Accelerated Venetoclax Escalation for Chronic Lymphocytic Leukemia

(SAVE Trial)

Overseen By Celeste Carey, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must be taking: Venetoclax

Must not be taking: CYP3A inhibitors, Coumadin

Disqualifiers: Richter's transformation, CNS involvement, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 5 days for dose ramp-up, followed by up to 6 cycles of additional treatment

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a faster method to increase doses of venetoclax, a medication for certain cancers, in individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The researchers aim to determine if patients can safely manage a quicker dose escalation over five days instead of the usual five weeks. Participants may also receive additional treatments like rituximab or obinutuzumab. Individuals with a confirmed diagnosis of CLL or SLL, experiencing symptoms that affect daily life, such as significant fatigue or spleen swelling, may be suitable for this trial. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to contribute to groundbreaking cancer research.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, you cannot take medications or foods that are strong inhibitors or inducers of CYP3A starting 1 week before the first dose of venetoclax. If you're on targeted therapies, a washout period of at least five half-lives is required. Corticosteroid therapy (prednisone or equivalent ≤20 mg daily) is allowed.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications or foods that strongly affect CYP3A enzymes at least one week before starting venetoclax. If you're on targeted therapies, a washout period (time without taking certain medications) of at least five half-lives is needed, unless otherwise approved by the study investigator.

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

Research has shown that venetoclax is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Studies have identified some common side effects, such as low blood cell counts, diarrhea, and nausea, which were mostly mild to moderate.

When combined with other treatments like obinutuzumab or rituximab, venetoclax maintains a similar safety profile. Patients might experience the same side effects, but these are usually manageable with proper care.

The FDA has already approved venetoclax for use in CLL, indicating a strong safety record when used as directed. Ongoing research is exploring a faster way to increase the dose, so safety data is still being collected. However, past findings provide a hopeful indication of its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about accelerated venetoclax escalation for chronic lymphocytic leukemia (CLL) because it aims to rapidly increase the dosage of venetoclax, potentially achieving full therapeutic effects much faster than traditional methods. Unlike standard CLL treatments, which usually require gradual dosage increases over several weeks to minimize the risk of tumor lysis syndrome (TLS), this approach seeks to safely escalate the dose over just five days. Additionally, venetoclax itself is a BCL-2 inhibitor, which works differently from many traditional CLL treatments by directly inducing cancer cell death. This accelerated approach could significantly reduce the time patients spend in the hospital and allow for quicker transitions to at-home care, potentially improving quality of life and treatment outcomes.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that venetoclax, the primary treatment in this trial, effectively treats chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Studies have found that venetoclax targets a protein called BCL2, which helps cancer cells survive. By blocking BCL2, venetoclax helps kill these cancer cells. In one study, 77% of patients with CLL that had returned or didn't respond to other treatments experienced a positive response to venetoclax. This drug has proven effective even in patients with high-risk genetic changes, such as a specific type of CLL called del(17p). Overall, venetoclax has a strong track record of helping patients with these blood cancers. Participants in this trial may also receive rituximab or obinutuzumab alongside venetoclax, as determined by their doctor. ^{4 5 6 7 8}

Who Is on the Research Team?

Jennifer Crombie, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Participants must have symptoms like anemia, weight loss, fatigue, fevers without infection, night sweats, and adequate organ function. They should not have had a recent stem cell transplant or other cancers and must be willing to use contraception.

Inclusion Criteria

My white blood cell count has rapidly increased recently.

My blood tests show worsening anemia or low platelets.

I have had significant weight loss, fatigue, fevers, or night sweats without infection.

Exclusion Criteria

My cancer has spread to my brain or spinal cord.

I had a stem cell transplant less than 6 months ago or I am being treated for graft vs. host disease.

I am taking Coumadin or another blood thinner.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax with accelerated dose increases over 5 days, followed by daily administration at home. Some may also receive rituximab or obinutuzumab.

5 days for dose ramp-up, followed by up to 6 cycles of additional treatment

Hospitalized for 5 days, then regular follow-ups

Active Follow-up

Participants are actively followed for approximately 3 months to monitor safety and effectiveness.

3 months

Long-term Follow-up

Participants enter a long-term follow-up period where they will be observed for a maximum of 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Rituximab
• Venetoclax

Trial Overview

The study tests if patients can safely handle a faster dose increase of Venetoclax compared to the standard schedule. It's for those at different risks for tumor lysis syndrome. Some may also receive Rituximab or Obinutuzumab as part of their treatment regimen.

How Is the Trial Designed?

Group I: Venetoclax Experimental Treatment 3 Interventions

Participants will be separated into two cohorts: Cohort A: Patients at low risk for TLS. Cohort B: Patients with both median and high risk for TLS. Five (5) participants from cohort A will be initially enrolled, if these first 5 participants tolerate the accelerated ramp-up, cohorts A and B will enroll simultaneously. All participants will be hospitalized and receive venetoclax daily with accelerated dose increases over 5 days to reach full dose. After reaching full dose, participants will be discharged and continue daily venetoclax at home. Per doctor assessment, some participants may also receive rituximab or obinutuzumab as part of the treatment regimen with venetoclax. Rituximab: Given every 28 days starting on the second study cycle and continuing for up to 6 cycles as per standard of care. Obinutuzumab: Days 1, 2, 8, and 15 of cycle 1 and once every 28 days there after for up to 6 cycles as per standard of care.

Venetoclax is already approved in United States, European Union for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Published Research Related to This Trial

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 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]

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 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 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]

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 of 18 pediatric and young adult patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), venetoclax demonstrated a complete remission rate of 61%, indicating its potential efficacy in this population.

No new safety concerns were identified with venetoclax, with myelosuppression being the most common side effect, and no deaths occurred within 30 days of starting treatment, suggesting it is a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Gibson, A., Trabal, A., McCall, D., et al.[2022]

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