CB-103 and Abemaciclib or Lenvatinib for the Treatment of Recurrent, Metastatic, or Advanced Adenoid Cystic Carcinoma with Activating NOTCH mutation

Inclusion Criteria

• Participants must have histologically confirmed adenoid cystic carcinoma (ACC) with evidence of recurrent, metastatic or advanced, incurable disease arising from any primary site
• Activating mutation in the NOTCH signaling pathway
• COHORT 1: In Cohort 1 only, patients must be treatment-naive to systemic therapy for recurrent, metastatic ACC (prior systemic chemotherapy as part of definitive or curative intent management is permitted)
• COHORT 2: In Cohort 2 only, prior multitargeted VEGFR TKI therapy (single agent) with lenvatinib as the only treatment for recurrent, metastatic ACC, and received immediately prior therapy before enrollment; the patient should have remained on lenvatinib for 12 weeks or longer and achieved clinical benefit at some point during therapy (response or stability) prior to documented disease progression. Prior systemic chemotherapy as part of definitive or curative intent management is permitted. * Any participant must obtain prior approval from insurance to reimburse for oral lenvatinib, or off-label drug assistance to secure lenvatinib for the duration of the study or agree to self-pay for oral lenvatinib or obtain institutional commitment from the study site to provide lenvatinib
• Age 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Patients able and willing to swallow capsules or tablets
• At least one measurable lesion (Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 14 days prior to study registration)
• Hemoglobin (Hgb) >= 9 g/dL (within 14 days prior to study registration)
• Platelet count >= 100 x 10^9/L (without transfusion within the last 5 days) (within 14 days prior to study registration)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 50 mL/min (estimated by Cockcroft-Gault formula) (within 14 days prior to study registration)
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN
• Total serum bilirubin =< 1.5 x ULN (within 14 days prior to study registration) (patients with Gilbert’s syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted)
• COHORT 2: Baseline proteinuria with a urinalysis or urine dipstick value of 2+ requires a spot urine protein/creatinine ratio of < 0.3 (or 24-hour urine collection protein value < 300 mg/g) in Cohort 2 only
• Participants with treated brain or central nervous system (CNS) metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no convincing evidence of progression and patients are neurologically stable with no new neurological deficits
• Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 7 days before start of study treatment
• Female and male subjects of childbearing potential must agree to use an adequate method of contraception to avoid pregnancy (with at least 99% certainty) from screening through 90-days or 3-months post-treatment completion
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients who received chemotherapy must have recovered (CTCAE grade ≤ 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy. A washout period of at least 21 days is required between last chemotherapy dose and start of therapy (provided the patient did not receive radiotherapy)

Exclusion Criteria

• Participant has untreated or clinically symptomatic CNS metastases and/or carcinomatous meningitis
• The patient has had major surgery within 14 days prior to study registration
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea)
• Impairment of gastrointestinal (GI) function or presence of GI disease that may significantly alter the absorption of the study agents (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C (for example, hepatitis B surface antigen positive). Screening is not required for enrollment
• The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
• Pregnant or lactating women. Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued
• Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and start of therapy. Patients on anticoagulants that require international normalized ratio (INR) monitoring (such as warfarin)
• The patient has received an experimental treatment in a clinical trial within the last 21 days, or is currently enrolled in any other type of medical research judged by the sponsor not to be scientifically or medically compatible with this study