Hyper-CVAD + Venetoclax for Acute Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: HIV medications
Disqualifiers: Secondary tumor, CNS pathology, others
No Placebo Group
Breakthrough Therapy
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).
12345What 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.
12367Eligibility 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.
+14 more
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
+10 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Phase 1bExperimental Treatment2 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 1aExperimental Treatment2 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead 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). .
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.
Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy.
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 plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. [2021]Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.
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.
Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]Venetoclax is a BCL-2 inhibitor that was approved in combination therapy with hypomethylating agents or low dose cytarabine for newly diagnosed acute myeloid leukemia (AML). The purpose of this review is to outline the most recent venetoclax-based combination therapies in newly diagnosed or relapsed myelodysplastic syndrome (MDS) and AML patients.