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

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

This phase II ComboMATCH treatment trial evaluates the effectiveness of palbociclib and binimetinib in treating patients with RAS-mutated cancers. Palbociclib and binimetinib are both in a class of medications called kinase inhibitors. They work by blocking the action of abnormal proteins that signals cancer cells to multiply. This trial may help researchers understand if giving the combination of palbociclib and binimetinib can help improve the amount of time before the cancer grows in patients with patients with low grade serous ovarian cancer who have certain changes in the tumor DNA. This trial may also help researchers understand if giving the combination of palbociclib and binimetinib can help improve outcomes among patients with low grade serous ovarian cancer who have previously received a MEK inhibitor. For patients with other tumors, with the exception of lung cancer, colon cancer, melanoma and low grade serous ovarian cancers, this trial may help researchers understand if giving the combination of palbociclib and binimetinib can improve the clinical outcome of survival without progression in patients who have certain changes in their tumor's DNA.

Study Overview

• Status: Active, not recruiting
• Conditions: Malignant Solid Neoplasm; Stage IV Pancreatic Cancer AJCC v8; Stage IV Ovarian Cancer AJCC v8; Ovarian Low Grade Serous Adenocarcinoma; Exocrine Pancreas Carcinoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Drug: Binimetinib; Drug: Palbociclib; Procedure: Bone Scan; Procedure: Biopsy Procedure

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 199
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Centro Comprensivo de Cancer de UPR
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
    • Mobile, Alabama, United States, 36688
      • University of South Alabama Mitchell Cancer Institute
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • California
    • Encinitas, California, United States, 92024
      • UC San Diego Health System - Encinitas
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Palo Alto, California, United States, 94304
      • VA Palo Alto Health Care System
    • San Diego, California, United States, 92103
      • UC San Diego Medical Center - Hillcrest
  • Colorado
    • Aurora, Colorado, United States, 80045
      • UCHealth University of Colorado Hospital
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
    • Fort Collins, Colorado, United States, 80528
      • Cancer Care and Hematology-Fort Collins
    • Greeley, Colorado, United States, 80631
      • UCHealth Greeley Hospital
    • Loveland, Colorado, United States, 80538
      • Medical Center of the Rockies
  • Florida
    • Aventura, Florida, United States, 33180
      • UM Sylvester Comprehensive Cancer Center at Aventura
    • Coral Gables, Florida, United States, 33146
      • UM Sylvester Comprehensive Cancer Center at Coral Gables
    • Deerfield Beach, Florida, United States, 33442
      • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
    • Gainesville, Florida, United States, 32610
      • UF Health Cancer Institute - Gainesville
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Miami, Florida, United States, 33176
      • UM Sylvester Comprehensive Cancer Center at Kendall
    • Plantation, Florida, United States, 33324
      • UM Sylvester Comprehensive Cancer Center at Plantation
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center-Boise
    • Boise, Idaho, United States, 83712
      • Saint Luke's Cancer Institute - Boise
    • Caldwell, Idaho, United States, 83605
      • Saint Alphonsus Cancer Care Center-Caldwell
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health - Coeur d'Alene
    • Fruitland, Idaho, United States, 83619
      • Saint Luke's Cancer Institute - Fruitland
    • Meridian, Idaho, United States, 83642
      • Saint Luke's Cancer Institute - Meridian
    • Nampa, Idaho, United States, 83687
      • Saint Alphonsus Cancer Care Center-Nampa
    • Nampa, Idaho, United States, 83687
      • Saint Luke's Cancer Institute - Nampa
    • Post Falls, Idaho, United States, 83854
      • Kootenai Clinic Cancer Services - Post Falls
    • Sandpoint, Idaho, United States, 83864
      • Kootenai Clinic Cancer Services - Sandpoint
  • Illinois
    • Barrington, Illinois, United States, 60010
      • Advocate Good Shepherd Hospital
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare-Bloomington
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare-Canton
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare-Carthage
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • John H Stroger Jr Hospital of Cook County
    • Chicago, Illinois, United States, 60657
      • Advocate Illinois Masonic Medical Center
    • Crystal Lake, Illinois, United States, 60014
      • AMG Crystal Lake - Oncology
    • Danville, Illinois, United States, 61832
      • Carle at The Riverfront
    • DeKalb, Illinois, United States, 60115
      • Northwestern Medicine Cancer Center Kishwaukee
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Decatur, Illinois, United States, 62526
      • Cancer Care Specialists of Illinois - Decatur
    • Dixon, Illinois, United States, 61021
      • Illinois CancerCare-Dixon
    • Downers Grove, Illinois, United States, 60515
      • Advocate Good Samaritan Hospital
    • Effingham, Illinois, United States, 62401
      • Crossroads Cancer Center
    • Effingham, Illinois, United States, 62401
      • Carle Physician Group-Effingham
    • Elgin, Illinois, United States, 60123
      • Advocate Sherman Hospital
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare-Eureka
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare-Galesburg
    • Geneva, Illinois, United States, 60134
      • Northwestern Medicine Cancer Center Delnor
    • Glenview, Illinois, United States, 60026
      • Northwestern Medicine Glenview Outpatient Center
    • Grayslake, Illinois, United States, 60030
      • Northwestern Medicine Grayslake Outpatient Center
    • Hazel Crest, Illinois, United States, 60429
      • Advocate South Suburban Hospital
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare-Kewanee Clinic
    • Lake Forest, Illinois, United States, 60045
      • Northwestern Medicine Lake Forest Hospital
    • Libertyville, Illinois, United States, 60048
      • Condell Memorial Hospital
    • Libertyville, Illinois, United States, 60048
      • AMG Libertyville - Oncology
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare-Macomb
    • Mattoon, Illinois, United States, 61938
      • Carle Physician Group-Mattoon/Charleston
    • New Lenox, Illinois, United States, 60451
      • UC Comprehensive Cancer Center at Silver Cross
    • O'Fallon, Illinois, United States, 62269
      • Cancer Care Center of O'Fallon
    • Oak Lawn, Illinois, United States, 60453-2699
      • Advocate Christ Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Outpatient Center - Oak Lawn
    • Orland Park, Illinois, United States, 60462
      • University of Chicago Medicine-Orland Park
    • Orland Park, Illinois, United States, 60462
      • Northwestern Medicine Orland Park
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Palos Heights, Illinois, United States, 60463
      • Advocate High Tech Medical Park
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare-Pekin
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare-Peru
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare-Princeton
    • Rockford, Illinois, United States, 61114
      • Mercyhealth Cancer Institute - Rockford
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
    • Springfield, Illinois, United States, 62702
      • Springfield Clinic
    • Springfield, Illinois, United States, 62781
      • Springfield Memorial Hospital
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
    • Warrenville, Illinois, United States, 60555
      • Northwestern Medicine Cancer Center Warrenville
    • Washington, Illinois, United States, 61571
      • Illinois CancerCare - Washington
  • Iowa
    • Ankeny, Iowa, United States, 50023
      • UI Health Care Mission Cancer and Blood - Ankeny Clinic
    • Cedar Rapids, Iowa, United States, 52403
      • Mercy Hospital
    • Cedar Rapids, Iowa, United States, 52403
      • Oncology Associates at Mercy Medical Center
    • Des Moines, Iowa, United States, 50309
      • UI Health Care Mission Cancer and Blood - Des Moines Clinic
    • Waukee, Iowa, United States, 50263
      • UI Health Care Mission Cancer and Blood - Waukee Clinic
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
  • Maine
    • Augusta, Maine, United States, 04330
      • Harold Alfond Center for Cancer Care
    • Brewer, Maine, United States, 04412
      • Lafayette Family Cancer Center-EMMC
    • Scarborough, Maine, United States, 04074
      • MaineHealth Maine Medical Center- Scarborough
    • South Portland, Maine, United States, 04106
      • MaineHealth Cancer Care and IV Therapy - South Portland
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
    • Cumberland, Maryland, United States, 21502
      • UPMC Western Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Trinity Health Saint Joseph Mercy Hospital Ann Arbor
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Brighton, Michigan, United States, 48114
      • Trinity Health IHA Medical Group Hematology Oncology - Brighton
    • Brighton, Michigan, United States, 48114
      • Trinity Health Medical Center - Brighton
    • Canton, Michigan, United States, 48188
      • Trinity Health IHA Medical Group Hematology Oncology - Canton
    • Canton, Michigan, United States, 48188
      • Trinity Health Medical Center - Canton
    • Chelsea, Michigan, United States, 48118
      • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
    • Chelsea, Michigan, United States, 48118
      • Chelsea Hospital
    • Dearborn, Michigan, United States, 48124
      • Corewell Health Dearborn Hospital
    • Escanaba, Michigan, United States, 49829
      • OSF Saint Francis Hospital and Medical Group
    • Farmington Hills, Michigan, United States, 48336
      • Corewell Health Farmington Hills Hospital
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesee Hematology Oncology PC
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Flint, Michigan, United States, 48503
      • Cancer Hematology Centers - Flint
    • Grand Rapids, Michigan, United States, 49503
      • Trinity Health Grand Rapids Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Corewell Health Grand Rapids Hospitals - Butterworth Hospital
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49009
      • Beacon Kalamazoo Cancer Center
    • Lansing, Michigan, United States, 48912
      • University of Michigan Health - Sparrow Lansing
    • Livonia, Michigan, United States, 48154
      • Trinity Health Saint Mary Mercy Livonia Hospital
    • Muskegon, Michigan, United States, 49444
      • Trinity Health Muskegon Hospital
    • Niles, Michigan, United States, 49120
      • Corewell Health Lakeland Hospitals - Niles Hospital
    • Norton Shores, Michigan, United States, 49444
      • Cancer and Hematology Centers of Western Michigan - Norton Shores
    • Pontiac, Michigan, United States, 48341
      • Trinity Health Saint Joseph Mercy Oakland Hospital
    • Pontiac, Michigan, United States, 48341
      • Michigan Healthcare Professionals Pontiac
    • Reed City, Michigan, United States, 49677
      • Corewell Health Reed City Hospital
    • Royal Oak, Michigan, United States, 48073
      • Corewell Health William Beaumont University Hospital
    • Saint Joseph, Michigan, United States, 49085
      • Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
    • Saint Joseph, Michigan, United States, 49085
      • Corewell Health Lakeland Hospitals - Saint Joseph Hospital
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Troy, Michigan, United States, 48085
      • Corewell Health Beaumont Troy Hospital
    • Wyoming, Michigan, United States, 49519
      • University of Michigan Health - West
    • Ypsilanti, Michigan, United States, 48197
      • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
    • Ypsilanti, Michigan, United States, 48106
      • Huron Gastroenterology PC
  • Minnesota
    • Bemidji, Minnesota, United States, 56601
      • Sanford Joe Lueken Cancer Center
    • Deer River, Minnesota, United States, 56636
      • Essentia Health - Deer River Clinic
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Cancer Center
    • Hibbing, Minnesota, United States, 55746
      • Essentia Health Hibbing Clinic
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Sandstone, Minnesota, United States, 55072
      • Essentia Health Sandstone
    • Virginia, Minnesota, United States, 55792
      • Essentia Health Virginia Clinic
  • Missouri
    • Cape Girardeau, Missouri, United States, 63703
      • Saint Francis Medical Center
    • City of Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center at Saint Peters Hospital
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center at West County Hospital
    • Farmington, Missouri, United States, 63640
      • Parkland Health Center - Farmington
    • Sainte Genevieve, Missouri, United States, 63670
      • Sainte Genevieve County Memorial Hospital
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63129
      • Siteman Cancer Center-South County
    • St Louis, Missouri, United States, 63136
      • Siteman Cancer Center at Christian Hospital
    • St Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Sullivan, Missouri, United States, 63080
      • Missouri Baptist Sullivan Hospital
    • Sunset Hills, Missouri, United States, 63127
      • BJC Outpatient Center at Sunset Hills
  • Montana
    • Anaconda, Montana, United States, 59711
      • Community Hospital of Anaconda
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
    • Bozeman, Montana, United States, 59715
      • Bozeman Health Deaconess Hospital
    • Great Falls, Montana, United States, 59405
      • Benefis Sletten Cancer Institute
    • Kalispell, Montana, United States, 59901
      • Logan Health Medical Center
    • Missoula, Montana, United States, 59804
      • Community Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • OptumCare Cancer Care at Charleston
    • Las Vegas, Nevada, United States, 89183
      • OptumCare Cancer Care at Fort Apache
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • Oswego, New York, United States, 13126
      • Upstate Cancer Center at Oswego
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Verona, New York, United States, 13478
      • Upstate Cancer Center at Verona
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Sanford Bismarck Medical Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Roger Maris Cancer Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Miami Valley Hospital South
    • Cincinnati, Ohio, United States, 45220
      • Good Samaritan Hospital - Cincinnati
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Columbus, Ohio, United States, 43214
      • Columbus Oncology and Hematology Associates Inc
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Miami Valley Hospital North
    • Dayton, Ohio, United States, 45415
      • Dayton Physician LLC - Englewood
    • Dayton, Ohio, United States, 45409
      • Premier Blood and Cancer Center
    • Delaware, Ohio, United States, 43015
      • Delaware Health Center-Grady Cancer Center
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Dublin, Ohio, United States, 43016
      • Dublin Methodist Hospital
    • Dublin, Ohio, United States, 43016
      • Columbus Oncology and Hematology Associates
    • Franklin, Ohio, United States, 45005-1066
      • Atrium Medical Center-Middletown Regional Hospital
    • Greenville, Ohio, United States, 45331
      • Miami Valley Cancer Care and Infusion
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Mansfield, Ohio, United States, 44903
      • OhioHealth Mansfield Hospital
    • Marion, Ohio, United States, 43302
      • OhioHealth Marion General Hospital
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Newberg, Oregon, United States, 97132
      • Providence Newberg Medical Center
    • Ontario, Oregon, United States, 97914
      • Saint Alphonsus Cancer Care Center-Ontario
    • Oregon City, Oregon, United States, 97045
      • Providence Willamette Falls Medical Center
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence Saint Vincent Medical Center
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16601
      • UPMC Altoona
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Erie, Pennsylvania, United States, 16505
      • UPMC Hillman Cancer Center Erie
    • Greensburg, Pennsylvania, United States, 15601
      • UPMC Cancer Centers - Arnold Palmer Pavilion
    • Mechanicsburg, Pennsylvania, United States, 17050
      • UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion
    • Media, Pennsylvania, United States, 19063
      • Riddle Memorial Hospital
    • Monroeville, Pennsylvania, United States, 15146
      • UPMC Hillman Cancer Center - Monroeville
    • Paoli, Pennsylvania, United States, 19301
      • Paoli Memorial Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
    • Pittsburgh, Pennsylvania, United States, 15237
      • UPMC-Passavant Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital
  • South Carolina
    • Boiling Springs, South Carolina, United States, 29316
      • Prisma Health Cancer Institute - Spartanburg
    • Easley, South Carolina, United States, 29640
      • Prisma Health Cancer Institute - Easley
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
    • Greenville, South Carolina, United States, 29615
      • Prisma Health Cancer Institute - Eastside
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Butternut
    • Greer, South Carolina, United States, 29650
      • Prisma Health Cancer Institute - Greer
    • Seneca, South Carolina, United States, 29672
      • Prisma Health Cancer Institute - Seneca
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center Oncology Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Abilene, Texas, United States, 79601
      • Hendrick Medical Center
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77070
      • Methodist Willowbrook Hospital
    • Houston, Texas, United States, 77094
      • Houston Methodist West Hospital
    • Nassau Bay, Texas, United States, 77058
      • Houston Methodist Saint John Hospital
    • Sugar Land, Texas, United States, 77479
      • Houston Methodist Sugar Land Hospital
    • The Woodlands, Texas, United States, 77385
      • Houston Methodist The Woodlands Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
    • Richmond, Virginia, United States, 23298
      • VCU Massey Comprehensive Cancer Center
  • Washington
    • Edmonds, Washington, United States, 98026
      • Swedish Cancer Institute-Edmonds
    • Issaquah, Washington, United States, 98029
      • Swedish Cancer Institute-Issaquah
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center-First Hill
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Healthcare
  • Wisconsin
    • Appleton, Wisconsin, United States, 54911
      • ThedaCare Regional Cancer Center
    • Ashland, Wisconsin, United States, 54806
      • Duluth Clinic Ashland
    • Burlington, Wisconsin, United States, 53105
      • Aurora Cancer Care-Southern Lakes VLCC
    • Cudahy, Wisconsin, United States, 53110
      • Aurora Saint Luke's South Shore
    • Eau Claire, Wisconsin, United States, 54701
      • Marshfield Medical Center-EC Cancer Center
    • Germantown, Wisconsin, United States, 53022
      • Aurora Health Care Germantown Health Center
    • Grafton, Wisconsin, United States, 53024
      • Aurora Cancer Care-Grafton
    • Green Bay, Wisconsin, United States, 54311
      • Aurora BayCare Medical Center
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital Cancer Center Green Bay
    • Green Bay, Wisconsin, United States, 54303
      • Saint Vincent Hospital Cancer Center at Saint Mary's
    • Janesville, Wisconsin, United States, 53548
      • Mercyhealth Hospital and Cancer Center - Janesville
    • Kenosha, Wisconsin, United States, 53142
      • Aurora Cancer Care-Kenosha South
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Medical Center
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital
    • Madison, Wisconsin, United States, 53718
      • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
    • Marinette, Wisconsin, United States, 54143
      • Aurora Bay Area Medical Group-Marinette
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center-Marshfield
    • Milwaukee, Wisconsin, United States, 53209
      • Aurora Cancer Care-Milwaukee
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Saint Luke's Medical Center
    • Milwaukee, Wisconsin, United States, 53233
      • Aurora Sinai Medical Center
    • Minocqua, Wisconsin, United States, 54548
      • Marshfield Medical Center - Minocqua
    • Oconto Falls, Wisconsin, United States, 54154
      • Saint Vincent Hospital Cancer Center at Oconto Falls
    • Oshkosh, Wisconsin, United States, 54904
      • Vince Lombardi Cancer Clinic - Oshkosh
    • Racine, Wisconsin, United States, 53406
      • Aurora Cancer Care-Racine
    • Rice Lake, Wisconsin, United States, 54868
      • Marshfield Medical Center-Rice Lake
    • Sheboygan, Wisconsin, United States, 53081
      • Vince Lombardi Cancer Clinic-Sheboygan
    • Stevens Point, Wisconsin, United States, 54482
      • Marshfield Medical Center-River Region at Stevens Point
    • Sturgeon Bay, Wisconsin, United States, 54235-1495
      • Saint Vincent Hospital Cancer Center at Sturgeon Bay
    • Summit, Wisconsin, United States, 53066
      • Aurora Medical Center in Summit
    • Two Rivers, Wisconsin, United States, 54241
      • Vince Lombardi Cancer Clinic-Two Rivers
    • Wauwatosa, Wisconsin, United States, 53226
      • Aurora Cancer Care-Milwaukee West
    • West Allis, Wisconsin, United States, 53227
      • Aurora West Allis Medical Center
    • Weston, Wisconsin, United States, 54476
      • Marshfield Medical Center - Weston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-A3 based on the presence of an actionable mutation as defined in EAY191.
• GENERAL ComboMATCH EAY191 REGISTRATION INCLUSION CRITERIA:
• Patients must be enrolled on the EAY191 registration study and be assigned to this protocol by EAY191
• Patients must have KRAS/NRAS/HRAS or RAF mutations or rare RAF fusions as determined by the ComboMATCH screening assessment
• Patients with low grade serous ovarian cancer who have progressed on a prior MEK inhibitor are not required to have a KRAS/NRAS/HRAS or BRAF alteration
• Patients must not have a BRAF V600E alteration as determined by the ComboMATCH screening assessment
• Patients with a tumor harboring KRAS G12C mutation will be eligible either after they have received a G12C inhibitor or can be enrolled if they do not meet eligibility for a G12C inhibitor. However, patients with tumors harboring KRAS G12C mutation will be prioritized for a G12C inhibitor-based substudy if eligible
• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to registration
• Please note the current actionable marker of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trials Support Unit (CTSU) website
• EAY191-A3 IELIGIBILITY CRITERIA:
• Histologically confirmed cancer for each cohort for which curable treatment modalities are not an option. Rare BRAF fusions and non-BRAF V600E aMOIs are acceptable. RB1 mutations or two copy RB1 deletions are excluded

• Tumor tissue must be available:

  • Adequate archival tumor specimen (obtained within 12 months of EAY191 registration which has not had a Response Evaluation Criteria in Solid Tumors (RECIST) response, complete response (CR) or partial response (PR), to any intervening therapy after collection of the tissue) must be available with formalin-fixed paraffin-embedded tumor tissue (blocks or slides) OR
  • Consent to a new tumor tissue biopsy which is not a representative target lesion. This lesion must be amenable to a minimal risk image-guided or direct vision biopsy A new biopsy is preferred but is not required for enrollment in EAY191-A3 if sufficient archival tissue is available as described above
• Measurable disease per RECIST 1.1. Of note, in the case when a baseline biopsy is done after scans are obtained, a lesion separate from one that is biopsied needs to be measurable per RECIST 1.1. All radiologic studies must be performed within 28 days prior to registration
• COHORT 1: Low grade serous ovarian cancer with KRAS, NRAS non-BRAF V600E aMOIs or rare RAF fusions are acceptable
• COHORT 1: No prior MEK inhibitor or CDK4/6 inhibitor therapy
• COHORT 1: Any number of prior therapies permitted
• COHORT 1: No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to registration
• COHORT 1: No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to registration
• COHORT 2: Low grade serous ovarian cancer
• COHORT 2: Prior progression of disease on a MEK inhibitor (prior binimetinib permitted)
• COHORT 2: If patient has previously received binimetinib, they cannot have required dose reduction or discontinuation of binimetinib due to adverse events
• COHORT 2: No prior receipt of a CDK4/6 inhibitor
• COHORT 2: No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to registration
• COHORT 2: No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to registration
• COHORT 3: Pancreatic cancer with KRAS/NRAS/HRAS, non-BRAF V600E aMOIs or rare RAF fusions are acceptable
• COHORT 3: No prior MEK inhibitor (MEKi) and CDK4/6i therapy
• COHORT 3: Progression after at least one line of prior therapy as long as there is no standard therapy available or acceptable to patients that is thought to be of benefit
• COHORT 3: Any number of prior therapies are permitted
• COHORT 3: No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to registration
• COHORT 3: No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to registration
• COHORT 4: KRAS/NRAS/HRAS non-BRAF V600E aMOIs or rare RAF fusions are acceptable
• COHORT 4: No prior MEKi and CDK4/6i therapy and progression after at least one line of prior therapy, as long as there is no standard therapy available or acceptable to patients that is thought to be of benefit
• COHORT 4: Any number of prior therapies are permitted
• COHORT 4: No more than 6 patients with a given tumor type allowed in this cohort
• COHORT 4: Any tumor type, except: LGSOC/NSCLC/CRC/pancreatic/melanoma
• COHORT 4: No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to registration
• COHORT 4: No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to registration
• Not pregnant and not nursing, because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin > 9 g/dL
• Creatinine =< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine clearance >= 30 mL/min as calculated by the Cockcroft-Gault formula
• Total bilirubin =< 1.5 x upper limit of normal (ULN). Patients with Gilbert syndrome may enroll if total bilirubin (bili) < 3 mg/dL (51 micromole/L)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Creatine phosphokinase (CPK) =< 2.5 x ULN
• Patients must be able to swallow oral formulations of the agents
• No history of interstitial lung disease. No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Patients should not have history of bowel perforation or intestinal fistulas in the last 6 months
• No patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease
• No active skin disorder that has required systemic therapy within the past 1 year
• No history of rhabdomyolysis

• No concurrent ocular disorders including:

  • Subjects with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
  • Subject with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO
  • Subjects with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions
• No patients with a history of hypersensitivity to any of the study drug(s)
• No prior allogeneic stem cell or solid organ transplantation
• Central nervous system (CNS) metastases must have been treated with local therapy (surgery, radiation, ablation) and patient off of systemic steroids, and brain metastases stable for at least 1 month
• No residual Common Terminology Criteria for Adverse Events (CTCAE) >= grade 2 toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients whose left ventricular ejection fraction (LVEF) has been evaluated by echocardiography (ECHO)/multigated acquisition scan (MUGA) are excluded if the most recent exam shows an LVEF < 50%
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
• No exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
• Patients treated with Cohort 1 control treatment binimetinib who experience disease progression may elect to migrate to cohort 2 and receive combination treatment with palbociclib and binimetinib. Patients who choose to do so must meet laboratory values and performance status requirements as above and must be begin treatment within 21 days. For patients who migrate from cohort 1 to cohort 2, the 28-day window restricting prior anti-cancer directed therapies does not apply to prior binimetinib. A new biopsy will not be required for migration, but the optional biopsy at disease progression should be encouraged

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination Cohorts 1, 2, 3, 4 (palbociclib, binimetinib); Patients receive palbociclib PO QD on days 1-21 and binimetinib PO BID on days 1-28 of each cycle. throughout the trial. 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 MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Binimetinib; Given PO; Other Names: ARRY-162; ARRY-438162; MEK162; Mektovi; ARRY 438162; ARRY 162; ARRY162; ARRY438162; MEK 162; MEK-162; Drug: Palbociclib; Given PO; Other Names: Ibrance; 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one; PD 0332991; PD 332991; PD 991; PD-0332991; PD0332991; Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy
Experimental: Monotherapy Cohort 1 (binimetinib); 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.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Binimetinib; Given PO; Other Names: ARRY-162; ARRY-438162; MEK162; Mektovi; ARRY 438162; ARRY 162; ARRY162; ARRY438162; MEK 162; MEK-162; Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) (Cohort 1)	Will compare the PFS distributions between those treated with palbociclib and binimetinib vs. binimetinib alone. PFS will be compared between the two treatment arms using Kaplan-Meier methods. The hazard ratio, median PFS, and estimated PFS rates at 6, 12, 18, 24, and 30 months will be estimated along with corresponding 95% confidence intervals. A log-rank test will be used to compare the PFS distributions between the two treatment arms in this cohort. In an ancillary manner, Cox proportional hazards models will also be used to assess the impact of treatment arm on PFS when stratifying on the stratification factors.	Time from randomization date until the time of disease progression or death due to any cause, assessed at 6, 12, 18, 24, and 30 months
Objective response rate (ORR) (Cohort 2)	The Simon optimal design used to evaluate efficacy in terms of the objective response rate after treatment in this population will use a two-stage design.	Up to 3 years
ORR (Cohort 3)	The Simon minimax design used to evaluate efficacy in terms of the objective response rate after treatment in this population will use a two-stage design.	Up to 3 years
ORR (Cohort 4)	The Simon minimax design used to evaluate efficacy in terms of the objective response rate after treatment in this histology/tumor agnostic population will use a two-stage design.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response (Cohort 1)	Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria will be estimated using ORR where ORR is defined as the number of evaluable patients achieving a response (partial response [PR] or complete response [CR] per RECIST v1.1) during treatment with study therapy divided by the total number of evaluable patients. Rates of response will be compared between treatment arms using a chi-square test (or Fisher's exact test as needed). Point estimates will be generated for objective response rates within each arm along with 95% confidence intervals using the Clopper-Pearson method.	Up to 3 years
Overall survival (OS) (All Cohorts)	Patients who are alive at last follow-up will be censored at that time point. The distribution of OS will be estimated using method of Kaplan-Meier. The median OS and 95% confidence interval will be reported.	From registration until death due to any cause, assessed up to 3 years
Duration of response (DoR) (All Cohorts)	DoR is defined for all evaluable patients who have achieved an objective response as time from the patient's earliest best objective status is first noted as either a CR or PR to the earliest date progression is documented, or death if no prior evidence of disease progression. The distribution of DoR will be estimated using the method of Kaplan-Meier.	From patient's earliest best objective status to earliest date of progression, assessed up to 3 years
Disease control (All Cohorts)	Disease control will be estimated using disease control rate (DCR), which is defined as the patients who experience CR or PR per RECIST 1.1 or maintain stable disease for at least 6 months after randomization divided by the total number of evaluable patients. DCR will be evaluated within cohorts, and for cohort 1 this will also be compared between treatment arms using a chi square test. Point estimates will be generated for disease control rates within each arm along with 95% confidence intervals using the Clopper-Pearson method.	Up to 3 years
Incidence of adverse events (AE) (All Cohorts)	All eligible patients that have initiated treatment will be considered evaluable for assessing AE rate(s). Patients will be evaluated for adverse events using the National Cancer Institute's Common Toxicity Criteria for Adverse Events version 5.0. The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the AE(s) to the study treatment will be taken into consideration.	Up to 3 years
PFS (Cohorts 2, 3, 4)	Disease progression will be determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and corresponding 95% confidence interval will be reported. Patients will be censored at the last disease assessment date if they were alive and progression-free at the time of their last assessment.	From study entry to the first of either disease progression or death from any cause, assessed up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TK1 activity (Cohorts 1 and 2)	Will explore TK1 activity before vs. after treatment and how this corresponds and correlates to clinical outcomes after treatment with palbociclib.	Up to 3 years
KRAS mutations (Cohorts 1 and 2)	Will characterize patients based on presence of KRAS mutations and how these correspond to efficacy outcomes such as PFS and response to treatment. Further, for cohort 1, will also evaluate how presence of this mutation influences outcomes in patients treated with monotherapy vs. the combination therapy. If numbers are sufficient, will also explore if KRAS mutation has any role as an effect modifier in this setting.	Up to 3 years
Determinants of response and resistance (Cohorts 1 and 2)	Will conduct whole-exome sequencing and ribonucleic acid (RNA)-sequencing at baseline, and on optional biopsy upon progression to assess determinants of response and resistance. For cohort 1, concordance of diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutation profile will be assessed.	Up to 3 years
Changes in plasma RAS allelic burden in KRAS-mutated tumors (Cohorts 1 and 2)	Will explore changes in plasma RAS allelic burden in KRAS-mutated tumors using ctDNA and correlate changes with clinical activity.	Up to 3 years
TK1 activity (Cohorts 3 and 4)	Will explore TK1 activity before vs. after treatment and how this corresponds and correlates to clinical outcomes after treatment with palbociclib.	Up to 3 years
Determinants of response (Cohorts 3 and4)	Will evaluate change in deoxyribonucleic acid (DNA), RNA, and ctDNA. Concordance of diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile will be assessed.	Up to 3 years
Signatures of intrinsic resistance or response (Cohorts 3 and 4)	Will evaluate change in DNA, RNA, and ctDNA. Concordance of diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile will be assessed.	Up to 3 years
Plasma RAS allelic burden in in relation to response (Cohorts 3 and 4)	Will evaluate change in DNA, RNA, and ctDNA. Concordance of diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile will be assessed.	Up to 3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Geoffrey I Shapiro, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2023
• Primary Completion (Estimated): August 26, 2026
• Study Completion (Estimated): August 26, 2026

Study Registration Dates

• First Submitted: September 22, 2022
• First Submitted That Met QC Criteria: September 22, 2022
• First Posted (Actual): September 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Digestive System Neoplasms; Digestive System Diseases; Genital Diseases, Female; Endocrine Gland Neoplasms; Pancreatic Diseases; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Ovarian Neoplasms; Pancreatic Neoplasms; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; binimetinib; palbociclib
• Other Study ID Numbers: NCI-2022-07266 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); EAY191-A3 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No