Copanlisib + Venetoclax for Mantle Cell Lymphoma

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inhibitors, Corticosteroids

Disqualifiers: HIV, Hepatitis B/C, Cardiovascular, others

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

Compensation: Varies

Number of Visits: 6

Duration: Up to 2 years

8 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects, best dose, and effectiveness of copanlisib and venetoclax in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Copanlisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving copanlisib and venetoclax may help treat patients with mantle cell lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take medications or foods that strongly affect CYP3A4 within 7 days of starting the study treatment, and you cannot be on high-dose corticosteroids.

What data supports the effectiveness of the drug combination Copanlisib and Venetoclax for treating Mantle Cell Lymphoma?

Venetoclax has shown effectiveness in treating Mantle Cell Lymphoma (MCL) when combined with other drugs, achieving high response rates and minimal residual disease clearance in patients. Additionally, Venetoclax has been effective in treating other types of blood cancers, such as chronic lymphocytic leukemia, with good response rates and safety profiles. ^{1 2 3 4 5}

Is the combination of Copanlisib and Venetoclax safe for treating Mantle Cell Lymphoma?

Venetoclax has been generally well tolerated in patients with various types of non-Hodgkin lymphoma, including mantle cell lymphoma, with most side effects being mild to moderate. Common serious side effects include low blood cell counts, which can be managed with supportive care and dose adjustments. ^{1 3 4 6 7}

What makes the drug combination of Copanlisib and Venetoclax unique for treating Mantle Cell Lymphoma?

The combination of Copanlisib and Venetoclax is unique because it targets specific proteins involved in cancer cell survival, potentially offering a new approach for treating Mantle Cell Lymphoma, a condition with limited standard treatment options. Venetoclax is known for its ability to inhibit BCL-2, a protein that helps cancer cells survive, while Copanlisib targets different pathways, which may enhance the overall effectiveness of the treatment. ^{1 2 4 6 8}

Research Team

Alexey Danilov

Principal Investigator

City of Hope Medical Cneter

Eligibility Criteria

This trial is for adults with mantle cell lymphoma that has returned or isn't responding to treatment. Participants must be able to take pills, have a life expectancy of at least 3 months, and proper organ function. They should not have HIV, hepatitis B or C, uncontrolled diseases like diabetes or heart conditions, and women must not be pregnant.

Inclusion Criteria

You are able to swallow pills or take medication by mouth.

Your doctor believes you will live for at least 3 more months.

Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)

Exclusion Criteria

You have already been treated with venetoclax or other experimental drugs that target BCL2, or with copanlisib.

- All other chemotherapy, radiation therapy within 30 days prior to initiation of therapy

- Targeted therapy within 6 half-lives

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive copanlisib intravenously on days 1, 8, and 15, and venetoclax orally daily on days 1-28. Treatment repeats every 28 days for up to 26 cycles.

Up to 2 years

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months for 2 years.

2 years

Every 3 months

Treatment Details

Interventions

• Copanlisib Hydrochloride
• Venetoclax

Trial Overview The trial is testing the combination of two drugs: Copanlisib Hydrochloride and Venetoclax. It aims to find the safest doses and see how effective they are against relapsed or refractory mantle cell lymphoma by blocking enzymes and proteins cancer cells need to grow.

Participant Groups

Group I: Treatment (copanlisib hydrochloride, venetoclax) Experimental Treatment 2 Interventions

Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15, and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Copanlisib will be given at 30mg, 45mg, or 60 mg depending on the assigned dose level. Venetoclax will have a weekly dose ramp up from 20mg, 50mg, 100mg, 200mg, and then 400mg thereafter.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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 a multicenter study of 28 patients with untreated mantle cell lymphoma (MCL), the combination of lenalidomide, rituximab, and venetoclax demonstrated a high overall response rate of 96% and a complete response rate of 86%, indicating strong efficacy for this treatment regimen.

The treatment was found to be safe, with no dose-limiting toxicities reported, although common side effects included neutropenia and thrombocytopenia, suggesting that this combination could be a promising option for patients who are ineligible for transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Phillips, TJ., Bond, D., Takiar, R., et al.[2023]

In a phase I trial involving 106 patients with various subtypes of non-Hodgkin lymphoma, venetoclax, a BCL-2 inhibitor, was found to be generally well tolerated, with a 44% overall response rate across different lymphoma types.

The study identified 1,200 mg as the recommended dose for future studies in follicular lymphoma and diffuse large B-cell lymphoma, while 800 mg was effective for mantle cell lymphoma, indicating varying efficacy based on lymphoma subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. Davids, MS., Roberts, AW., Seymour, JF., et al.[2018]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[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 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, a BCL-2 antagonist, is effective in treating chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML), but many patients eventually develop resistance to the treatment.

Understanding the mechanisms of resistance to venetoclax is crucial for developing new combination therapies, which are currently being tested in clinical trials to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to venetoclax resistance is paved with mutations, metabolism, and more. Sullivan, GP., Flanagan, L., Rodrigues, DA., et al.[2023]

References

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

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

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

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. [2023]

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

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. [2019]

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

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. [2018]

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

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

Venetoclax: First Global Approval. [2018]

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

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

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

The path to venetoclax resistance is paved with mutations, metabolism, and more. [2023]