Dasatinib or Venetoclax for T-Cell Leukemia

Overseen By Seth E. Karol, MD, MSCI

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 inducers

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong or moderate CYP3A4 inducers (like rifampin, carbamazepine, phenytoin, and St. John's wort) at least 7 days before starting the trial. Also, avoid grapefruit, Seville oranges, and starfruit 3 days before starting the trial.

What data supports the effectiveness of the drugs Dasatinib and Venetoclax for T-Cell Leukemia?

Research shows that Venetoclax, a drug that helps cancer cells die, has shown promise in treating various blood cancers, including T-cell leukemia. Additionally, combining Venetoclax with Dasatinib, another cancer drug, has been effective in treating certain types of leukemia, suggesting potential benefits for T-cell leukemia as well. ^{1 2 3 4 5}

What makes the drug combination of Dasatinib and Venetoclax unique for T-Cell Leukemia?

The combination of Dasatinib and Venetoclax is unique because it targets both BCL-2 and ABL/LYN pathways, potentially overcoming resistance seen with single-agent therapies and showing superior antileukemic efficacy compared to using either drug alone. ^{1 2 5 6 7}

What is the purpose of this trial?

This is a clinical trial testing whether the addition of one of two chemotherapy agents, dasatinib or venetoclax, can improve outcomes for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma or mixed phenotype acute leukemia. Primary Objective * To evaluate if the end of induction MRD-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231. * To evaluate if the end of induction MRD-negative rate is higher in patients with ETP or near-ETP ALL treated with venetoclax compared to similar patients treated with 4-drug induction on AALL1231. Secondary Objectives * To assess the event free and overall survival of patients treated with this therapy. * To compare grade 4 toxicities, event-free survival (EFS) and overall survival (OS) of patients treated with this therapy in induction and reinduction to toxicities of similar patients treated on TOT17.

Research Team

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia, lymphoma, or mixed phenotype acute leukemia. Specific eligibility criteria are not provided but typically include factors like age range, disease stage, and overall health status.

Inclusion Criteria

I have been diagnosed with a specific type of leukemia or lymphoma.

I haven't had chemotherapy, except as part of the INITIALL trial.

Enrollment on INITIALL

Exclusion Criteria

I am unable or unwilling to agree to the study's terms.

I have severe nerve pain or damage.

Pregnant or lactating

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

Induction

Remission Induction includes 3 days of therapy on the INITIALL classification protocol and 4 weeks of induction treatment with various drugs including dexamethasone, vincristine, daunorubicin, and others based on immunophenotype.

4 weeks

Weekly visits for drug administration

Early Post Induction

Includes Consolidation, High-Dose Methotrexate, Intensification, Interim 1, Reinduction 1, Interim 2, and Reinduction 2 with various chemotherapy regimens.

Approximately 1 year

Maintenance

Early and Late Maintenance Therapy with mercaptopurine, methotrexate, and other drugs, lasting approximately 75 weeks.

75 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 4 months for 1 year, every 6 months for another year, and then yearly.

Up to 10 years

Treatment Details

Interventions

• Dasatinib
• Venetoclax

Trial Overview The trial tests if adding dasatinib or venetoclax to standard chemotherapy improves outcomes in patients. It measures the rate of MRD-negative responses at the end of induction therapy and compares survival rates and severe toxicities to previous studies.

Participant Groups

Group I: Patients with T-LLy Experimental Treatment 11 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Bortezomib, IT MHA Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, IT MHA, Methotrexate, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Bortezomib Maintenance: Mercaptopurine, Methotrexate, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, IT MHA, Thioguanine

Group II: Patients with T-ALL (except ETP or near-ETP) Experimental Treatment 12 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Dasatinib, IT MHA Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, IT MHA, Methotrexate, Dasatinib, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol Maintenance: Mercaptopurine, Methotrexate, Nelarabine, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, Dasatinib, IT MHA, Thioguanine

Group III: Patients with ETP or near-ETP ALL or MPAL Experimental Treatment 12 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Venetoclax, IT MHA Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, IT MHA, Methotrexate, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Venetoclax Maintenance: Mercaptopurine, Methotrexate, Nelarabine, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, IT MHA, Thioguanine

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

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]

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 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]

A patient with relapsed T-cell acute lymphoblastic leukemia (T-ALL) showed a clinical response to venetoclax, an oral BCL-2 inhibitor, combined with a hypomethylating agent, highlighting a potential new treatment strategy for this challenging condition.

Given that less than 7% of patients with relapsed T-ALL achieve long-term survival, targeting antiapoptotic proteins like BCL-2 could offer a promising approach to improve outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. Farhadfar, N., Li, Y., May, WS., et al.[2021]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[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 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]

References

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

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

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

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

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

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

4. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]

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

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

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

Venetoclax: First Global Approval. [2018]