Dasatinib or Venetoclax for T-Cell Leukemia

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding dasatinib or venetoclax, both types of targeted therapy, to the usual chemotherapy can improve treatment outcomes for children and young adults with aggressive blood cancers, such as T-cell leukemia. Researchers aim to determine if these drugs can reduce cancer cells more effectively than the standard approach. The study seeks participants recently diagnosed with T-cell acute lymphoblastic leukemia, lymphoblastic lymphoma, or mixed phenotype acute leukemia who have just started treatment. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in cancer treatment.

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.

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

A previous study found dasatinib combined with other treatments to be generally safe. Although 88% of patients experienced some side effects, serious ones occurred in only 19% of patients. This indicates that while side effects can happen, many patients tolerate dasatinib well.

Research has shown that venetoclax is promising for treating certain blood cancers. One study demonstrated its effectiveness in patients with difficult-to-treat T-cell leukemia. However, detailed information about side effects specific to venetoclax in this context remains limited.

This trial is in Phase 2, indicating that earlier studies have suggested these treatments might be safe, but researchers continue to monitor for any serious side effects. Both dasatinib and venetoclax have been used for other conditions, which can provide some reassurance about their overall safety. However, joining a clinical trial involves potential unknown risks, so discussing any concerns with the study team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Dasatinib and Venetoclax for T-cell leukemia because these treatments bring fresh approaches compared to traditional chemotherapy. Dasatinib stands out due to its ability to specifically target and inhibit the BCR-ABL tyrosine kinase, a protein that can promote cancer cell growth. Venetoclax, on the other hand, targets the BCL-2 protein, which helps cancer cells survive, thereby promoting cell death in these stubborn leukemia cells. These targeted mechanisms offer hope for more effective treatments with potentially fewer side effects than the broader-acting chemotherapies currently in use.

What evidence suggests that this trial's treatments could be effective for T-cell leukemia?

Studies have shown that dasatinib, which participants in this trial may receive, effectively treats certain types of leukemia. For patients with acute lymphoblastic leukemia (ALL), dasatinib has been linked to good survival rates, with 71% of patients living without major health events for four years. It has proven effective when combined with standard chemotherapy, particularly improving outcomes in young patients.

Research indicates that venetoclax, another treatment option in this trial, can be effective for specific leukemia types, including T-cell acute lymphoblastic leukemia (T-ALL). Some patients with T-ALL, especially those with early T-cell precursor (ETP) features, have responded very well to venetoclax. Additionally, when combined with mild chemotherapy, venetoclax has resulted in patients living without the disease for over four years on average in newly diagnosed ALL cases. ^{2 5 6 7 8}

Who Is on the Research Team?

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. onclive.com onclive.com/view/dasatinib-plus-car-t-cell-therapy-shows-efficacy-in-ph-acute-lymphoblastic-leukemia

Dasatinib Plus CAR T-Cell Therapy Shows Efficacy in Ph+ ... Dasatinib plus CAR T cells led to high CMR and LFS rates with a good safety profile in Ph-positive acute lymphoblastic leukemia.

2. news.bms.com news.bms.com/news/details/2017/Sprycel-dasatinib-Added-to-Standard-Chemotherapy-Demonstrates-Three-Year-Survival-Benefit-in-Pediatric-Patients-with-Newly-Diagnosed-Philadelphia-Chromosome-Positive-Acute-Lymphoblastic-Leukemia/default.aspx

Sprycel (dasatinib) Added to Standard Chemotherapy ... Showed event-free and overall survival rates of 65.5% and 91.5%, respectively 14.2% of patients treated with Sprycel induction therapy ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5799051/

The Efficacy of Reduced-dose Dasatinib as a Subsequent ... The aim of this study was to prospectively investigate the efficacy and safety profiles of low-dose dasatinib therapy (50 mg once daily).

4. sprycel-hcp.com sprycel-hcp.com/efficacy-newly-diagnosed

SPRYCEL® (dasatinib) Efficacy - Newly Diagnosed Patients SPRYCEL patients achieved higher & faster cCCyR* and MMR† rates at Years 1 and 5 vs imatinib · Fatal adverse reactions occurred in 3 patients (4%), all of which ...

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2758575

Effect of Dasatinib vs Imatinib in the Treatment of Pediatric ... By intention-to-treat analysis, the 4-year event-free survival rate in the dasatinib group (71.0%; 95% CI, 56.2%-89.6%) was significantly better ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12006910/

Dasatinib and CAR T-Cell Therapy in Newly Diagnosed ... The results showed this treatment was associated with high CMR and LFS rates with a good safety profile.

7. sprycel-hcp.com sprycel-hcp.com/safety-newly-diagnosed

SPRYCEL® (dasatinib) Safety Profile - Newly Diagnosed ... In the overall population of 2712 SPRYCEL-treated adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse ...

8. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35232

Comparison of long‐term outcomes between imatinib and ... The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation.