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

Malignant Solid Neoplasm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05554367
• Other study ID #: NCI-2022-07266
• Secondary ID: NCI-2022-07266EA
• Status: Recruiting
• Phase: Phase 2
• Start date: December 13, 2023
• Est. completion date: August 26, 2026

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 199
• Est. completion date: August 26, 2026
• Est. primary completion date: August 26, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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 BRAF alterations RAF mutations or 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: www.ctsu.org (final URL pending)
• 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
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. There is a mandatory baseline biopsy for all ComboMATCH studies. Hence, patient must have a biopsiable lesion at baseline. 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 randomization
• 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 of the first dose of study therapy
• 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 the start of study treatment
• 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 of the first dose of study therapy
• 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 the start of study treatment. Patients migrating from cohort 1 may have received binimetinib within 28 days of registering to cohort 2
• 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 of the first dose of study therapy
• 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 the start of study treatment
• 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 of the first dose of study therapy
• 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 the start of study treatment
• Not pregnant and not nursing, because this study involves an investigational agent 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 or grade 2 neuropathy
• 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

Related Conditions & MeSH terms

• Malignant Solid Neoplasm
• Pancreatic Carcinoma
• Pancreatic Neoplasms
• Stage IV Ovarian Cancer AJCC v8
• Stage IV Pancreatic Cancer AJCC v8

Intervention

Drug:
• Binimetinib
Given PO

Procedure:
• Biopsy
Undergo biopsy
• Biospecimen Collection
Undergo collection of blood samples
• Bone Scan
Undergo bone scan
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Palbociclib
Given PO

Locations

Country	Name	City	State
United States	Hendrick Medical Center	Abilene	Texas
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	ThedaCare Regional Cancer Center	Appleton	Wisconsin
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Harold Alfond Center for Cancer Care	Augusta	Maine
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Billings Clinic Cancer Center	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	UPMC Western Maryland	Cumberland	Maryland
United States	Carle at The Riverfront	Danville	Illinois
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Premier Blood and Cancer Center	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Columbus Oncology and Hematology Associates	Dublin	Ohio
United States	Dublin Methodist Hospital	Dublin	Ohio
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Beaumont Hospital - Farmington Hills	Farmington Hills	Michigan
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Northwestern Medicine Glenview Outpatient Center	Glenview	Illinois
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Northwestern Medicine Grayslake Outpatient Center	Grayslake	Illinois
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	M D Anderson Cancer Center	Houston	Texas
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin
United States	Ascension Borgess Cancer Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	OhioHealth Mansfield Hospital	Mansfield	Ohio
United States	OhioHealth Marion General Hospital	Marion	Ohio
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Community Medical Center	Missoula	Montana
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Mount Sinai Hospital	New York	New York
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	Cancer and Hematology Centers of Western Michigan - Norton Shores	Norton Shores	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Northwestern Medicine Orland Park	Orland Park	Illinois
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Corewell Health Lakeland Hospitals - Saint Joseph Hospital	Saint Joseph	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Munson Medical Center	Traverse City	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Carle Cancer Center	Urbana	Illinois
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	University of Michigan Health - West	Wyoming	Michigan
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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