CB-103 + Venetoclax for Advanced Cancer

Overseen By Glenn Hanna, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Glenn J. Hanna

Must not be taking: Anticoagulants

Disqualifiers: Untreated CNS metastases, Major surgery, Severe renal impairment, Active infections, Cardiovascular syncope, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: Up to 2 years or until disease progression, therapy intolerance, or participant withdrawal

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to treat advanced adenoid cystic carcinoma by testing combinations of oral medications, such as CB-103, which targets the NOTCH pathway involved in tumor growth. The goal is to determine if these treatments can slow tumor progression and improve survival rates. Participants will receive different medication combinations, including Lenvatinib or Abemaciclib, alongside CB-103, depending on the trial cohort. Ideal candidates have advanced adenoid cystic carcinoma with NOTCH pathway mutations and can take oral medications. As a Phase 1 and Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a required washout period of at least 21 days after chemotherapy and 14 days after radiotherapy before starting the trial treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is exploring how a combination of two drugs, CB-103 and lenvatinib, might treat advanced adenoid cystic carcinoma (ACC). Lenvatinib, already used for other cancers, is generally considered safe. Studies have shown lenvatinib's promise in treating certain cancers, though it can cause side effects like high blood pressure, diarrhea, and tiredness.

CB-103 is a new drug targeting the NOTCH pathway in cancer cells, which aids tumor growth. Researchers are still assessing the safety of CB-103 as it undergoes testing in trials like this one. Its study alongside lenvatinib means researchers are closely monitoring for any side effects.

Prospective participants should know that early studies primarily focus on ensuring treatment safety. Regular health check-ups will monitor and manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because CB-103 offers a fresh approach by targeting the Notch signaling pathway, which is crucial for cancer cell growth. This is different from most standard treatments for advanced cancers, which often focus on blocking hormones or using chemotherapy to kill rapidly dividing cells. The combination with Abemaciclib or Lenvatinib adds another layer by either inhibiting cell cycle progression or blocking receptor pathways involved in tumor growth. Together, these combinations are designed to tackle cancer from multiple angles, potentially leading to more effective results for patients.

What evidence suggests that this trial's treatments could be effective for advanced adenoid cystic carcinoma?

Research has shown that using CB-103 with lenvatinib, one of the combinations tested in this trial, might help treat adenoid cystic carcinoma (ACC) by targeting the NOTCH pathway, often active in these tumors. Lenvatinib has proven effective in various cancers, including ACC, by stopping the growth of blood vessels that tumors need. Studies suggest that CB-103 can enhance this effect by blocking the NOTCH signals that aid cancer growth.

Another approach in this trial combines CB-103 with abemaciclib. Abemaciclib targets proteins that help cancer cells multiply and has shown positive results in other cancers. Together with CB-103, this combination aims to block both growth signals and cell division, potentially controlling the tumor more effectively. These combinations aim to slow tumor growth and improve survival for patients with ACC. ^{1 3 6 7 8}

Who Is on the Research Team?

Glenn J. Hanna, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with advanced adenoid cystic carcinoma (ACC) that's NOTCH active. They should have good organ function, no severe illnesses, and agree to use effective contraception. Treatment-naïve patients or those who've had certain therapies can join specific cohorts.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I agree to use birth control during the study.

I have another cancer that won't affect this treatment's safety or results.

Exclusion Criteria

I currently have an active infection (bacterial, fungal, or viral).

I have finished radiotherapy and recovered from its immediate side effects.

I have brain metastases or carcinomatous meningitis that are untreated or causing symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive CB-103 in combination with either Abemaciclib or Lenvatinib in 28-day cycles

Up to 2 years or until disease progression, therapy intolerance, or participant withdrawal

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• CB-103
• Lenvatinib
• Venetoclax

Trial Overview The study tests CB-103 alone or combined with Venetoclax in treating ACC by inhibiting the NOTCH pathway and blocking BCL-2 protein. Lenvatinib targets VEGFR pathways. The aim is to slow tumor growth and improve survival.

How Is the Trial Designed?

Group I: Experimental: Cohort 2B- Lenvatinib + CB-103 Experimental Treatment 2 Interventions

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.

Group II: Experimental: Cohort 2A- Lenvatinib + CB-103 Experimental Treatment 2 Interventions

A modified 3+3 dose escalation design will be used. 3-9 participants will receive: * Standard of care VEGFR TKI. * 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.

Group III: Experimental: Cohort 1B - CB-103 + Abemaciclib Experimental Treatment 2 Interventions

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 Abemaciclib 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.

Group IV: Experimental: Cohort 1A - CB-103 + Abemaciclib Experimental Treatment 2 Interventions

A modified 3+3 dose escalation design will be used. 3-9 participants will receive: * Standard of care Abemaciclib. * 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.

Who Is Running the Clinical Trial?

Glenn J. Hanna

Lead Sponsor

Trials

6

Recruited

160+

Cellestia Biotech AG

Industry Sponsor

Trials

3

Recruited

90+

Adenoid Cystic Carcinoma Research Foundation

Collaborator

Trials

7

Recruited

160+

Published Research Related to This Trial

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[2018]

In a phase I clinical study involving patients with cervical cancer, the combination of irinotecan (CPT-11) and nedaplatin showed a 50% response rate, indicating potential efficacy in treating this type of cancer.

The maximum tolerated doses were determined to be 60 mg/m² for both CPT-11 and nedaplatin, with notable adverse effects including leukopenia and neutropenia, which were observed in a significant percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of combination chemotherapy using irinotecan hydrochloride and nedaplatin for advanced or recurrent cervical cancer. Machida, S., Ohwada, M., Fujiwara, H., et al.[2018]

In a study of 11 patients with advanced or metastatic colorectal cancer, the FOLFOX4 regimen showed a 0% response rate, while mFOLFOX6 had a 71% response rate as a first-line therapy, indicating that mFOLFOX6 is more effective.

Patients who responded to FOLFOX4/mFOLFOX6 or FOLFIRI had significantly longer survival times (7 to 27 months) compared to those who did not respond (4 to 8 months), suggesting that these treatments can be effective for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of fluorouracil, leucovorin plus oxaliplatin (FOLFOX4 and modified FOLFOX6) followed by fluorouracil, leucovorin plus irinotecan(FOLFIRI)for advanced or metastatic colorectal cancer--case studies. Ohtani, H., Arimoto, Y., Nishio, K., et al.[2016]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Lenvatinib (LEN) is an effective multikinase inhibitor used for treating certain types of cancer, but it often causes significant adverse events (AEs) like hypertension and diarrhea, which can lead to dose modifications or discontinuation of treatment.

A multidisciplinary approach to managing these AEs is crucial for maintaining treatment efficacy and patient safety, as it helps address the side effects that frequently arise during LEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature. Denaro, N., Latina, A., Cesario, F., et al.[2019]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The maximum tolerated dose (MTD) of lenvatinib when combined with carboplatin and paclitaxel for treating advanced non-small-cell lung cancer (NSCLC) is established at 4 mg taken twice daily, showing manageable side effects.

The treatment regimen resulted in a response rate of 68% and a median progression-free survival of 9.0 months, indicating promising antitumor activity in chemotherapy-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. Nishio, M., Horai, T., Horiike, A., et al.[2021]

A 71-year-old patient with recurrent cervical cancer who is a compound heterozygote for UGT1A1*6 and UGT1A1*28 experienced significant hematotoxicity (grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia) while receiving irinotecan hydrochloride (CPT-11) at a dose of 60 mg/m², indicating potential risks associated with this treatment in similar patients.

Despite the absence of previous case reports linking serious adverse events to CPT-11 in this genetic context, the observed severe side effects suggest that careful monitoring and dose adjustments are necessary for patients with these UGT1A1 variants undergoing combined chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. Takatori, E., Shoji, T., Miura, Y., et al.[2018]

Citations

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2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40684084/

Abemaciclib in combination with endocrine therapy for the ... Best tumor response was recorded in 78.2% (n = 136) of patients; 0.7% had complete response, 27.9% had partial response, 59.6% had stable ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12275406/

Abemaciclib in combination with endocrine therapy for the ... Best tumor response was recorded in 78.2% (n = 136) of patients; 0.7% had complete response, 27.9% had partial response, 59.6% had stable ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-04526

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5. dana-farber.org dana-farber.org/clinical-trials/23-011

A phase 1/2 study of CB-103 (oral pan-NOTCH inhibitor ... 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 ...

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CB-103 With Either Lenvatinib or Abemaciclib in Patients ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10361059/

Efficacy and safety of Lenvatinib-based combination ... Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC).

8. eisai.com eisai.com/news/2025/pdf/enews202551pdf.pdf

LENVIMA® (lenvatinib) in Combination with ... Eisai is committed to expanding the potential clinical benefits of lenvatinib for cancer treatment, as it seeks to contribute to addressing the ...