Copanlisib + Venetoclax for Mantle Cell Lymphoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments, copanlisib and venetoclax, for individuals with mantle cell lymphoma. The goal is to determine the optimal dose, understand side effects, and evaluate the effectiveness of these treatments for lymphoma that has returned or does not respond to other treatments. Copanlisib blocks certain enzymes to stop cancer cell growth, while venetoclax targets a protein that aids cancer cell survival. Individuals who have undergone at least one previous treatment for mantle cell lymphoma without improvement or who experienced disease progression might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

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

A previous study found that copanlisib was mostly well-tolerated by patients with recurring conditions, meaning the side effects were generally manageable. Importantly, no patients in this study died from treatment-related side effects.

Venetoclax, another treatment under investigation, also demonstrated promising safety results. In studies involving high-risk patients with relapsed mantle cell lymphoma, venetoclax achieved a 40% success rate in reducing the cancer. While effective, it can have side effects like any medication.

As this trial is in the early stages (Phase 1 and Phase 2), researchers are closely studying the treatments for safety in humans. Although initial findings are promising, this phase focuses on ensuring the treatments are safe and determining the best dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of copanlisib and venetoclax for treating Mantle Cell Lymphoma because these drugs work in unique ways compared to standard treatments like chemotherapy and immunotherapy. Copanlisib is a PI3K inhibitor, which targets and blocks the signaling pathways cancer cells use to grow and survive. Meanwhile, venetoclax is a BCL-2 inhibitor that works by triggering cancer cells to undergo programmed cell death. The combination of these two mechanisms offers a powerful one-two punch against the cancer, potentially overcoming resistance to existing therapies and providing new hope for patients with this condition.

What evidence suggests that copanlisib and venetoclax might be effective for mantle cell lymphoma?

Research has shown that venetoclax alone holds promise for treating mantle cell lymphoma (MCL), particularly in patients who have tried other treatments. For high-risk patients with relapsed MCL, venetoclax achieved a response rate of 40% and a median progression-free survival of 3.7 months. Copanlisib works differently by blocking certain enzymes that cancer cells need to grow. In this trial, participants will receive a combination of copanlisib and venetoclax, aiming to use both methods to fight cancer cells more effectively. This approach aims to improve outcomes for patients with relapsed or treatment-resistant MCL. ^{6 7 8 9 10}

Who Is on the Research Team?

Alexey Danilov

Principal Investigator

City of Hope Medical Cneter

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04939272

Study Details | NCT04939272 | Copanlisib and Venetoclax ...

This phase I/II trial studies the side effects, best dose, and effectiveness of copanlisib and venetoclax in treating patients with mantle cell lymphoma ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04939272?term=AREA%5BInterventionSearch%5D(BAY-80-6946)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=3

Copanlisib and Venetoclax for the Treatment of Relapsed ...

See Delay Results Type in the Results Data Element ... These trials gather additional information about a drug's safety, efficacy, or optimal use.

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10320213/

A multicenter analysis of the outcomes with venetoclax in ...

In high-risk patients with relapsed MCL, most of whom received prior BTKi, venetoclax resulted in ORR of 40% and median PFS of 3.7 months.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6355471/

Efficacy of venetoclax monotherapy in patients with relapsed ...

Survival outcome of patients with relapsed, refractory mantle cell lymphoma on venetoclax monotherapy. (A) Progression-free survival of all patients.(B) Overall ...

5.

researchgate.net

researchgate.net/publication/393390934_Next-Generation_Therapies_in_Mantle_Cell_Lymphoma_MCL_The_Evolving_Landscape_in_Treatment_of_RelapseRefractory_After_CAR-T_Cells

Next-Generation Therapies in Mantle Cell Lymphoma (MCL)

The aim of this review is to explore the main therapeutic strategies emerging in the context of MCL patients who failed or are not eligible for CAR-T-cells ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7876879/

Efficacy and safety of copanlisib in patients with relapsed ...

Copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03877055

A Study of Copanlisib and Ibrutinib in Mantle Cell Lymphoma

The purpose of this study is to test the safety and any good and bad side effects of combining 2 study drugs, copanlisib and ibrutinib.

8.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/nda/2017/209936Orig1s000MultidisciplineR.pdf

209936Orig1s000 - accessdata.fda.gov

The complete response rate was 14.4% and partial response rate was 44.2%. The safety profile of copanlisib is tolerable and manageable in ...

9.

mdpi.com

mdpi.com/2072-6694/17/13/2239

Next-Generation Therapies in Mantle Cell Lymphoma (MCL)

No pts died due to treatment-related AEs. These data confirmed that this setting of patients remains an unmet clinical need; however, the drug-conjugated ...

10.

clinicaltrials.bayer.com

clinicaltrials.bayer.com/study/17120

Lymphoma, Mantle-Cell | Study 17120

The primary objective of this study is to assess objective response rate (ORR) in patients with relapsed or refractory MCL who failed ibrutinib treatment or ...