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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two existing cancer drugs, Duvelisib and Venetoclax, to determine their effectiveness in treating T-cell lymphoma that has returned or not responded to previous treatments. The main goal is to assess the safety and effectiveness of using these drugs together. The trial seeks participants whose lymphoma has returned or worsened after at least two other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to groundbreaking research.

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.

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

Research shows that the safety of using duvelisib and venetoclax together remains under investigation. Duvelisib has received approval for treating certain types of leukemia and lymphoma, indicating its safety for those uses. Venetoclax is also approved for some patients with acute myeloid leukemia, suggesting it is generally safe for those cases as well.

However, using these two drugs together is experimental, and researchers are still assessing their combined safety. Other studies suggest that while these drugs can be effective, they may cause side effects. Although specific side effects aren't listed, similar treatments can lead to tiredness or nausea.

The ongoing study aims to determine safe doses and identify any new side effects from using the two drugs together. Participants will receive close monitoring to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for T-cell lymphoma, which often include chemotherapy and radiation, the combination of duvelisib and venetoclax targets specific pathways to disrupt cancer cell survival. Duvelisib works by inhibiting PI3K, a protein involved in cancer cell growth, while venetoclax targets BCL-2, a protein that helps cancer cells avoid death. This dual-targeted approach could offer a more precise attack on cancer cells, potentially leading to better outcomes with fewer side effects. Researchers are excited about this treatment because it represents a novel way to directly interfere with the mechanisms that allow cancer cells to thrive.

What evidence suggests that the combination of Duvelisib and Venetoclax could be effective for T-Cell Lymphoma?

Research has shown that combining duvelisib and venetoclax effectively treats certain blood cancers. For patients with chronic lymphocytic leukemia (CLL) that has returned or not responded to other treatments, about 97% experienced positive results with this treatment. After one year, 72% of these patients continued to respond well, and 44% showed no signs of cancer. This combination targets specific parts of cancer cells to destroy them. Early findings also suggest this treatment could benefit patients with challenging conditions like Richter syndrome, a type of lymphoma. These promising results indicate that this combination might also be effective for treating relapsed or hard-to-treat non-Hodgkin lymphoma (NHL). In this trial, participants will receive a combination of duvelisib and venetoclax, with varying doses tested to determine the most effective and safe regimen. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9845779/

Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in ... This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid ...

2. onclive.com onclive.com/view/duvelisib-plus-venetoclax-is-active-in-relapsed-refractory-cll-and-richter-syndrome

Duvelisib Plus Venetoclax Is Active in Relapsed/Refractory ... Duvelisib plus venetoclax is effective in relapsed/refractory CLL and RS, especially in high-risk TP53-aberrant patients and those post-BTK ...

3. investor.verastem.com investor.verastem.com/news-releases/news-release-details/verastem-oncology-present-phase-2-primo-study-data-evaluating/

Verastem Oncology to Present Phase 2 PRIMO Study Data ... Preclinical data highlighting the effectiveness of duvelisib in combination with venetoclax in Richter syndrome will also be presented.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03534323

Duvelisib and Venetoclax in Relapsed or Refractory CLL or ... In laboratory studies and in other clinical trials that included participants with CLL, duvelisib was effective at killing CLL cells. Venetoclax is a tablet ...

5. healthtree.org healthtree.org/cll/community/articles/new-oral-treatment-for-rr-cll-and-richter-syndrome

Venetoclax & Duvelisib for CLL & Richter Syndrome 97% of CLL patients responded to treatment · After 12 months, 72% of patients continued to respond to treatment, with 44% achieving a complete ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06810778/duvelisib-and-venetoclax-in-patients-with-relapsed-or-refractory-peripheral-t-cell-lymphoma-ptcl

Duvelisib and Venetoclax in Patients With Relapsed or ... This is an open-label, phase I/II study of duvelisib in combination with Venetoclax for patients with relapsed/refractory NHL.

7. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper199234.html

Paper: A Phase 2 Study of Duvelisib and Venetoclax in ... 11 pts of 29 achieved BM-uMRD after 12 cycles and electively discontinued therapy, 3 of whom later restarted V once MRD re-detected (median yrs ...