Hyper-CVAD + Venetoclax for Acute Leukemia

Overseen By David McCall, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: HIV medications

Disqualifiers: Secondary tumor, CNS pathology, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal dose of a leukemia treatment that combines hyper-CVAD with venetoclax, a targeted therapy. It focuses on patients whose leukemia has returned or hasn't responded to previous treatments. Researchers test different doses of venetoclax to determine the highest dose patients can tolerate without severe side effects. Individuals with relapsed or hard-to-treat leukemia, who have at least 5% cancer cells in their bone marrow or blood, may be suitable for the trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should be at least 2 weeks or 5 half-lives from prior therapy, except for certain medications like hydroxyurea, glucocorticoids, or low dose cytarabine. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining hyper-CVAD with venetoclax might be safe and manageable for treating leukemia. One study found that using low-intensity chemotherapy with venetoclax was safe for patients who had already undergone many treatments. These patients had acute lymphoblastic leukemia (ALL) that either returned or didn't respond to previous treatments. Another study suggested this combination could also be safe for children, teenagers, and young adults.

Regarding dasatinib, this drug has already received FDA approval for other uses, indicating its general safety for humans, although individual reactions can differ.

As this treatment remains in the early stages of research, scientists are still determining the safest dose. They prioritize safety and carefully monitor for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute leukemia because they introduce novel approaches to tackling the disease. Unlike the standard chemotherapy regimens, Venetoclax is a targeted therapy that inhibits the BCL-2 protein, a key player in cancer cell survival. This mechanism could potentially enhance the effectiveness of the chemotherapy backbone, Hyper-CVAD, by making cancer cells more susceptible to treatment. Additionally, Dasatinib, a tyrosine kinase inhibitor, targets specific proteins involved in cancer cell growth, offering a multi-pronged attack against the leukemia cells. This combination of targeted therapies with conventional chemotherapy is promising for improving outcomes in patients with acute leukemia.

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

Studies have shown that combining venetoclax with chemotherapy, such as hyper-CVAD, can enhance treatment effectiveness for acute leukemia. Research suggests venetoclax might enable lower chemotherapy doses while maintaining strong results. In some studies, venetoclax with high-dose chemotherapy led to more patients achieving molecular remission, where no detectable signs of leukemia remain. Although specific data for this exact combination is still being gathered, early findings are promising. This trial will explore the optimal dosage combinations of venetoclax and hyper-CVAD to maximize benefits and minimize side effects. Participants in Phase 1a will receive varying doses of venetoclax to determine the highest tolerable dose, while those in Phase 1b will receive the recommended dose identified in Phase 1a. ^{3 6 7 8 9}

Who Is on the Research Team?

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for pediatric patients with certain types of leukemia that have come back or didn't respond to previous treatments. These leukemias include acute undifferentiated, mixed phenotype, and others of the lymphoid lineage.

Inclusion Criteria

I am on a stable low-dose steroid treatment.

I am using topical steroids for skin GVHD.

It has been over 30 days since my last stem cell transplant.

Exclusion Criteria

I have not had major surgery or a serious injury in the last 14 days.

I have had another type of cancer or a specific leukemia crisis, with some exceptions.

Participants currently enrolled in another ongoing clinical trial with investigational products

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Treatment

Participants receive escalating doses of venetoclax in combination with hyper-CVAD to determine the maximum tolerated dose

Varies per cohort

Phase 1b Treatment

Participants receive venetoclax at the recommended dose found in Phase 1a in combination with hyper-CVAD

Varies per participant

Follow-up

Participants are monitored for safety and effectiveness after treatment

Average of 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• Hyper-CVAD
• Venetoclax

Trial Overview The study aims to determine the appropriate dose for a treatment combo: hyper-CVAD with dasatinib and venetoclax, in children who have relapsed or refractory leukemia.

How Is the Trial Designed?

Group I: Phase 1b Experimental Treatment 2 Interventions

Participants enrolled in Phase 1b, will receive venetoclax at the recommended dose that was found in Phase 1. The study doctor will discuss with you the doses the participants will receive as part of hyper-CVAD based on standard of care.

Group II: Phase 1a Experimental Treatment 2 Interventions

Participants enrolled in Phase 1a, the dose of venetoclax the participant receive will depend on when the participant joins this study. The first group of participants will receive the lowest dose level of venetoclax. Each new group will receive a higher dose of venetoclax than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of venetoclax is found. The study doctor will discuss with you the doses the participants will receive as part of hyper-CVAD based on standard of care.

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

Approved in United States as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in Canada as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

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 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]

The combination of tyrosine kinase inhibitors (TKIs) like dasatinib and ponatinib with the BCL-2 inhibitor venetoclax shows strong synergy in reducing cell viability and inducing apoptosis in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) cells, suggesting a promising new treatment strategy.

In tests with primary Ph(+)ALL patient samples in mice, the dasatinib-venetoclax combination was well-tolerated and demonstrated superior effectiveness compared to either drug alone, indicating its potential to enhance treatment outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leonard, JT., Rowley, JS., Eide, CA., et al.[2021]

In a phase 3 trial involving 211 adults with acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, the combination of venetoclax and low-dose cytarabine (LDAC) showed a clinically meaningful improvement in overall survival, with a median survival of 8.4 months compared to 4.1 months for LDAC alone.

The treatment also resulted in higher remission rates, with 48% of patients achieving complete remission or complete remission with incomplete blood count recovery, while maintaining a manageable safety profile, despite some significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Wei, AH., Montesinos, P., Ivanov, V., et al.[2021]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39546748/

Venetoclax plus low-intensity chemotherapy for adults with ... In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9504828/

The Emerging Role of Venetoclax-Based Treatments in ... Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-05154

Hyper-CVAD in Combination with Venetoclax for the ... This phase I trial tests the safety, side effects, best dose and effectiveness of venetoclax in combination with hyperfractionated cyclophosphamide, ...

4. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

5. mdpi.com mdpi.com/1422-0067/24/23/16708

Recent Updates in Venetoclax Combination Therapies ... In 82 patients over 60 years receiving VTX in combination with LDAC, the CR/CRi rate was 54%, and the median overall survival (OS) was 10.1 months [30]. Despite ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06466395

NCT06466395 | A Phase I Study of Hyper-CVAD In ... To characterize the safety and tolerability of hyper-CVAD in combination with venetoclax. Secondary Objectives. To determine the preliminary assessment of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10875259/

A phase 1/2 study of mini-hyper-CVD plus venetoclax ... Low-intensity chemotherapy plus venetoclax was safe and active in heavily pretreated relapsed/refractory ALL. The CR/CRi rate of 57% compares favorably with ...

8. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2023-1044.html

A phase I study of hyper-CVAD in combination with ... To find the recommended dose of hyper-CVAD in combination with venetoclax that can be given to participants with relapsed or refractory leukemia.

9. dana-farber.org dana-farber.org/for-physicians/clinical-resources/hematologic-malignancies/advances-newsletter/2023-issue-17/venetoclax-plus-mini-hyper-cvd

Clinical Trial Spotlight: Venetoclax plus Mini-hyper-CVD for ... Dana-Farber discusses the success of venetoclax plus mini-hyper CVD in the treatment of hematologic malignancies in their Winter 2023 ...