Venetoclax Combination Therapy for Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: CYP3A4 inducers, Live vaccines
Disqualifiers: T cell ALL, Active infection, Others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
This phase I trial tests the safety, side effects, and best dose of venetoclax in combination with a pediatric-inspired chemotherapy regimen known as C10403 in treating patients with newly diagnosed B cell acute lymphoblastic leukemia. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. The C10403 regimen is composed of the chemotherapy drugs cytarabine, cyclophosphamide, daunorubicin, mercaptopurine, pegaspargase, vincristine, and methotrexate, all which work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It also consists of prednisone, which is an anti-inflammatory drug that lowers the body's immune response and is used with other drugs in the treatment of some types of some types of cancer. This study may help researchers learn if adding venetoclax to the pediatric-inspired C10403 regimen can be tolerated and help treat older patients.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot take strong or moderate CYP3A4 inducers within 14 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.
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 longer progression-free survival when used in combination with other drugs like obinutuzumab and rituximab. It is also being developed for use in acute myeloid leukemia and other blood cancers, indicating its potential effectiveness in various types of leukemia.12345
What safety data exists for Venetoclax combination therapy in humans?
Venetoclax, also known as Venclexta, has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Common side effects include myelosuppression (a decrease in bone marrow activity) and neutropenia (low levels of a type of white blood cell), which can be managed with supportive care and dose adjustments. No new safety concerns were identified in children and adolescents with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL).12567
What makes Venetoclax combination therapy unique for treating leukemia?
Venetoclax is unique because it specifically targets and inhibits a protein called BCL-2, which helps cancer cells survive, making it different from traditional chemotherapy that targets rapidly dividing cells. This targeted approach can potentially lead to fewer side effects and improved effectiveness in treating leukemia.89101112
Eligibility Criteria
Adults aged 18-54 with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) can join this trial. They must be in good physical condition, not pregnant or breastfeeding, and willing to use non-hormonal birth control. People with certain heart conditions, other cancers, uncontrolled infections or those who have taken strong medications that affect liver enzymes recently cannot participate.Inclusion Criteria
Alanine aminotransferase (ALT) =< 2.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
My leukemia involves the bone marrow.
Note: Echocardiogram to be performed within 42 days prior to day 1 of protocol therapy
See 15 more
Exclusion Criteria
I do not have any other active cancer.
I have not received any live vaccines recently.
You have eaten grapefruit, grapefruit products, Seville oranges, or star fruit within three days before starting the study drug.
See 14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Induction
Patients receive venetoclax and a combination of chemotherapy drugs including cytarabine, prednisone, vincristine, daunorubicin, pegaspargase, and methotrexate
4 weeks
Weekly visits for drug administration
Extended Induction
Patients continue to receive venetoclax and chemotherapy drugs if they have stable disease or partial response after initial induction
2 weeks
Consolidation
Patients receive venetoclax and a combination of chemotherapy drugs including cyclophosphamide, cytarabine, mercaptopurine, vincristine, pegaspargase, and methotrexate
12 weeks
Bi-weekly visits for drug administration
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 1 year
Every 3 months
Treatment Details
Interventions
- C10403 (Chemotherapy)
- Venetoclax (Bcl-2 Inhibitor)
Trial OverviewThe trial is testing the safety and optimal dose of a drug called Venetoclax when added to a pediatric-inspired chemotherapy regimen (C10403). This combination targets cancer cell growth by blocking essential proteins and using various chemo drugs to kill or stop cancer cells from dividing.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Treatment (venetoclax, C10403 regimen)Experimental Treatment9 Interventions
See Detailed Description
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
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.
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.
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: 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 for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. [2022]Venetoclax is approved for adult patients with chronic lymphocytic leukemia and acute myeloid leukemia. Expanding its use to the pediatric population is currently under investigation, but more robust data are needed. We retrospectively analyzed the safety and efficacy of venetoclax in children/AYA with ALL/LBL. We identified 18 patients (T-cell ALL, n = 7; T-cell LBL, n = 6; B-cell ALL, n = 5) aged 6-22 years. No new venetoclax safety signals were identified; the most common toxicity was myelosuppression. No deaths occurred within 30 days from the start of the therapy. A mean of 2.6 (range 0-8) prior lines of therapy were given. The mean duration of venetoclax was 4.06 months (range 0.2-24.67 months). Complete remission was achieved in 11 (61%) patients. Of the eight patients who remain alive, four are continuing on venetoclax combination therapy, and four proceeded to hematopoietic stem cell transplantation. Three patients who initially achieved CR, later relapsed, and are deceased. Nine patients are deceased, and one patient was lost to follow-up. Overall survival is 9.14 months (range 1.1-33.1), and progression-free survival is 7.34 months (range 0.2-33.1). This is the largest cohort of pediatric/AYA patients who received venetoclax for ALL/LBL. Our data support the consideration of venetoclax-based regimens in pediatric patients with R/R ALL/LBL and its investigation as upfront therapy for T-cell ALL/LBL.
Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported.
Paclitaxel-based combination chemotherapy for breast cancer. [2015]Clinical trials to develop paclitaxel (Taxol)-containing combinations started in 1992 with several approaches to combine doxorubicin and paclitaxel. Schedule-dependent toxicity limited doses in the initial trials, although antitumor activity was high. More recently, a well-tolerated, highly effective doxorubicin/paclitaxel regimen was developed with the use of bolus anthracycline administration and a 3-hour infusion of paclitaxel. Combinations of paclitaxel with cisplatin have provided mixed results. Paclitaxel combined with fluorouracil (5-FU) and folinic acid proved effective in patients with extensive prior chemotherapy; the addition of mitoxantrone (Novantrone) to this combination was feasible, well tolerated, and possibly enhanced the efficacy of paclitaxel and 5-FU. Combinations of paclitaxel with cyclophosphamide (Cytoxan, Neosar), vinorelbine (Navelbine), edatrexate, and radiation continue in clinical development.
Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018]Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC.
Paclitaxel combination therapy in the treatment of metastatic breast cancer: a review. [2015]Combinations of active antineoplastic agents have been the most effective treatment for metastatic breast cancer. Criteria for an effective combination include use of drugs with different mechanisms of action, nonoverlapping toxic effects, and synergistic, or at least additive, antitumor activity. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with its unique mechanism of action, offers an excellent opportunity for development of effective combination therapy against breast cancer. However, a number of problems have hindered the rapid development of effective combinations. The most obvious problem is the lack of a defined optimal dose and schedule of administration. The second problem has been the demonstration of unexpected interactions between paclitaxel and the other component(s) of the combination, often resulting in unusual and serious toxic effects. This review will focus on the phase I and II trials of paclitaxel in combination with established antineoplastic drugs (except doxorubicin and congeners, which is covered elsewhere in this issue) for breast cancer: cisplatin, 5-fluorouracil with or without folinic acid, cyclophosphamide, radiation therapy, as well as novel investigational agents or strategies, edatrexate, monoclonal antibodies to oncogenes, growth factors, and gene therapy with insertion of multidrug resistance gene into blood stem cells. Combination therapy offers exciting possibilities of enhanced antitumor efficacy. However, given the unexpected and serious toxic effects observed, only proven combinations should be used outside the context of a clinical trial. Additionally, the burden of proof will be to show that these combinations have increased antitumor activity, decreased toxicity, or both compared with single-agent paclitaxel.
Antimetaboliths in the prophylaxis and treatment of central nervous system leukemia. [2013]The results of the administration of two antimetabolites, methotrexate (MTX) and cytosine arabinoside (Ara-C), for the prevention and treatment of established central nervous system (CNS) disease in children with acute lymphoblastic leukemia are discussed. Two protocols (L-2 and L-10) for the management of patients with acute lymphoblastic leukemia have been developed. In the L-2 protocol, prophylaxis consists of repeated intralumbar injections of MTX alone, and in the L-10 regimen, both MTX and Ara-C are administered; for the patients with an initial leukocyte count of greater than or equal to 25,000/mm3, the two drugs are given intraventricularly instead of by the usual intralumbar route. In the treatment of established CNS leukemia, intralumbar MTX and Ara-C in addition to CNS irradiation are employed; for maintenance, periodic intraventricular MTX injections are given. Of the 70 children receiving the L-2 protocol, four developed CNS leukemia and in a fifth patient, CNS and bone marrow relapse were concurrent. Among the 31 children receiving the L-10 regimen, CNS disease has been observed in only one child. Of the five children treated for the established CNS leukemia, recurrence was observed in two at 19 and 29 months after remission; the other three remain in remission for 2, 15, and 39 months, respectively.
Toxicity study of cytosine arabinoside and methotrexate in the maintenance therapy of childhood leukemia. A Southwest Oncology Group study. [2019]In a toxicity study to determine the feasibility of treating patients with acute lymphocytic leukemia (ALL) using an intravenous combination of cytosine arabinoside (Ara-C) and methotrexate (MTX), the drugs were given either simultaneously or sequentially every two weeks. Twenty-nine patients were studied, 17 treated simultaneously, 12 treated sequentially. The tolerated doses of Ara-C and MTX were 60 mg/m2 and 90 mg/m2, respectively, for the simultaneous treatment schedule and 90 mg/m2 and 150 mg/m2, respectively, for the sequential treatment schedule. The dose-limiting factor of the drug combination was gastrointestinal toxicity. The observed recurrent vomiting on both schedules rendered the treatment unsuitable for maintenance therapy.