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

10 Participants Needed

Trial Summary

What is the purpose of this trial?

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) * Abemaciclib (CDK4/6 inhibitor) * Lenvatinib (a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI))

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.

What data supports the effectiveness of the drug Venetoclax for advanced cancer?

Venetoclax has shown effectiveness in treating chronic lymphocytic leukemia (CLL), achieving high response rates and improving progression-free survival when combined with other treatments. It is also being studied for use in other blood cancers, indicating its potential in treating various types of cancer. ^{1 2 3 4 5}

What safety data exists for CB-103 + Venetoclax in humans?

Lenvatinib, a component of the treatment, has been associated with side effects like high blood pressure, diarrhea, weight loss, and fatigue, which sometimes require stopping or adjusting the dose. These side effects have been observed in various cancers, indicating the need for careful monitoring during treatment. ^{6 7 8 9 10}

What makes the drug combination of CB-103, Lenvatinib, and Venetoclax unique for advanced cancer?

The combination of CB-103, Lenvatinib, and Venetoclax is unique because it targets cancer cells through multiple mechanisms: CB-103 inhibits a specific pathway involved in cancer cell growth, Lenvatinib blocks proteins that help tumors form blood vessels, and Venetoclax induces cancer cell death by targeting a protein that prevents apoptosis (programmed cell death). This multi-targeted approach may offer a novel treatment option for advanced cancers where standard treatments are limited. ^{11 12 13 14 15}

Research Team

Glenn J. Hanna, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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.

The patient has a personal history of specific cardiovascular conditions

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

2. New Zealand pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. [2018]

4. Cyprus pubmed.ncbi.nlm.nih.gov

Combination of Venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia: A case series from a single center. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]

6. England pubmed.ncbi.nlm.nih.gov

A randomized, open-label, single-dose, two-cycle crossover study to evaluate the bioequivalence and safety of lenvatinib and Lenvima® in Chinese healthy subjects. [2022]

7. Switzerland 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. [2019]

8. France pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. [2021]

10. Greece pubmed.ncbi.nlm.nih.gov

Leaky Gut and Severe Adverse Events in Advanced Hepatocellular Carcinoma Treated With Lenvatinib. [2022]

11. Japan 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. [2016]

12. United States pubmed.ncbi.nlm.nih.gov

Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. [2022]

13. Australia pubmed.ncbi.nlm.nih.gov

Effects of bolus injection of 5-fluorouracil on steady-state plasma concentrations of 5-fluorouracil in Japanese patients with advanced colorectal cancer. [2021]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Phase I study of combination chemotherapy using irinotecan hydrochloride and nedaplatin for advanced or recurrent cervical cancer. [2018]

15. Australia 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. [2018]