Abemaciclib, Avutometinib, and Fulvestrant for the Treatment of Metastatic or Locally Recurrent Hormone Receptor Positive/HER2 Negative Breast Cancer

Inclusion Criteria

• Participants must have histologically or cytologically confirmed hormone receptor positive (HR+), HER2 negative metastatic or locally recurrent unresectable invasive breast cancer. ER, progesterone receptor (PR) and HER2 measurements should be performed according to institutional guidelines, in a Clinical Laboratory Improvement Act (CLIA)-approved setting. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines
• Participants must have measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Participants must have radiological or objective evidence of progression on any cyclin-dependent kinase (CDK) 4/6 inhibitor-containing regimen in the metastatic setting, and/or relapse/progression during or within 12 months of completion of any CDK4/6 inhibitor-containing regimen in the adjuvant setting. It is not mandatory to have a CDK4/6 inhibitor-containing regimen as the most recent treatment
• Participants must have progressed on no more than two prior cytotoxic chemotherapy regimens (including antibody-drug conjugates with a cytotoxic payload) in the metastatic setting. Biologics, non-cytotoxic therapy, targeted therapy, and immunotherapy will not be considered prior lines. For both the phase I and phase II portions of the trial, there is no limit on prior lines of endocrine therapy in the adjuvant or metastatic setting. In Phase 2 only: progression on prior fulvestrant is required
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 (Karnofsky > 50%)
• Absolute neutrophil count >= 1.5 x 10^9/L
• Platelets >= 75,000/ul
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5mg/dL (=< 3.0mg/dL in patients with known Gilbert syndrome)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN)
• Adequate renal function with a creatinine clearance rate of >= 50 mL/min as calculated by the Cockcroft-Gault formula
• International normalized ratio (INR) =< 1.5 and partial thromboplastin time (PTT) =< 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation
• Creatine phosphokinase (CPK) =< 2.5 x ULN
• Adequate cardiac function with left ventricular ejection fraction >= 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan
• Baseline corrected QT (QTc) interval < 480 ms using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a complete or incomplete right or left bundle branch block
• Adequate recovery from toxicities related to prior systemic treatments, surgery, or radiotherapy to at least Grade 1 by CTCAE v5.0 Exceptions include alopecia and peripheral neuropathy grade =< 2
• Age >= 18 years
• Men and pre- and postmenopausal women are eligible. Ongoing GNRH agonist is required in pre-menopausal women or male participants for at least 4 weeks prior to study entry. If men or pre-menopausal women have not received regular GNRH agonist for at least 4 weeks prior to study entry, these patients will be excluded
• Women of childbearing potential (WOCP) must have a negative serum or urine pregnancy test performed within 7 days of cycle 1 (C1) day 1 (D1). Pregnancy testing does not need to be pursued in female participants who are: * Age > 60 years; or * Age < 60 years with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; or * Status post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
• WOCP, including women who are made postmenopausal through use of GNRH agonists, must agree to use an adequate method of contraception for at least 30 days after the last dose of abemaciclib or avutometinib (VS-6766) and for one year after the last dose of fulvestrant
• Males who are sexually active with WOCP must agree to follow instructions for method(s) of contraception for the duration of study treatment and for 90 days after the last dose of abemaciclib or avutometinib (VS-6766) and for one year after the last dose of fulvestrant. Males must agree not to donate sperm for the duration of protocol treatment and for at least 90 days after the last dose of protocol therapy
• For Phase 2 only: Participants must be willing to undergo a research biopsy at baseline and on-treatment. If biopsy is not feasible or safe, permission must be obtained from the Dana-Farber Cancer Institute (DFCI) sponsor-investigator to forgo the mandatory research biopsies. Formal eligibility exception would not be required in these circumstances. Biopsies are optional in Phase 1
• Participants must be able to swallow and retain oral medication
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Participants with active brain metastases or with known carcinomatous meningitis are excluded. Stable, treated brain metastases are allowed (this includes participants who have previously received local therapy including radiotherapy +/- surgery to their brain metastases, and do not require systemic steroids for management of symptoms from CNS metastatic lesions). Any patients with documented brain metastasis not meeting above criteria for stable treated brain metastasis are considered to have active brain metastases
• Phase I: Participants who have discontinued prior abemaciclib for toxicity, at any dose
• Phase II: Participants who have discontinued prior abemaciclib for toxicity, if that toxicity occurred at or above 100 mg BID (the dose of abemaciclib that is incorporated into phase II of this trial)
• Participants who have discontinued prior fulvestrant for toxicity
• Prior treatment with any MEK inhibitor
• In a participant with known tumor genomic profiling which shows clear Rb loss, enrollment is not recommended (though is not prohibited). Knowledge of tumor genomic profiling is not required for study eligibility
• Participants who have received another investigational agent within at least 30 days or 5 half-lives of the first dose of study drug, whichever is shorter, or is currently enrolled in any medical device research or other research that is judged by the sponsor to not be scientifically or medically compatible with this study
• Participants who have received a chemotherapy agent or immunotherapy within 21 days of the first dose of study drug
• Participants who have received an endocrine or biologic agent within 14 days of the first dose of study drug
• Participants who have completed radiation within 14 days of the first dose of study drug. If radiation was to the brain, participants are excluded if they completed radiation within 28 days of the first dose of study drug. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy
• Participants who have had major surgery within 14 days of the first dose of study drug
• Participants with the following pre-existing ocular pathology are excluded: * Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes * Patients 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 * Patients 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
• History of rhabdomyolysis or neuromuscular disorders that are associated with elevated CK (eg inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association Class III or IV), active ischemic heart disease, myocardial infarction within the previous six months, syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), uncontrolled diabetes mellitus, severe obstructive pulmonary disease, or severe chronic liver or renal disease, or sudden cardiac arrest
• Individuals with a history of a second malignancy are ineligible except for the following circumstances * Individuals with a history of other malignancies are potentially eligible if they have been disease-free for at least 5 years and are deemed by the treating investigator to be at low risk for recurrence of that malignancy * Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years and there is no evidence of disease recurrence for 1 year or more since completion of appropriate therapy: cervical cancer in situ, and non-melanoma cancer of the skin * Patients with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the sponsor-investigator to determine eligibility
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib (VS-6766) (including inactive ingredients mannitol, magnesium stearate, HPMC [hydroxypropylmethylcellulose] shells), abemaciclib, or fulvestrant
• Known history of testing positive for human immunodeficiency virus (HIV) with history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, or need to receive combination antiretroviral therapy for HIV that are strong CYP3A4 inhibitors or inducers
• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (for example, hepatitis B surface antigen positive). Testing is not required for enrollment. Patients with chronic HBV infection who meet criteria for anti-HBV therapy should be on suppressive antiviral therapy prior to initiation of study therapy. Patients with a history of HCV infection will need to have completed curative antiviral treatment with HCV viral load below the limit of quantification. Patients with untreated HCV may be enrolled if the HCV is stable and if the patient is not at risk for hepatic decompensation. Patients that need to receive antiviral therapy for HBV or HCV that are strong CYP3A4 inhibitors or inducers will be excluded
• Participants exposed to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with avutometinib within 5 half-lives (if known), or 14 days prior to the first dose of study drug, including: * Strong CYP3A4 inhibitors or inducers * Strong CYP2C9 inhibitors or inducers * P-glycoprotein (P-gp) inhibitors or inducers * Strong breast cancer resistance protein (BCRP) inhibitors or inducers
• Pregnant women are excluded from this study because effect of combination VS-766, abemaciclib, and fulvestrant on a developing fetus is unknown. Breastfeeding should be discontinued prior to entry onto the study
• Participants with the inability to swallow oral medications, impaired gastrointestinal absorption due to gastrectomy or other major surgical resection involving the stomach or small bowel, preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or other medical issue that would impact absorption of oral medication in the opinion of the investigator are excluded
• Participants with active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), or fungal infection (requiring IV antifungal treatment at time of initiating study treatment), or severe acute respiratory syndrome from coronavirus 2 (SARS-Cov2) infection =< 28 days prior to first dose of study treatment
• Participants on treatment with warfarin are excluded. Individuals on treatment with warfarin must be transitioned to anticoagulation instead with low-molecular-weight heparin or a direct oral anticoagulant prior to first dose of study treatment
• Participants with any other serious and/or uncontrolled preexisting medical condition(s) (e.g. interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, other cardiac, gastrointestinal, pulmonary, psychiatric, neurological, or genetic conditions, etc.) that in the opinion of the Investigator would place the patient at unacceptably high risk for toxicity and therefore preclude participation in this study