Dasatinib or Venetoclax for T-Cell Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: St. Jude Children's Research Hospital
Must not be taking: CYP3A4 inducers
Disqualifiers: HIV, Hepatitis B, Hepatitis C, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
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.
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.
12345What 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.
12567Eligibility 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
+2 more
Exclusion Criteria
I am unable or unwilling to agree to the study's terms.
I have severe nerve pain or damage.
Pregnant or lactating
+5 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Group I: Patients with T-LLyExperimental Treatment11 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 Treatment12 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 MPALExperimental Treatment12 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
St. Jude Children's Research HospitalMemphis, TN
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Who Is Running the Clinical Trial?
St. Jude Children's Research HospitalLead Sponsor
AbbVieIndustry Sponsor
References
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .
Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. [2021]Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph(+)ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)-mediated proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph(+)ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph(+)ALL and should be further evaluated for patient care.
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.
Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. [2021]Despite improvements in first-line treatment of T-cell acute lymphoblastic leukemia (T-ALL), the outcome of relapsed T-ALL remains dismal with less than 7% achieving a long-term survival. Thus, there is an unmet need for new treatment strategies to improve outcomes in this setting. Suppression of apoptosis is one of the hallmarks of anticancer drug resistance. Hence, over the past few years, antiapoptotic proteins have become an attractive target for therapeutic intervention in several hematologic malignancies. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor of B-cell lymphoma 2 (BCL-2), a key regulator of the intrinsic apoptotic pathway. Recent preclinical studies have suggested that inhibition of BCL-2 may be a novel therapeutic strategy for patients with T-ALL. Herein, we report a case of clinical response to venetoclax in combination with a hypomethylating agent in a patient with relapsed T-ALL after allogeneic stem cell transplant and review the existing literature.
Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.
The path to venetoclax resistance is paved with mutations, metabolism, and more. [2023]Venetoclax is a B cell lymphoma 2 (BCL-2)-selective antagonist used to treat chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Although this has been a promising therapeutic option for these patients, many of these patients develop resistance and relapsed disease. Here, we summarize the emerging mechanisms of resistance to venetoclax treatment, discuss the promising combination strategies, and highlight the combinations that are currently in clinical trials. Efforts to understand mechanisms of resistance are critical to advance the development of new targeted therapeutic strategies and further our understanding of the biological functions of BCL-2 in tumor cells.
Venetoclax: First Global Approval. [2018]Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.