Venetoclax + Vincristine for Acute Lymphoblastic Leukemia

Not currently recruiting at 177 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ECOG-ACRIN Cancer Research Group

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, CNS leukemia, Burkitt's, 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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well two drugs, venetoclax and vincristine, work together to treat acute lymphoblastic leukemia (ALL) that has returned or resisted treatment. Venetoclax may block a protein essential for cancer cell survival, while vincristine helps stop cancer cells from growing and spreading. The trial will study the side effects and optimal dose of venetoclax when combined with vincristine. It seeks participants with relapsed or hard-to-treat T-cell or B-cell ALL after other chemotherapy treatments. This trial may suit those whose previous ALL treatments were unsuccessful. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong and moderate CYP3A inhibitors and inducers at least 7 days before starting the study drug. If you are on any experimental medications, you must stop them 21 days before registration. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

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

Research has shown that combining venetoclax with liposomal vincristine is safe for individuals with relapsed or hard-to-treat acute lymphoblastic leukemia (ALL). Studies have demonstrated promising results, with some patients achieving no detectable cancer cells in their bone marrow, known as MRD negative status, a positive outcome.

The safety of venetoclax combined with vincristine sulfate is also under investigation. Venetoclax has been successfully used in treating various blood cancers and has FDA approval for other conditions, which supports its safety profile.

Both combinations of venetoclax with vincristine (liposomal and sulfate) are undergoing careful study. Early results suggest they are well-tolerated, but ongoing monitoring for any side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using venetoclax and vincristine liposomal for Acute Lymphoblastic Leukemia (ALL) because they bring fresh approaches to treatment. Unlike traditional chemotherapy drugs, venetoclax specifically targets and blocks the BCL-2 protein, which helps cancer cells survive, making it a more targeted therapy. Meanwhile, vincristine liposomal, a newer formulation, may offer improved delivery and reduced toxicity compared to standard vincristine sulfate. These features have the potential to enhance effectiveness and minimize side effects, offering hope for better outcomes in ALL patients.

What evidence suggests that venetoclax and vincristine could be effective for acute lymphoblastic leukemia?

Research has shown that combining venetoclax with vincristine may treat acute lymphoblastic leukemia (ALL) more effectively than vincristine alone. In this trial, participants will receive a combination of venetoclax and either vincristine liposomal or vincristine sulfate. Earlier studies have shown promising results, with 22% of patients having no detectable signs of the disease after treatment. Venetoclax blocks a protein called Bcl-2, which cancer cells need to survive, while vincristine stops cancer cells from growing and dividing. Early findings suggest that this combination could be a promising new option for those with recurring or difficult-to-treat ALL. ^{1 2 5 6 7}

Who Is on the Research Team?

Neil D Palmisiano

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for adults with T-cell or B-cell acute lymphoblastic leukemia that has returned or isn't responding to treatment. Participants must not be pregnant, should use effective contraception, and have no severe active infections like poorly controlled HIV. They shouldn't have other serious medical conditions that could affect participation, nor a history of certain cancers unless cured over 5 years ago. Recent chemotherapy recipients and those with high-grade peripheral neuropathy are excluded.

Inclusion Criteria

My liver tests are within normal limits.

Patients with serious medical or psychiatric illness that in the opinion of the primary investigator is likely to interfere with study participation may not be enrolled

My kidney function is good, with a creatinine clearance of at least 50 mL/min.

Exclusion Criteria

I have a history of disorders related to lymphocyte proliferation.

I haven't had any cancer, except for skin cancer, in the last 5 years.

My HIV is not well-controlled, or my CD4 count is below 400.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Patients receive venetoclax orally once daily on days 1-42 of cycle 1 and days 43-70 of cycle 2. Vincristine liposomal is administered intravenously weekly for 4 weeks starting on day 15 of cycle 1.

10 weeks

Weekly visits for vincristine administration

Phase II Treatment

Patients receive venetoclax orally once daily on days 1-28 of each cycle. Vincristine liposomal is administered intravenously weekly for 4 weeks on day 1 of each cycle or vincristine sulfate weekly on days 1, 8, 15, and 22 of cycle 1 and once every 4 weeks on day 1 of each subsequent cycle.

28 days per cycle, repeated

Weekly visits for vincristine administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Every 6 months for 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Venetoclax
• Vincristine Liposomal

Trial Overview The study is testing the combination of venetoclax, which blocks enzymes cancer cells need to grow, and vincristine liposomal, a chemotherapy drug that kills or stops cancer cells from dividing. The goal is to find the best dose of venetoclax and see if this combo works better for relapsed or refractory acute lymphoblastic leukemia.

How Is the Trial Designed?

Group I: Phase Ib (venetoclax, vincristine liposomal) Experimental Treatment 6 Interventions

Patients receive venetoclax PO QD on days 1-42 of cycle 1 and days 43-70 of cycle 2. Patients also receive vincristine liposomal IV over 1 hour weekly for 4 weeks starting on day 15 of cycle 1. Patients who achieve at least a stable disease response may continue treating at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the trial. Patients may also undergo CT and/or PET scan as well as a lumbar puncture as clinically indicated.

Group II: Phase II (venetoclax, vincristine liposomal/sulfate) Experimental Treatment 7 Interventions

Patients receive venetoclax PO QD on days 1-28 of each cycle. Patients also receive vincristine liposomal IV over 1 hour weekly for 4 weeks on day 1 of each cycle or vincristine sulfate IV weekly on days 1, 8, 15, and 22 of cycle 1 and once every 4 weeks on day 1 of each subsequent cycle. Cycles repeat every 28 days. Patients who achieve at least a stable disease response may continue treating at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the trial. Patients may also undergo CT and/or PET scan as well as a lumbar puncture as clinically indicated.

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?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

Coadministration of azithromycin with venetoclax resulted in a modest reduction in venetoclax levels (25% lower maximum concentration and 35% lower area under the curve), but did not require any dose adjustments, indicating that azithromycin is a safe option for patients taking venetoclax.

The study involved 12 healthy female subjects and found that venetoclax was well tolerated with no serious adverse events, suggesting that azithromycin can be used as an alternative antibiotic without significantly impacting venetoclax pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Agarwal, SK., Tong, B., Bueno, OF., et al.[2019]

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 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]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

Venetoclax combined with hypomethylators and low-dose cytarabine has shown high response rates and improved overall survival in older, untreated patients with acute myeloid leukemia, based on preliminary data from small, uncontrolled studies.

The efficacy of venetoclax appears to stem from its ability to target leukemia stem cells by altering the metabolic environment, which is particularly effective in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Pollyea, DA., Jordan, CT.[2020]

Venetoclax is an effective oral medication for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), showing significant efficacy when combined with other therapies like obinutuzumab and azacitidine.

While venetoclax is associated with adverse events such as neutropenia and gastrointestinal disorders, the article emphasizes the importance of managing these side effects to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. Waggoner, M., Katsetos, J., Thomas, E., et al.[2022]

Venetoclax is an effective and well-tolerated treatment for advanced hematological malignancies, particularly in patients with chronic lymphocytic leukemia, showing a satisfactory overall event rate of 73%.

The most common adverse events associated with venetoclax include nausea, diarrhea, and thrombocytopenia, but these are generally mild and manageable, with few cases of severe complications like tumor lysis syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. Li, Q., Cheng, L., Shen, K., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11474352/

A phase 1 trial of venetoclax in combination with liposomal ... The combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03504644

Venetoclax and Vincristine in Treating Patients With ... Giving venetoclax together with vincristine may work better in treating patients with acute lymphoblastic leukemia compared to vincristine alone. Detailed ...

3. blog-ecog-acrin.org blog-ecog-acrin.org/now-enrolling-phase-ii-of-ea9152-for-acute-lymphoblastic-leukemia/

Phase II of EA9152 for Acute Lymphoblastic Leukemia Five-year survival rates approach just 40%. The current strategy for patients after relapse is additional multi-agent chemotherapy aimed at ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39415930/

A phase 1 trial of venetoclax in combination with liposomal ... The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses.

5. researchgate.net researchgate.net/publication/382993307_A_phase_1_trial_of_venetoclax_in_combination_with_liposomal_vincristine_in_patients_with_relapsed_or_refractory_B-cell_or_T-cell_acute_lymphoblastic_leukemia_Results_from_the_ECOG-ACRIN_EA9152_protoco

A phase 1 trial of venetoclax in combination with liposomal ... Twenty‐two percent of evaluable patients ( N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).

6. blog-ecog-acrin.org blog-ecog-acrin.org/re-opened-trial-ea9152-for-t-cell-or-b-cell-acute-lymphoblastic-leukemia/

EA9152 for T-cell or B-cell Acute Lymphoblastic Leukemia Early clinical experience with venetoclax has demonstrated its efficacy in a variety of hematologic malignancies, some leading to FDA approvals.

7. adisinsight.springer.com adisinsight.springer.com/trials/700295121

A Phase IB/II Study of Venetoclax (ABT-199) in Combination ... The purose of this trial is to study the side effects and best dose of venetoclax and how well it works when given together with vincristine liposomal in.