Venetoclax + Tocilizumab for Multiple Myeloma

Overseen By Jonathan L. Kaufman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Acute infection, Cardiovascular disability, Active malignancies, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 21 days per cycle

72 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial finds out the best dose and side effects of venetoclax and tocilizumab in treating patients with t(11;14) multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Tocilizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Tocilizumab is used to treat side effects from immune therapy in patients with myeloma. Giving venetoclax and tocilizumab may kill more cancer cells.

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

The trial requires that you stop taking any ongoing anti-myeloma therapy and certain medications like strong or moderate CYP3A inhibitors or inducers at least 7 days before starting the study drug. Additionally, you should not have received any anti-myeloma therapy within 14 days prior to the first dose.

What data supports the effectiveness of the drug combination Venetoclax and Tocilizumab for treating multiple myeloma?

Venetoclax has shown promising results in treating relapsed or refractory multiple myeloma, especially in patients with a specific genetic feature called t(11;14), with high response rates and improved survival outcomes. While Tocilizumab is not specifically mentioned in the context of multiple myeloma, it is known for its role in reducing inflammation, which might complement Venetoclax's effects. ^{1 2 3 4 5}

Is the combination of Venetoclax and Tocilizumab generally safe for humans?

Tocilizumab has been used safely in patients with rheumatoid arthritis, but it can cause side effects like changes in blood lipid levels and blood-related issues. There is no specific safety data available for the combination of Venetoclax and Tocilizumab, but Tocilizumab alone has a known safety profile in other conditions. ^{6 7 8 9 10}

What makes the drug Venetoclax unique for treating multiple myeloma?

Venetoclax is unique because it targets a specific protein called BCL-2, which helps cancer cells survive, and is particularly effective in multiple myeloma patients with a specific genetic feature called t(11;14) translocation. This makes it different from other treatments that may not target this protein or genetic feature. ^{2 3 4 11 12}

Research Team

Jonathan L. Kaufman, MD

Principal Investigator

Emory University

Eligibility Criteria

Adults with relapsed or refractory multiple myeloma characterized by t(11;14) translocation, who have tried at least three prior therapies including a proteasome inhibitor, an IMiD agent, and a CD38 monoclonal antibody. Participants must not be pregnant or breastfeeding, should have adequate organ function and no recent significant medical conditions or treatments that could interfere with the study.

Inclusion Criteria

I can perform daily activities with minimal assistance.

I am a woman who is either postmenopausal, cannot have children, or I am using birth control as specified.

I have multiple myeloma, treated with 3+ therapies including a proteasome inhibitor, an IMiD agent, and a CD38 antibody, and positive for t(11;14).

Exclusion Criteria

I have not had any active cancers in the last 3 years, except for certain skin cancers, low-grade prostate cancer, or cancers that were completely removed or treated.

I do not have any major health issues like heart problems or infections that are not under control.

You have eaten grapefruit, Seville oranges, or star fruit within 3 days before taking the study drug.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive tocilizumab intravenously on day -7 of cycle 1, and on day 1 of subsequent cycles. Patients also receive venetoclax orally on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks, then every 6 months

1 visit (in-person) after treatment, then biannual follow-ups

Treatment Details

Interventions

• Tocilizumab
• Venetoclax

Trial Overview The trial is testing the combination of Venetoclax and Tocilizumab to determine the optimal doses and potential side effects in patients whose multiple myeloma has returned after treatment or hasn't responded to previous therapy. Venetoclax targets proteins essential for cancer cell survival while Tocilizumab may prevent tumor growth.

Participant Groups

Group I: Treatment (venetoclax, tocilizumab) Experimental Treatment 2 Interventions

Patients receive tocilizumab IV on day -7 of cycle 1, and on day 1 of subsequent cycles. Patients also receive venetoclax PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Venetoclax is already approved in United States, European Union for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Venetoclax, a BCL-2 inhibitor recently approved for chronic lymphocytic leukemia, shows promise in treating relapsed multiple myeloma (MM), particularly in patients with the t(11;14) genetic alteration, which is associated with high BCL-2 expression.

Current phase 1/2 clinical trials indicate that venetoclax not only improves outcomes for patients with t(11;14) but also has potential efficacy in a broader range of relapsed MM cases, paving the way for more personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for the treatment of multiple myeloma. Vaxman, I., Sidiqi, MH., Gertz, M.[2019]

In a phase I study involving 48 patients with relapsed or refractory multiple myeloma (RRMM), the combination of venetoclax with daratumumab and dexamethasone (VenDd) showed a remarkable overall response rate of 96%, indicating its strong efficacy, especially in patients with the t(11;14) translocation.

The combination of venetoclax with bortezomib, daratumumab, and dexamethasone (VenDVd) also demonstrated significant efficacy, with a 92% overall response rate, and an 18-month progression-free survival rate of 66.7%, suggesting that these combinations could provide durable responses in RRMM treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). Bahlis, NJ., Baz, R., Harrison, SJ., et al.[2022]

In a review of 7 clinical trials involving 482 patients with relapsed/refractory multiple myeloma, venetoclax demonstrated a high overall response rate of 76%, indicating it is an effective treatment option.

The study found that while venetoclax is associated with some adverse events, the overall rate of severe adverse events (Grade 3 or higher) was 84%, suggesting that while it is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. Gao, X., Zeng, H., Zhao, X., et al.[2023]

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 a study involving 58 multiple myeloma patients with the t(11;14) translocation, venetoclax demonstrated a high objective response rate of 94% in relapsed/refractory cases, with a median progression-free survival of 10.0 months and overall survival of 14.6 months.

Remarkably, venetoclax was also effective in patients with high-risk features, such as deletion 17p and renal failure, with 42% of renal failure cases improving, including some patients becoming dialysis independent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers. Szita, VR., Mikala, G., Kozma, A., et al.[2023]

In a study of 45 Costa Rican patients with rheumatoid arthritis who were unresponsive to other treatments, 48.9% achieved clinical remission after 3 months of treatment with intravenous tocilizumab (4mg/kg), and this increased to 75% by 12 months.

The treatment was found to be safe, with a low incidence rate of serious adverse events (0.98 per 100 patients/year), all related to infections but with no fatal outcomes reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis. Cordero-Alfaro, M., León-Céspedes, C., Ramos-Esquivel, A.[2021]

In a study of 88 rheumatoid arthritis patients treated with tocilizumab, specific genetic variations (SNPs) in the IL6R gene were linked to certain adverse effects, such as dyslipidemia and hematological issues.

These findings suggest that SNPs in the IL6R gene could serve as potential biomarkers to predict the risk of tocilizumab toxicity, which may help personalize treatment strategies for patients with rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis. Sainz, L., Riera, P., Moya, P., et al.[2023]

In a study analyzing 274,693 adverse drug reactions (ADRs) from the European EudraVigilance database, rivaroxaban and dabigatran were found to have significantly higher risks of gastrointestinal ADRs compared to apixaban and vitamin K antagonists (VKAs).

All tested anticoagulants increased the risk of vascular disorders, but none showed a significant increase in the risk of adverse reactions related to the nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of adverse drug reactions among direct-acting oral anticoagulants and vitamin K antagonists using the EudraVigilance database. Pardo-Cabello, AJ., Manzano-Gamero, V., Luna, JD.[2023]

Tocilizumab, an interleukin-6 receptor antagonist, has shown significant clinical improvements in rheumatoid arthritis patients at doses greater than 4 mg/kg, with the most effective dose being 8 mg/kg, which also reduces joint damage as seen in radiographic measures.

While tocilizumab is effective, it is associated with common adverse effects such as liver function abnormalities, infections, and neutropenia, highlighting the need for further research to better understand its safety profile and optimal use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. Plushner, SL.[2016]

Pharmacogenomic studies have identified specific genetic markers, such as certain HLA alleles, that are strongly associated with severe adverse drug reactions (ADRs), which can help predict and prevent these unpredictable reactions in patients.

Understanding these genetic markers can lead to personalized medicine approaches, allowing healthcare providers to avoid prescribing drugs that may cause severe ADRs based on a patient's genetic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice. Wang, CW., Preclaro, IAC., Lin, WH., et al.[2022]

Venetoclax, when combined with carfilzomib and dexamethasone, showed rapid initial effectiveness in two patients with multiple myeloma harboring the t(11,14)(q13;q32) genetic alteration, but the responses were short-lived, indicating a need for ongoing monitoring and potential adjustments in treatment.

The emergence of the t(11;14)(q13;q32) alteration during the disease progression highlights the importance of regular cytogenetic testing in multiple myeloma, as it can influence treatment strategies and outcomes in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory multiple myeloma harboring t(11,14)(q13;q32): two case reports and a review of the literature. Abuelgasim, KA., Alherz, N., Alhejazi, A., et al.[2021]

In a phase 3 trial involving 291 patients with relapsed or refractory multiple myeloma, venetoclax combined with bortezomib and dexamethasone significantly improved progression-free survival compared to placebo, with a median of 22.4 months versus 11.5 months (hazard ratio 0.63).

Despite its efficacy, the venetoclax group experienced higher rates of serious treatment-emergent adverse events, particularly infections, leading to increased mortality, which underscores the need for careful patient selection for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Kumar, SK., Harrison, SJ., Cavo, M., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax for the treatment of multiple myeloma. [2019]

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

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). [2022]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. [2023]

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

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

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

Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers. [2023]

6. Spain pubmed.ncbi.nlm.nih.gov

Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Comparative study of adverse drug reactions among direct-acting oral anticoagulants and vitamin K antagonists using the EudraVigilance database. [2023]

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

Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. [2016]

10. Switzerland pubmed.ncbi.nlm.nih.gov

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory multiple myeloma harboring t(11,14)(q13;q32): two case reports and a review of the literature. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. [2021]