RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer

Required: ESR1 overexpression (≥ 1 percent of tumor cell nuclei immunoreactive by IHC)

ER-positive disease, defined as ≥ 1 percent of tumor cell nuclei being immunoreactive by immunohistochemistry (IHC)

Required: TP53 wild-type

patients must have wildtype TP53 as assessed either by immunohistochemistry or any CLIA-certified next-generation sequencing assay

Cannot have received: chemotherapy

Exception: within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study medication

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

Cannot have received: immune therapy

Exception: within 4 weeks prior to the first dose of study medication

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

Cannot have received: investigational therapy

Exception: within 4 weeks prior to the first dose of study medication

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

Cannot have received: tyrosine kinase inhibitor

Exception: within 5 half-lives of study entry

Participants who have had tyrosine kinase inhibitor (TKI) therapy within 5 half-lives of study entry

Cannot have received: radiation therapy

Exception: within 2 weeks of the first dose of study medication

Participants who have had radiation therapy within 2 weeks of the first dose of study medication

Cannot have received: CDK4/6 inhibitor (abemaciclib)

Exception: 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 ≤18 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.

Participants who have received previous treatment with CDK4/6 inhibitors, including but not limited to previous abemaciclib therapy.

Cannot have received: metformin (metformin)

Exception: if enrolling to Cohort 3

Participants who are currently receiving metformin therapy (if enrolling to Cohort 3)

Cannot have received: PI3K pathway inhibitor

Exception: For 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 mTOR inhibitor therapy such as everolimus.

For 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 mTOR inhibitor therapy such as everolimus.