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

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the effectiveness of the drug Venetoclax for treating acute leukemia?

Research shows that Venetoclax, when combined with other treatments, has been effective in improving outcomes for patients with certain types of leukemia, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In particular, combining Venetoclax with other drugs like dasatinib has shown promising results in enhancing treatment effectiveness for acute lymphoblastic leukemia (ALL). ^{1 2 3 4 5}

What makes the drug combination of Hyper-CVAD and Venetoclax unique for treating acute leukemia?

The combination of Hyper-CVAD and Venetoclax is unique because Venetoclax is a BCL-2 inhibitor that helps restore the ability of cancer cells to die, and it is being explored in combination with other treatments like Hyper-CVAD for acute leukemia, which is not a standard treatment yet. This combination aims to enhance treatment effectiveness by targeting cancer cells more precisely. ^{1 2 3 6 7}

Research Team

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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 using topical steroids for skin GVHD.

I am on a stable low-dose steroid treatment.

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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 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]

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. England pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]

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

Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. [2021]

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

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. [2021]

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

Venetoclax: First Global Approval. [2018]

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

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]