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

40 Participants Needed

Trial Summary

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.

What data supports the idea that Accelerated Venetoclax Escalation for Chronic Lymphocytic Leukemia is an effective drug?

The available research shows that Venetoclax is effective for treating Chronic Lymphocytic Leukemia (CLL). In one study, it achieved response rates of about 80% in patients whose CLL had returned or was resistant to other treatments. Another study found that when Venetoclax was combined with another drug, Obinutuzumab, it helped patients live longer without their disease getting worse compared to a different treatment. This combination also led to higher rates of patients having no detectable disease after treatment. Additionally, Venetoclax was shown to be more effective than another treatment option, Bendamustine plus Rituximab, in prolonging the time patients lived without their disease progressing. These studies suggest that Venetoclax is a strong option for treating CLL, especially for those who have not responded well to other treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Venetoclax for treating Chronic Lymphocytic Leukemia?

Venetoclax, when used in combination with obinutuzumab, has shown to significantly improve progression-free survival and achieve higher response rates in patients with previously untreated chronic lymphocytic leukemia (CLL) compared to traditional chemoimmunotherapy. Additionally, venetoclax combined with rituximab has been effective in prolonging progression-free survival in relapsed or refractory CLL, providing durable responses with a manageable safety profile. ^{1 2 3 4 6}

What safety data is available for Venetoclax in treating Chronic Lymphocytic Leukemia?

Venetoclax has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80%. In combination with obinutuzumab, it has been shown to have a tolerable safety profile, with notable adverse events like grade 3 or 4 neutropenia being manageable with supportive therapy and dose modifications. In pivotal clinical trials, Venetoclax, either as monotherapy or in combination with rituximab, provided durable responses and had a manageable safety profile in adults with relapsed or refractory CLL. No new safety signals were identified in pediatric populations, with myelosuppression being the most common toxicity. ^{1 2 3 4 7}

Is venetoclax safe for treating chronic lymphocytic leukemia?

Venetoclax has been shown to have an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), with manageable side effects like neutropenia (low white blood cell count). It has been used safely in both adults and children, with no new safety concerns identified in studies. ^{1 2 3 4 7}

Is the drug Venetoclax a promising treatment for Chronic Lymphocytic Leukemia?

Yes, Venetoclax is a promising drug for treating Chronic Lymphocytic Leukemia. It has shown high response rates, meaning it works well for many patients, and it can be taken as a pill. It is effective both for patients who have not been treated before and for those whose disease has returned or not responded to other treatments. Venetoclax can be used alone or with other drugs, and it helps patients live longer without their disease getting worse. ^{1 2 3 4 8}

How is the drug venetoclax unique for treating chronic lymphocytic leukemia?

Venetoclax is unique because it is a first-in-class, oral drug that selectively inhibits BCL-2, a protein that helps cancer cells survive. This drug is effective for both untreated and relapsed chronic lymphocytic leukemia (CLL), offering a chemotherapy-free option with a convenient once-daily regimen. ^{1 2 3 4 8}

What is the purpose of this trial?

This research study is trying to determine which patients with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), as grouped by their risk for tumor lysis syndrome (TLS), are able to safely tolerate an accelerated, daily venetoclax dose ramp-up rather than the standard approved schedule (5-week dose ramp-up). The name of the study drug involved in this study is: * Venetoclax The following drugs may also be included in some participants treatment regimen: * Obinutuzumab * Rituximab

Research Team

Jennifer Crombie, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

References

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. [2018]

4. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. [2022]

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

The path to venetoclax resistance is paved with mutations, metabolism, and more. [2023]