Duvelisib + Venetoclax for T-Cell Lymphoma

Overseen By Vanessa Crowell

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Venetoclax, PI3K inhibitors, Coumadin, others

Disqualifiers: HIV, Hepatitis B/C, CNS involvement, others

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

Compensation: Varies

Number of Visits: 2

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot take certain medications like strong inhibitors or inducers of CYP3A, and you should avoid grapefruit and similar products. If you're on targeted therapies, a washout period (time without taking certain medications) of at least five half-lives is required before starting the trial.

What data supports the effectiveness of the drugs Duvelisib and Venetoclax for T-Cell Lymphoma?

Venetoclax has shown effectiveness in treating various blood cancers, including chronic lymphocytic leukemia (CLL), by helping to kill cancer cells. Although this data is from different types of blood cancers, it suggests potential benefits for T-Cell Lymphoma as well. ^{1 2 3 4 5}

Is the combination of Duvelisib and Venetoclax safe for humans?

Duvelisib was generally well tolerated in a study with Japanese patients with relapsed or refractory lymphoma, with some experiencing low blood cell counts and liver function changes. Venetoclax has been used safely in patients with various blood cancers, with careful dose adjustments to prevent tumor lysis syndrome (a condition where cancer cells break down too quickly). ^{1 6 7 8 9}

What makes the drug combination of Duvelisib and Venetoclax unique for T-Cell Lymphoma?

The combination of Duvelisib and Venetoclax is unique because Duvelisib targets specific enzymes (PI3K-δ and -γ) involved in cancer cell growth, while Venetoclax is a BCL-2 inhibitor that helps restore the natural process of cell death in cancer cells. This dual approach may offer a novel way to treat T-Cell Lymphoma by attacking the cancer cells through different mechanisms. ^{1 3 6 9 10}

What is the purpose of this trial?

This is an open-label, phase I/II study of duvelisib in combination with Venetoclax for patients with relapsed/refractory NHL. Duvelisib is an FDA approved, marketed product used to treat certain patients with leukemia and lymphoma and Venetoclax, which is approved for treatment of certain patients with acute myeloid leukemia. The combination of these two drugs is experimental. Experimental means that it is not approved by the United States Food and Drug Administration (FDA). The researchers want to find out how safe it is to combine these drugs and how well this combination can work for your cancer.

Eligibility Criteria

This trial is for patients with various types of T-cell lymphoma, including cutaneous and peripheral forms, who have not responded to previous treatments. Participants must meet specific health criteria to be eligible.

Inclusion Criteria

My condition worsened after two prior treatments.

I can take care of myself but might not be able to do heavy physical work.

Phase II: Same as Phase I

Exclusion Criteria

I haven't had cancer treatment in the last 2 weeks, with some exceptions.

My cancer has spread to my brain or spinal cord.

I am eligible for a stem cell transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Determine the dose, schedule, safety, and tolerability of duvelisib in combination with venetoclax using a 3 + 3 design

21 days

Weekly visits during Cycle 1

Phase II Treatment

Evaluate the efficacy of the RP2D of duvelisib and venetoclax in patients with relapsed/refractory PTCL

Up to 1 year

Weekly visits through cycles 1-2, once per cycle during cycles 3-7, every 2 cycles from cycle 8-13, and every 3 cycles thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if clinically benefitting

Beyond 2 years

Treatment Details

Interventions

• Duvelisib
• Venetoclax

Trial Overview The study tests a combination of two drugs: Duvelisib, approved for leukemia and lymphoma treatment; and Venetoclax, approved for acute myeloid leukemia. Their combined effect on T-cell lymphoma is being evaluated.

Participant Groups

Group I: Arm Treatment (Duvelisib and Venetoclax) Experimental Treatment 2 Interventions

Phase I: In the phase I study, 2 dose levels of duvelisib (15 and 25 mg BID) and 3 dose levels of venetoclax (200, 400, and 800 mg QD) will be evaluated. Patients will start with 15 mg BID of duvelisib and 200 mg QD of venetoclax. We use a traditional 3 + 3 design to accrue patients to each combination cohort. There are 5 possible dosing combinations to be tested, with up to 18 patients planned to be enrolled. Enrollment may stop early based on DLTs. The DLT assessment window is defined as Day 1-21 of Cycle 1 (21 days). De-escalation will occur if unexpected toxicity is observed and both drugs will be reduced for the next lower dosing cohort. Increasing drug dosing levels will be performed in parallel cohorts, each increasing either venetoclax or duvelisib.

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Findings from Research

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 study of 436 patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), venetoclax demonstrated a high efficacy, with 75% of patients showing objective responses and 22% achieving complete remission (CR/CRi).

Patients who achieved CR/CRi had a remarkable 3-year progression-free survival (PFS) estimate of 83%, while factors like bulky lymphadenopathy and B-cell receptor inhibitor (BCRi) refractoriness were linked to lower response rates and shorter duration of response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Roberts, AW., Ma, S., Kipps, TJ., et al.[2021]

Venetoclax is a highly effective small-molecule inhibitor targeting BCL2, showing a remarkable 79% response rate and 20% complete remission in patients with chronic lymphocytic leukemia (CLL) during a phase II trial.

The drug induces rapid apoptosis and significantly reduces tumor size within hours of administration, demonstrating both high efficacy and safety, and has been approved by the FDA and EMA for specific patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Targeting BCL2 in Hematological Cancers. Scheffold, A., Jebaraj, BMC., Stilgenbauer, S.[2019]

In a study involving 10 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the addition of rituximab to venetoclax therapy resulted in a 50% response rate, with three patients achieving complete responses and two achieving partial responses.

The combination treatment was well tolerated, suggesting that adding rituximab after progression on venetoclax may provide a beneficial option for some patients with R/R CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. Handunnetti, S., Anderson, MA., Roberts, AW., et al.[2022]

Duvelisib, a dual inhibitor of PI3K-δ and -γ, was well tolerated in a phase I study involving 7 Japanese patients with relapsed or refractory lymphoma, with no dose-limiting toxicities reported.

The treatment showed promising preliminary efficacy, with an overall response rate of 71.4%, including one complete response and several partial responses among the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma. Izutsu, K., Kato, K., Kiyoi, H., et al.[2022]

References

1. 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]

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

Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. [2021]

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

Lisaftoclax in Combination with Alrizomadlin Overcomes Venetoclax Resistance in Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: Preclinical Studies. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Venetoclax: Targeting BCL2 in Hematological Cancers. [2019]

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

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma. [2022]

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

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice. [2021]

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

Exposure-response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma. [2019]

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

Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies. [2018]

10. 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]