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

Sponsor

Glenn J. Hanna (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05774899

Collaborator

Adenoid Cystic Carcinoma Research Foundation (Other), Cellestia Biotech AG (Industry)

Enrollment

Location

Arms

37.6

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief 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))

Condition or Disease	Intervention/Treatment	Phase
Adenoid Cystic Carcinoma Metastatic Adenoid Cystic Carcinoma Recurrent Adenoid Cystic Carcinoma	Drug: CB-103 Drug: Venetoclax Drug: Lenvatinib	Phase 1/Phase 2

Detailed Description

This is a phase 2, open-label, non-randomized, parallel cohort, multicenter study investigating the novel pan-NOTCH inhibitor, CB-103, in combination with the BCL2 inhibitor, Venetoclax, and CB-103 in combination with the multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), Lenvatinib for patients with advanced, incurable, or metastatic adenoid cystic carcinoma (ACC) with a Notch pathway activating mutation.

Participants will be placed into one of two treatment groups: Cohort 1: CB-103 + Venetoclax or Cohort 2: VEGFR TKI Lenvatinib + CB-103. Cohort 1 will enroll participants who have not received treatment for ACC while Cohort 2 will enroll participants immediately after receiving Lenvatinimb and after showing prior disease progression.

The U.S. Food and Drug Administration (FDA) has not approved CB-103 as a treatment for any disease.

The FDA has not approved Venetoclax or Lenvatinib for advanced adenoid cystic carcinoma (ACC)), but it has been approved for other uses or cancer types.

Study procedures include screening for eligibility, treatment visits, radiologic scans of tumors, and blood tests.

Participation in this study is expected to last about 2 years or until disease progression, therapy intolerance, or participant withdrawal.

It is expected that about 32 people will take part in this research study.

Cellestia Biotech AG is supporting this research study by providing funding.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

34 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Study of CB-103 (Oral Pan-NOTCH Inhibitor) With or Without Venetoclax in Patients With NOTCH Activated Adenoid Cystic Carcinoma (ACC)

Anticipated Study Start Date :

Apr 15, 2023

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental: Cohort 1A - CB-103 + Venetoclax (Ramp-Up) A modified 3+3 dose escalation design will be used. 3-9 participants will receive: Cycle 1 Days 1 - 28 of 28-day cycle: Predetermined dose of CB-103 2x daily on five consecutive days followed by two days of treatment break in each treatment week. Days 8 - 28 of 28-day cycle: Predetermined dose of Venetoclax 1x daily. A safety review will be performed by primary investigation after completion of the ramp-up phase.	Drug: CB-103 First-in-class pan-NOTCH inhibitor, capsule taken orally. Drug: Venetoclax BCL-2 inhibitor, tablet taken orally. Other Names: Venclexta and Venclyxto
Experimental: Experimental: Cohort 1B - CB-103 + Venetoclax Participants will receive: Cycle 1 - End of Treatment --Days 1- 28 of 28-day cycle: Predetermined dose of CB-103 2x daily on five consecutive days followed by two days of treatment break in each treatment week and predetermined dose of Venetoclax 1x daily. Therapy will continue until disease progression, therapy intolerance, or participant withdrawal. End of Treatment (EOT) visit within 30 days of last administration of study treatments.	Drug: CB-103 First-in-class pan-NOTCH inhibitor, capsule taken orally. Drug: Venetoclax BCL-2 inhibitor, tablet taken orally. Other Names: Venclexta and Venclyxto
Experimental: Experimental: Cohort 2A- Lenvatinib + CB-103 A modified 3+3 dose escalation design will be used. 3-9 participants will receive: Continue standard of care VEGFR TKI at prior dose and schedule. Cycle 1 - End of Treatment --Days 1- 28 of 28-day cycle: Predetermined dose of CB-103 2x daily on five consecutive days followed by two days of treatment break in each treatment week. A safety review will be performed by primary investigation after completion of the ramp-up phase.	Drug: CB-103 First-in-class pan-NOTCH inhibitor, capsule taken orally. Drug: Lenvatinib Per standard care, capsule taken orally. Other Names: Lenvima
Experimental: Experimental: Cohort 2B- Lenvatinib + CB-103 Participants will receive: Continue standard of care VEGFR TKI at prior dose and schedule. Cycle 1 - End of Treatment --Day 1- 28 of 28-day cycle: Predetermined dose of CB-103 2x daily on five consecutive days followed by two days of treatment break in each treatment week. Therapy will continue until disease progression, therapy intolerance, or participant withdrawal. End of Treatment (EOT) visit within 30 days of last administration of study treatments.	Drug: CB-103 First-in-class pan-NOTCH inhibitor, capsule taken orally. Drug: Lenvatinib Per standard care, capsule taken orally. Other Names: Lenvima

Outcome Measures

Primary Outcome Measures

Progression-Free Survival (PFS) of Cohort 1 [At 4 months]
Progression-Free Survival (PFS) is defined as the time from study registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Median PFS will be estimated via the Kaplan-Meier method to estimate all time-to-event endpoints with corresponding 95% confidence intervals (CI) for the median or time-specific event time
Progression-Free Survival (PFS) of Cohort 2 [At 4 months]
Progression-Free Survival (PFS) is defined as the time from study registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.

Secondary Outcome Measures

Number of Participants with treatment related Adverse Events per CTCAE 5.0 [Up to 2 years]
Assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Overall Response Rate (ORR) [From enrollment to end of treatment up to 2 years]
Per RECIST v1.1
Overall Survival (OS) [Up to 2 years]
Overall Survival (OS) is defined as the time from study registration to death due to any cause, or censored at date last known alive.
Duration of Overall Response (DOR) [Up to 2 years]
The duration of overall response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented. Participants without events reported are censored at the last disease evaluation).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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