Venetoclax + Vyxeos for Leukemia
Recruiting in Palo Alto (17 mi)
Overseen byJohn Perentesis, MD
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Children's Hospital Medical Center, Cincinnati
Must not be taking: Investigational drugs, Anti-cancer agents
Disqualifiers: APML, CNS status 3, Ph+ leukemia, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This study evaluates the safety and tolerability of combining venetoclax with Vyxeos (CPX-351) in pediatric and young adult patients with acute leukemia that has come back or not responded to treatment.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications, but you cannot be on other anti-cancer agents, except for certain exceptions like intrathecal agents or hydroxyurea.
What data supports the effectiveness of the drug Venetoclax for leukemia?
Venetoclax has shown effectiveness in treating chronic lymphocytic leukemia (CLL), achieving high response rates and prolonging progression-free survival when used alone or in combination with other drugs. It has also been studied in combination with low-dose cytarabine for acute myeloid leukemia, showing a trend towards improved survival.
12345Is the combination of Venetoclax and Vyxeos safe for humans?
Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and acute myeloid leukemia, with common side effects including low potassium levels, vomiting, and constipation. The safety of Vyxeos (a combination of daunorubicin and cytarabine) is not specifically detailed in the provided research, but Venetoclax has been studied in combination with other treatments and found to be manageable.
12367What makes the drug combination of Venetoclax and Vyxeos unique for treating leukemia?
The combination of Venetoclax and Vyxeos is unique because Venetoclax is a targeted therapy that inhibits a protein helping cancer cells survive, while Vyxeos is a liposomal formulation of two chemotherapy drugs, daunorubicin and cytarabine, designed to improve delivery and effectiveness. This combination aims to enhance treatment outcomes by using both targeted and traditional chemotherapy approaches.
1891011Eligibility Criteria
This trial is for young patients aged 1-39 with acute leukemia that's relapsed or hasn't responded to treatment. They should have recovered from previous therapies and not have certain other health conditions like Fanconi Anemia or Wilson's Disease, be pregnant, breastfeeding, or unable to swallow pills.Inclusion Criteria
I am between 1 and 39 years old.
I've recovered from previous cancer treatments and it's been enough time since my last major therapy.
My leukemia has returned or didn't respond to treatment.
+2 more
Exclusion Criteria
You have been diagnosed with certain types of leukemia, genetic disorders, or other medical conditions. You are pregnant or breastfeeding, have an uncontrolled infection, have received a high amount of radiation to the chest area, cannot swallow pills, have recently received certain medications or treatments, are currently taking experimental drugs or other anti-cancer medications (with a few exceptions), or are unable to follow the safety monitoring requirements of the study.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single course of venetoclax and Vyxeos. Venetoclax is given daily with a 3-day ramp-up, and Vyxeos is administered intravenously on Days 1, 3, and 5.
3-4 weeks
3 visits (in-person) for Vyxeos administration
Follow-up
Participants are monitored for safety, tolerability, and response to treatment, including pharmacokinetic analysis and cardiac function assessment.
60 days
Participant Groups
The study tests combining Venetoclax with Vyxeos (CPX-351) in pediatric and young adult patients. It aims to assess the safety of this combination therapy in those whose acute leukemia has returned or is resistant to standard treatments.
1Treatment groups
Experimental Treatment
Group I: Venetoclax and Vyxeos combinationExperimental Treatment2 Interventions
Venetoclax will be given orally on Days per the assigned dose level. A single course consisting of 3 doses of Vyxeos and 7-21 doses of venetoclax depending on the assigned dose level will be administered to participants in this study. Vyxeos will be administered by central venous catheter over 90 minutes on Day 1, 3, and 5.
Venetoclax is given daily by mouth per assigned dose level.
Venetoclax is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Venclexta for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
🇪🇺 Approved in European Union as Venclyxto for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cincinnati Children's Hospital Medical CenterCincinnati, OH
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Who Is Running the Clinical Trial?
Children's Hospital Medical Center, CincinnatiLead 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: 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: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.
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 plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27).
[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial]. [2021]Objective: To investigate the safety and efficacy of venetoclax with low-dose cytarabine (LDAC) in Chinese patients with acute myeloid leukemia (AML) who are unable to tolerate intensive induction chemotherapy. Methods: Adults ≥ 18 years with newly diagnosed AML who were ineligible for intensive chemotherapy were enrolled in this international, randomized, double-blind, placebo-controlled trial. Globally, patients (n=211) were randomized 2∶1 to either venetoclax with LDAC or placebo with LDAC in 28-d cycles, with LDAC on days 1-10. The primary endpoint was OS; the secondary endpoints included response rates, event-free survival, and adverse events. Results: A total of 15 Chinese patients were enrolled (venetoclax arm, n=9; placebo arm, n=6) . The median age was 72 years (range, 61-86) . For the primary analysis, the venetoclax arm provided a 38% reduction in death risk compared with the placebo[hazard ratio (HR) , 0.62 (95%CI 0.12-3.07) ]. An unplanned analysis with an additional 6 months of follow-up demonstrated a median OS of 9.0 months for venetoclax compared with 4.1 months for placebo. The complete remission (CR) rates with CR with incomplete blood count recovery (CRi) were 3/9 (33%) and 0/6 (0%) , respectively. The most common non-hematologic adverse effects (venetoclax vs placebo) were hypokalemia[5/9 (56%) vs 4/6 (67%) ], vomiting[4/9 (44%) vs 3/6 (50%) ], constipation[2/9 (22%) vs 4/6 (67%) ], and hypoalbuminemia[1/9 (11%) vs 4/6 (67%) ]. Conclusion: Venetoclax with LDAC demonstrated meaningful efficacy and a manageable safety profile in Chinese patients consistent with the observations from the global VIALE-C population, making it an important treatment option for patients with newly diagnosed AML who are otherwise ineligible for intensive chemotherapy.
6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). [2022]VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1-23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352.
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.
Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. [2023]In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan.
A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). [2022]Evidence that a venetoclax (VEN)-combined regimen is effective in relapsed/refractory acute myeloid leukemia (R/R AML) is emerging. However, it is unknown how VEN-combined low intensity treatment compares to intensive chemotherapy (IC) in medically fit patients with R/R AML.
Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).