Palbociclib and Binimetinib in RAS-Mutant Cancers, A ComboMATCH Treatment Trial

PRIMARY OBJECTIVES:

I. To determine whether palbociclib and binimetinib combination therapy improves progression free survival (PFS) compared to binimetinib alone in patients with MEK-inhibitor naive low-grade serous ovarian cancer (LGSOC) harboring MAP kinase activation (KRAS/NRAS/non BRAF V600E mutation). (Cohort 1) II. To determine whether palbociclib and binimetinib improves clinical activity in comparison to historical control, as measured by objective response rate (ORR), in women with LGSOC whose disease has previously progressed on a MEK inhibitor. (Cohort 2) III. To determine whether palbociclib and binimetinib combination therapy improves the objective response rate compared to historical control in patients with pancreatic cancer harboring any KRAS/NRAS/HRAS mutation or non-BRAF V600E aMOIs or rare RAF fusion. (Cohort 3) IV. To determine whether palbociclib and binimetinib combination therapy improves objective response rate compared to historical control in patients with tumors harboring any KRAS/NRAS/HRAS mutations or non-BRAF V600E aMOIs or rare RAF fusions (excluding LGSOC, non-small cell lung cancer \[NSCLC\], colorectal cancer, pancreatic cancer and melanoma). (Cohort 4)

SECONDARY OBJECTIVES:

I. To determine whether palbociclib and binimetinib combination therapy improves objective response rate (ORR), overall survival (OS), duration of response (DOR), and disease control rate (DCR) compared to binimetinib alone in patients with MEK inhibitor-naïve LGSOC. (Cohort 1) II. Conduct whole-exome sequencing to evaluate concordance with the designated laboratory result. (Cohort 1) III. To assess the clinical activity of palbociclib and binimetinib as measured by PFS, OS, DOR, and DCR in women with LGSOC whose disease has previously progressed on a MEK inhibitor. (Cohort 2) IV. Conduct whole-exome sequencing to evaluate concordance with the designated laboratory result. (Cohort 2) V. To assess the clinical activity of palbociclib and binimetinib as measured by PFS, OS, DOR, and DCR in patients with RAS mutated pancreatic cancer. (Cohort 3) VI. Conduct whole-exome sequencing to evaluate concordance with the designated laboratory result. (Cohort 3) VII. To assess the clinical activity of palbociclib and binimetinib as measured by PFS, OS, DOR, and DCR in patients with RAS mutated cancers, excluding LGSOC, NSCLC, colorectal cancer (CRC), pancreatic cancer and melanoma. (Cohort 4) VIII. Conduct whole-exome sequencing to evaluate concordance with the designated laboratory result. (Cohort 4)

EXPLORATORY OBJECTIVES:

I. Explore thymidine kinase 1 (TK1) activity in response to palbociclib. (Cohort 1) II. Assess the correlation between presence of KRAS mutation and activity of both monotherapy and the combination. (Cohort 1) III. Conduct ribonucleic acid (RNA)-sequencing (seq) to assess determinants of response and resistance. (Cohort 1) IV. Explore changes in plasma RAS allelic burden in KRAS-mutated tumors using circulating tumor deoxyribonucleic acid (ctDNA) and correlate changes with clinical activity. (Cohort 1) V. Explore TK1 activity in response to palbociclib.(Cohort 2) VI. Assess the correlation between presence of KRAS mutation and activity of the combination. (Cohort 2) VII. Conduct RNA-seq to assess determinants of response and resistance. (Cohort 2) VIII. Explore changes in plasma RAS allelic burden in KRAS-mutated tumors using ctDNA and correlate changes with clinical activity. (Cohort 2) IX. Explore TK1 activity in response to palbociclib. (Cohort 3) X. Evaluate changes in deoxyribonucleic acid (DNA), RNA and ctDNA to evaluate concordance with the designated laboratory result and to assess determinants of response, signatures of intrinsic resistance or response and the plasma RAS allelic burden in relation to treatment response, respectively. (Cohort 3) XI. Explore TK1 activity in response to palbociclib. (Cohort 4) XII. Evaluate changes in DNA, RNA and ctDNA to evaluate concordance with the designated laboratory result and to assess determinants of response, signatures of intrinsic resistance or response and the plasma RAS allelic burden in relation to treatment response, respectively. (Cohort 4)

OUTLINE: Patients with KRAS, NRAS, non-BRAF V600E aMOIs or rare RAF fusions LGSOC, naïve to MEK or CDK4/6 inhibitor therapy are randomized to either combination cohort 1 or monotherapy cohort 1. Patients with LGSOC who have received prior MEK inhibitor therapy are assigned to combination cohort 2. Patients with KRAS/NRAS/HRAS/non-V600E a MOIs or rare RAF fusion pancreatic cancer are assigned to combination cohort 3. Patients with all other KRAS/NRAS/HRAS, non -BRAF V600E a MOIs or rare FAR fusion tumor types (excluding LGSOC, NSCLC, CRC, pancreatic, and melanoma) are assigned to combination cohort 4.

COMBINATION COHORTS 1, 2, 3, 4: Patients receive palbociclib orally (PO), once per day (QD) on days 1-21 and binimetinib PO twice per day (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity for up to 3 years. Patients may also undergo biopsy at screening and undergo magnetic resonance imaging (MRI), computed tomography (CT), bone scan, and collection of blood samples during screening, on study, and/or during follow up.

MONOTHERAPY COHORT 1: Patients receive binimetinib PO BID daily, in the absence of disease progression or unacceptable toxicity, for up to 3 years. Patients who experience disease progression may elect to migrate to the combination cohort. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.

After completion of study treatment, patients are followed up every 3 months for up to 3 years following registration.