A Phase 1/2 Study CB-103 With or Without Venetoclax in Patients With NOTCH ACC

• Status: Not yet recruiting
• Trial end date: 2026-06-01
• Target enrollment: 0
• Participant gender: All

Summary

The goal of this study is to treat patients with NOTCH active advanced adenoid cystic carcinoma (ACC) tumors with a combination or two different oral medications to slow tumor growth and improve survival outcomes.

The names of the study drugs involved in this study are:

• CB-103 (an oral NOTCH pathway inhibitor)

• Venetoclax (a BCL-2 inhibitor)

• Lenvatinib (a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI))

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Glenn J. Hanna
• Collaborators: Adenoid Cystic Carcinoma Research Foundation; Cellestia Biotech AG
• Treatments: Lenvatinib; Venetoclax

Criteria

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.

• In Cohort 1 only, patients must be treatment-naïve to systemic therapy for recurrent, metastatic ACC (prior systemic chemotherapy as part of definitive or curative intent management is permitted).

• 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 (RECIST v1.1)

• 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 neutronphil count (ANC) ≥1 x 109/L

• Hemoglobin (Hgb) ≥9 g/dL

• Platelet count ≥75 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) ≤2.5x ULN; if liver function abnormalities are due to underlying malignancy and known hepatic metastases, then AST and ALT must be ≤5x ULN

• Total serum bilirubin ≤1.5x ULN

• 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 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 (see Appendix B).

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.

Exclusion Criteria:

• Participant has untreated or clinically symptomatic CNS metastases and/or carcinomatous meningitis

• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or an unstable cardiac arrhythmia

• 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)

• 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.

• Radiation therapy within 1 week of initial study drug dosing, unless the radiation comprised a limited field to a non-visceral structure (e.g. bone metastasis)

• Patients on anticoagulants that require INR monitoring (such as warfarin)

• Corrected QTcF >450 msec for males and >470 msec for females in screening