Duvelisib + Venetoclax for Chronic Lymphocytic Leukemia

Not currently recruiting at 6 trial locations

Overseen By Celeste Celeste

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Venetoclax, Duvelisib, Coumadin, others

Disqualifiers: HIV, Hepatitis B, Cardiovascular, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with chronic lymphocytic leukemia (CLL) or Richter's Syndrome, a rare transformation of CLL. Researchers are testing duvelisib, a new drug, alongside venetoclax, which has already received approval for use. The goal is to determine if this combination can effectively control these conditions. Individuals with CLL or Richter’s Syndrome that has worsened or returned after prior treatment might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial requires stopping certain medications that strongly affect the liver enzyme CYP3A at least one week before starting the study drug. If you're on targeted cancer therapies, a washout period (time without taking these medications) of at least five half-lives is needed. Other medications, like corticosteroids under 20 mg daily, are allowed.

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

Research is examining the safety of combining two drugs, duvelisib and venetoclax, to treat chronic lymphocytic leukemia (CLL) and Richter's Syndrome. Studies have shown that patients can tolerate this combination, though some side effects occur. Common side effects include low blood cell counts, diarrhea, and infections, which are typical for cancer treatments and require careful monitoring.

Venetoclax has received FDA approval for certain blood cancers, so doctors are familiar with its use and side effect management. Duvelisib, however, remains under study for safety. While it shows promise, researchers are still identifying potential risks.

In summary, while patients can tolerate this treatment, awareness of possible side effects is crucial, and discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Duvelisib and Venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because they utilize unique mechanisms of action compared to traditional therapies like chemotherapy or monoclonal antibodies. Duvelisib is a dual inhibitor targeting specific enzymes (PI3K-δ and PI3K-γ) that play a role in cancer cell survival and proliferation. Venetoclax works by inhibiting BCL-2, a protein that prevents cancer cell death, thus promoting the natural process of apoptosis in cancer cells. Together, these treatments could offer a more targeted approach, potentially leading to more effective and faster results in combating CLL.

What evidence suggests that the combination of duvelisib and venetoclax could be an effective treatment for chronic lymphocytic leukemia?

In this trial, participants will receive a combination of duvelisib and venetoclax to treat chronic lymphocytic leukemia (CLL). Studies have shown that this combination looks promising for treating CLL. Research suggests that duvelisib can enhance the effectiveness of venetoclax, a drug that helps destroy cancer cells. Duvelisib has proven effective for patients whose CLL has returned or hasn't responded to other treatments. Venetoclax, already approved by the FDA for CLL, works by targeting a protein that helps cancer cells survive. Together, these drugs have shown strong potential to improve outcomes for patients with CLL. ^{1 2 4 5 6}

Who Is on the Research Team?

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma needing treatment, or those with Richter's Syndrome after at least one prior therapy (not applicable for Richter's). Must have adequate blood counts, liver and kidney function, agree to use contraception, and be able to consent. Excludes those with central nervous system involvement, recent transplants or active infections, certain virus histories, major surgery within 4 weeks, gastrointestinal disease requiring therapy, pregnancy/breastfeeding individuals.

Inclusion Criteria

My liver is working well.

Ability to understand and the willingness to sign a written informed consent document

I have been diagnosed with CLL/SLL needing treatment or have DLBCL due to Richter's Syndrome.

Exclusion Criteria

I am taking less than 20 mg of corticosteroids daily.

Known hypersensitivity to duvelisib and/or its excipients

I have a lung condition or severe breathing problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Determine the safe dose of venetoclax with duvelisib and observe side effects

7 weeks

Participants admitted for initial dose of venetoclax at each dose escalation

Phase II Treatment

Evaluate the effectiveness of duvelisib and venetoclax combination for CLL or Richter's Syndrome

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Duvelisib
• Venetoclax

Trial Overview The trial is testing a new drug called duvelisib in combination with an FDA-approved drug venetoclax. It aims to treat participants who have relapsed or are not responding well to previous treatments for CLL/SLL/RS. The study will assess the effectiveness and safety of this drug combo.

How Is the Trial Designed?

Group I: Duvelisib +Venetoclax, Experimental Treatment 2 Interventions

Duvelisib will be given alone for the first seven days. On day 8 Venetoclax will be added. * Duvelisib will be administered orally twice daily * Venetoclax will be administered orally daily * All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation

Duvelisib is already approved in United States for the following indications:

Approved in United States as Copiktra for:

• Relapsed or refractory chronic lymphocytic leukemia (CLL)
• Relapsed or refractory small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Secura Bio, Inc.

Industry Sponsor

Trials

9

Recruited

200+

Published Research Related to This Trial

The study established the maximum tolerated dose (MTD) for the combination treatment NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma, with 32 out of 56 patients receiving the MTD, indicating a manageable safety profile despite some patients experiencing severe treatment-related adverse events.

Patients treated with NALIRIFOX showed a median progression-free survival of 9.2 months and overall survival of 12.6 months, suggesting that this treatment regimen may be effective for this difficult-to-treat cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. Wainberg, ZA., Bekaii-Saab, T., Boland, PM., et al.[2021]

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]

Venetoclax, an oral BCL-2 inhibitor, is an effective long-term treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), particularly those with high-risk features like chromosome 17p deletion, based on a safety analysis of 350 patients.

The treatment is generally well tolerated, with manageable side effects; however, common adverse events included diarrhea (41%), neutropenia (40%), and nausea (39%), and serious infections occurred in 15% of patients, indicating the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Davids, MS., Hallek, M., Wierda, W., et al.[2019]

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 phase III study involving 220 previously untreated patients with metastatic colorectal cancer, both treatment sequences (FOLFIRI followed by FOLFOX6 and vice versa) resulted in similar median survival rates of approximately 21.5 months and 20.6 months, indicating comparable efficacy.

The study revealed distinct toxicity profiles for each treatment sequence, with FOLFIRI causing more mucositis and nausea/vomiting, while FOLFOX6 was associated with higher rates of neutropenia and neurosensory toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. Tournigand, C., André, T., Achille, E., et al.[2023]

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 is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5540815/

Duvelisib treatment is associated with altered expression of ... We then demonstrated that previous duvelisib treatment enhanced the ability of the BCL2 inhibitor venetoclax (ABT-199) to induce apoptosis in CLL cells. These ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2018/211155Orig1Orig2s000MultidisciplineR.pdf

211155Orig1s000 211155Orig2s000 - accessdata.fda.gov chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. • Accelerated approval for the ...

3. 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 ...

4. researchgate.net researchgate.net/publication/346687893_Updated_Results_from_a_Phase_III_Study_of_Duvelisib_and_Venetoclax_in_Patients_with_Relapsed_or_Refractory_CLLSLL_or_Richter's_Syndrome

Updated Results from a Phase I/II Study of Duvelisib and ... Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/ ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...

6. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/1763/427529/A-Phase-I-Study-of-Duvelisib-and-Venetoclax-in

A Phase I Study of Duvelisib and Venetoclax in Patients with ... Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia ( ...