CB-103 combined with lenvatinib or abemaciclib for NOTCH-activated adenoid cystic carcinoma

A Phase 1/2 Study of CB-103 (Oral Pan-NOTCH Inhibitor) With Abemaciclib or Lenvatinib in Combination in Patients With NOTCH Activated Adenoid Cystic Carcinoma (CALCulus)

This study tests whether combining the NOTCH inhibitor CB-103 with either lenvatinib or abemaciclib can slow tumor growth in adults with NOTCH-activated advanced or metastatic adenoid cystic carcinoma.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Dana-Farber Cancer Institute (other)
• Drugs / interventions: Lenvatinib, chemotherapy
• Locations: 1 site (Boston, Massachusetts)
• Trial ID: NCT05774899 on ClinicalTrials.gov

What this trial studies

This is a phase 1/2, open-label, non-randomized, parallel-cohort multicenter trial of the pan-NOTCH inhibitor CB-103 given with either the CDK4/6 inhibitor abemaciclib (cohort 1) or the VEGFR tyrosine kinase inhibitor lenvatinib (cohort 2) in patients with advanced, incurable, or metastatic adenoid cystic carcinoma that harbors activating NOTCH mutations. About 32 adults will be enrolled and assigned to one of the two oral combination cohorts. Participants undergo molecular screening for NOTCH activation, regular radiologic tumor scans, blood tests, and safety monitoring, and treatment continues until progression, unacceptable toxicity, or withdrawal for up to roughly two years. The trial collects safety and efficacy outcomes to see if these combinations slow tumor growth and are tolerable in this population.

Who should consider this trial

Good fit: Adults (≥18) with recurrent, metastatic, or otherwise incurable adenoid cystic carcinoma that has an activating NOTCH pathway mutation and who meet cohort-specific prior-treatment requirements are the intended candidates.

Not a fit: Patients without a NOTCH activating mutation, those with disease amenable to curative therapy, or individuals who cannot take oral kinase inhibitors or meet safety criteria are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, these combinations could slow tumor growth, delay disease progression, and potentially extend survival or time without symptoms for patients with NOTCH-activated ACC.

How similar studies have performed: Lenvatinib has shown some activity in prior ACC studies and CDK4/6 inhibitors have limited data in ACC, while pan-NOTCH inhibition with agents like CB-103 is a novel approach that has not yet been proven in this disease.

Eligibility criteria

Participants must meet the following eligibility criteria at the time of screening to be eligible to participate in the study:

Eligibility Criteria

1. Participants must have histologically confirmed adenoid cystic carcinoma (ACC) with evidence of recurrent, metastatic or advanced, incurable disease arising from any primary site
2. Activating mutation in the NOTCH signaling pathway
3. In Cohort 1 only, prior multitargeted VEGFR TKI or systemic therapy is permitted.
4. In Cohort 2 only, no prior multitargeted VEGFR TKI therapy is permitted, but prior systemic chemotherapy as part of definitive or curative intent management is permitted.

   a. 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.
5. Age 18 years or older
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
7. Patients able and willing to swallow oral capsules or tablet medications.
8. At least one measurable lesion (RECIST v1.1)
9. Participant must have organ and marrow function as defined below within 14 days prior to study registration (ULN=upper limit of normal per institution):

   Absolute neutrophil count (ANC) ≥1.5 x 109/L Hemoglobin (Hgb) ≥9 g/dL (patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion).

   Platelet count ≥100 x 109/L (without transfusion within the last 5 days) Serum creatinine ≤1.5x ULN or serum creatinine clearance (CrCl) ≥50 mL/min (estimated by Cockcroft-Gault formula) Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x ULN Total serum bilirubin ≤1.5x ULN (patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted).
10. 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
11. Participants with treated brain or 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.
12. Female subjects of childbearing potential should have a negative serum pregnancy test within 7 days before start of study treatment.
13. 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 (see Appendix B).
14. 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.
15. 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

1. Participant has untreated or clinically symptomatic CNS metastases and/or carcinomatous meningitis
2. The patient has had major surgery within 14 days prior to study registration.
3. 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).
4. Impairment of 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)
5. 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.
6. 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
7. 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.
8. 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 INR monitoring (such as warfarin). The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, 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.
9. Corrected QTcF \>450 msec for males and \>470 msec for females in screening

Where this trial is running

Boston, Massachusetts

• Dana Farber Cancer Institute — Boston, Massachusetts, United States (RECRUITING)

Study contacts

• Principal investigator: Glenn Hanna, MD — Dana-Farber Cancer Institute
• Study coordinator: Glenn Hanna, MD

Conditions: Adenoid Cystic Carcinoma, Metastatic Adenoid Cystic Carcinoma, Recurrent Adenoid Cystic Carcinoma, ACC