidal antiinflammatory drug [NSAIDS], etc.). Note: While on study, participants are permitted to receive such therapy if requiring medical intervention
• COHORTS 6 AND 7: Inability to determine the corrected QT interval using Fridericia’s formula (QTcF) on the electrocardiogram (ECG) (i.e., unreadable or not interpretable) or QTcF > 480 msec (determined by mean of triplicate ECGs at screening)
• COHORTS 6 AND 7: Participants with type 1 diabetes or uncontrolled type 2 diabetes
• COHORTS 6 AND 7: Participants who have previously received any PI3K pathway inhibitors are ineligible. Up to 10 patients in Cohort 6 and up to 10 patients in Cohort 7 may have received prior mammalian target of rapamycin (mTOR) inhibitor therapy such as everolimus