Venetoclax + Obinutuzumab for Leukemia
Palo Alto (17 mi)Overseen byDeborah M Stephens
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: National Cancer Institute (NCI)
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.
What data supports the idea that Venetoclax + Obinutuzumab for Leukemia is an effective drug?The available research does not provide specific data on the effectiveness of Venetoclax + Obinutuzumab for Leukemia. Instead, it focuses on methotrexate and its resistance in leukemia treatment. Therefore, no direct comparison or effectiveness data for Venetoclax + Obinutuzumab is available from the provided information.12345
What safety data exists for Venetoclax + Obinutuzumab in leukemia treatment?The provided research does not contain specific safety data for the combination of Venetoclax (also known as Venclexta, ABT 0199, ABT 199, GDC-0199, RG-7601, RO-5537382, VENCLYXTO, Venclyxto) and Obinutuzumab (also known as Gazyva) in leukemia treatment. The articles focus on chemotherapy-induced nausea and vomiting and do not address the safety profile of Venetoclax and Obinutuzumab.6791011
Is the drug Obinutuzumab, Venetoclax a promising treatment for leukemia?Yes, the combination of Obinutuzumab and Venetoclax is a promising treatment for leukemia. Studies show it leads to longer periods without the disease getting worse and higher rates of complete response compared to other treatments. It is especially beneficial for patients who cannot handle intense chemotherapy.812131415
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any prior CLL-directed therapy or strong inhibitors or inducers of CYP3A4/5. If you're on high-dose corticosteroids for CLL, you must stop at least 4 weeks before enrolling. Please consult with your doctor for specific guidance.
Eligibility Criteria
This trial is for adults diagnosed with high-risk CLL or SLL within the last year, who have not received prior CLL-directed therapy. They must have certain genetic markers, adequate organ function, and no active hepatitis B or C. Participants should be able to take oral medications and agree to quality of life assessments if they can complete forms in specified languages.Inclusion Criteria
I do not have an active hepatitis B or C infection, or if I have latent hepatitis B, I agree to take preventive treatment.
I finished treatment for autoimmune issues from CLL over 4 weeks ago.
I can take medicine by mouth.
My genetic test results from a certified lab are less than a year old.
I am 18 years old or older.
My CLL has a high-risk score or complex genetic changes.
I am taking no more than 20 mg/day of prednisone or its equivalent for a condition other than CLL/SLL.
I can take care of myself and am up and about more than half of my waking hours.
I do not have an active hepatitis B or C infection.
I have never been treated with anti CD20 monoclonal antibodies.
Exclusion Criteria
I do not have uncontrolled autoimmune blood disorders.
I do not meet the criteria for active chronic lymphocytic leukemia treatment.
I do not have serious heart problems like uncontrolled irregular heartbeat or severe heart failure.
I do not have any known bleeding disorders.
I am not on strong medication that affects venetoclax metabolism.
I do not have cirrhosis.
Treatment Details
The study compares early versus delayed treatment using venetoclax (a medication that blocks a protein cancer cells need) and obinutuzumab (an antibody that helps the immune system fight cancer) in patients with newly diagnosed high-risk CLL/SLL to see which timing might lead to better outcomes.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm II (early V-O)Experimental Treatment8 Interventions
Treatment begins as soon as eligibility criteria are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration and biopsy throughout the trial.
Group II: Arm I (delayed V-O)Active Control8 Interventions
Treatment begins once 2018 IWCLL indications are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration and biopsy throughout the trial.
Obinutuzumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
🇪🇺 Approved in European Union as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
Find a clinic near you
Research locations nearbySelect from list below to view details:
Seattle Cancer Care Alliance at Overlake Medical CenterBellevue, WA
Trinity Health Medical Center - CantonCanton, MI
Langlade Hospital and Cancer CenterAntigo, WI
Aspirus Medford HospitalMedford, WI
More Trial Locations
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Who is running the clinical trial?
National Cancer Institute (NCI)Lead Sponsor
References
Selective treatment of SCID mice bearing methotrexate-transport-resistant human acute lymphoblastic leukemia tumors with trimetrexate and leucovorin protection. [2021]Impaired transport of methotrexate (MTX) is a common resistance mechanism of tumor cells to this drug. Trimetrexate (TMTX), a second-generation folate antagonist, is still active against MTX-transport-resistant cells because it enters cells by passive diffusion and does not use the reduced folate transport system for cell entry. Therefore, although leucovorin (LV) protects MTX-sensitive cells from TMTX toxicity, MTX-transport defective cells are poorly rescued by LV. Severe combined immunodeficiency mice bearing MTX-transport-resistant CCRF-CEM acute lymphoblastic leukemia tumors were treated with TMTX alone or with the combination of TMTX and LV, with tumor regressions in both groups (P
Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. [2021]Cellular methotrexate (MTX) resistance may cause treatment failure in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS). After short-term exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX (P
Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. [2019]Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P
Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials. [2022]Methotrexate (MTX) is a key drug in the curative regimen of children with acute lymphocytic leukemia. This drug is widely used not only in the treatment of neoplastic diseases such as leukemia, lymphoma, choriocarcinoma, head and neck cancer and osteogenic sarcoma, but also for various autoimmune diseases, e.g., rheumatoid arthritis and psoriasis, and for the prevention of graft-versus-host disease after transplantation. The development of drug resistance is the limiting factor in the use of MTX. This review will outline the mechanisms of acquired and natural resistance to MTX that have been studied in patients affected by acute lymphocytic leukemia and acute myelocytic leukemia and the cell cycle genes involved in MTX resistance. This information may improve the use of MTX or could lead to the development of better drugs. Moreover a short description of newer antifolates with their mechanisms of action is presented.
Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy. [2021]Methotrexate (MTX) is one of the leading drugs in the treatment of leukemia, but extensive metabolism to 7-hydroxymethotrexate (7-OHMTX) can limit its therapeutic efficacy. In this study we investigated whether 7-OHMTX itself can provoke anti-folate resistance that may further disrupt MTX efficacy. For this purpose, we developed resistance to 7-OHMTX as well as MTX in 2 human leukemia cell lines (CCRF-CEM and MOLT-4) by stepwise exposure to increasing concentrations of 7-OHMTX and MTX. Consequently, both leukemia cell lines displayed marked levels of resistance to 7-OHMTX (> 10-fold) and MTX (> 75-fold). The underlying mechanism of resistance in the MTX-exposed cells was a marked decrease (> 10-fold) in reduced folate carrier (RFC)-mediated cellular uptake of MTX. This was associated with transcriptional silencing of the RFC gene in MTX-resistant CCRF-CEM cells. In contrast, the molecular basis for the resistance to 7-OHMTX was due solely to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity, which conferred more than 100-fold MTX resistance upon a short-term exposure to this drug. This is the first demonstration that 7-OHMTX can provoke distinct modalities of antifolate resistance compared with the parent drug MTX. The implications of this finding for MTX efficacy and strategies to circumvent MTX resistance are discussed.
Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects. [2018]Mirtazapine and olanzapine are easy-to-use psychiatric drugs with potent antinausea effects. Ondansetron and later members of the 'setron class are currently standard treatments for cancer chemotherapy-related nausea and emesis. They are potent 5-HT3 blockers, but it is often not appreciated that mirtazapine and olanzapine bind with similar affinity to 5-HT3 receptors, have a longer half-life, are considerably cheaper than the 'setron class, and often offer better and smoother 24-h nausea control than 'setron class drugs. Mirtazapine and olanzapine often have salutary antianxiety effects and improve sleep quality. They occasionally relieve chemotherapy-related and advanced cancer-related nausea and appetite decrease better than the 'setron group that are specifically marketed for nausea control. Mirtazapine and olanzapine frequently give potent nausea reduction and appetite increase in advanced cancer-related cachexia. Several cytokine changes potentially induced by mirtazapine and olanzapine use are discussed that may have salutary effects in several cancers. We suggest mirtazapine and olanzapine be included as first-line options in treating both chemotherapy- and advanced cancer-related nausea. Multiple clinical and economic advantages of mirtazapine and olanzapine over currently used 'setron class medicines are reviewed. Double-blind studies against the 'setron class drugs are warranted.
Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant. [2022]Rolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP.
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). .
Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate. [2019]Chemotherapy-induced nausea and vomiting (CINV) negatively impacts patients' quality of life. The emetogenicity of high-dose methotrexate in children and adolescents with cancer is incompletely characterized. At our institution, a number of patients with acute lymphoblastic leukemia (ALL) have received aprepitant with courses of high-dose methotrexate after poor CINV control with prior courses.
Hydration requirements with emetogenic chemotherapy: granisetron extended-release subcutaneous versus palonosetron. [2018]This retrospective analysis evaluated chemotherapy-induced nausea and vomiting (CINV)-related hydration needs with palonosetron or granisetron extended-release subcutaneous (GERSC), approved in 2016 for CINV prevention.
Impact of adjuvant lorazepam with granisetron on chemotherapy-induced nausea and vomiting in pediatric patients with acute lymphoblastic leukemia. [2020]Chemotherapy-induced nausea and vomiting (CINV) affects quality of life for patients with cancer undergoing chemotherapy. We aimed to assess the effect of lorazepam with granisetron on CINV in children with acute lymphoblastic leukemia (ALL).
Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
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 consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.
Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. [2022]This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.