Palbociclib and Binimetinib in RAS-Mutant Cancers, A ComboMATCH Treatment Trial
Study Phase: Phase 2
Recruitment Status: Recruiting
Start Date: December 13, 2023
End Date: August 26, 2026
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
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Conditions:
- Pancreatic Neoplasms
- Cystadenocarcinoma, Serous