Nemtabrutinib for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
+109 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Merck Sharp & Dohme LLC
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?Researchers are looking for new ways to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). CLL and SLL are types of blood cancer. Researchers want to know if people who take nemtabrutinib compared to those who take the standard treatments in this study will live longer without their cancer growing, spreading or returning (progression free survival).
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.
What data supports the idea that Nemtabrutinib for Chronic Lymphocytic Leukemia is an effective drug?
The available research does not provide specific data on Nemtabrutinib for Chronic Lymphocytic Leukemia. However, it does mention other treatments like bendamustine and rituximab, which have shown high response rates in relapsed or refractory cases. For example, bendamustine and rituximab have been effective in improving outcomes, and the combination of venetoclax and rituximab has shown better progression-free survival compared to bendamustine and rituximab. Without specific data on Nemtabrutinib, it's unclear how it compares to these treatments.
12345What safety data is available for Nemtabrutinib in treating Chronic Lymphocytic Leukemia?
The safety data for Nemtabrutinib, also known as MK-1026 or ARQ 531, specifically for Chronic Lymphocytic Leukemia (CLL), is not directly addressed in the provided research. However, safety data for related treatments like Bendamustine and Rituximab, which are often used in combination therapies for CLL, is available. Bendamustine has been associated with hematological events and gastrointestinal disturbances, with late onset neutropenia (LON) being a notable concern, especially in combination with Rituximab. The BRIGHT study indicates that Bendamustine plus Rituximab (BR) is noninferior to standard regimens but has higher incidences of vomiting and drug-hypersensitivity reactions. Close monitoring and prophylactic measures are recommended for managing LON in patients undergoing BR treatment.
678910Is the drug Nemtabrutinib a promising treatment for Chronic Lymphocytic Leukemia?
Nemtabrutinib, when combined with other drugs like bendamustine and rituximab, shows promise in treating Chronic Lymphocytic Leukemia (CLL). These combinations have been effective in improving response rates and managing the disease, especially in patients who have relapsed or have not responded to previous treatments.
1341112Eligibility Criteria
This trial is for adults with untreated CLL/SLL who don't have TP53 mutations. They must need treatment, be able to take pills, and not have had major surgery recently or active hepatitis. People with other progressing cancers or severe bleeding disorders can't join.Inclusion Criteria
I have been diagnosed with CLL/SLL and need treatment.
I can swallow and keep down pills.
I have CLL/SLL without TP53 mutations, and my 11q and IGHV status are known.
Exclusion Criteria
I have no progressing cancer or treated cancer in the last 3 years, except for certain skin cancers or localized cancers that were treated.
I am still recovering from major surgery or have ongoing complications.
I have a history of severe bleeding disorders.
+2 more
Participant Groups
The study compares Nemtabrutinib's effectiveness and safety against standard chemoimmunotherapy (FCR/BR) in extending the time patients live without disease progression. Participants will either receive Nemtabrutinib or a combination of chemotherapy drugs plus Rituximab.
2Treatment groups
Experimental Treatment
Active Control
Group I: NemtabrutinibExperimental Treatment1 Intervention
Administered daily via oral tablet.
Group II: FCR or BRActive Control7 Interventions
Investigator's choice of fludarabine plus cyclophosphamide plus rituximab (FCR) OR bendamustine plus rituximab (BR). Participants will receive either rituximab or specified approved rituximab biosimilar.
Bendamustine is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Treanda for:
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
🇪🇺 Approved in European Union as Ribomustin for:
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
- Multiple myeloma
🇨🇦 Approved in Canada as Levact for:
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
🇯🇵 Approved in Japan as Bendamustine hydrochloride for:
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Highlands Oncology Group ( Site 5205)Springdale, AR
Hattiesburg Clinic Hematology/Oncology ( Site 5216)Hattiesburg, MS
Clermont Oncology Center ( Site 5224)Clermont, FL
Medical Oncology Associates, PS ( Site 5206)Spokane, WA
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Who Is Running the Clinical Trial?
Merck Sharp & Dohme LLCLead Sponsor
References
Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. [2018]Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression-free survival (PFS) after BR is
Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab.
First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. [2022]Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab.
Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. [2019]Despite initial responses > 90% with fludarabine and rituximab-based regimens, patients with chronic lymphocytic leukemia (CLL) invariably relapse and require further treatment. Ofatumumab and bendamustine have each shown efficacy in relapsed/refractory CLL with overall response rates (ORRs) of 58% and 76%, respectively. Given excellent data with bendamustine and rituximab in relapsed/refractory CLL/small lymphocytic lymphoma (SLL), this phase II study evaluated the combination of ofatumumab and bendamustine in previously treated patients. Patients received ofatumumab 300 mg intravenously (IV) day - 7, followed by ofatumumab 1000 mg IV day 1 and bendamustine 70 mg/m(2) days 1 and 2 of each 28-day cycle. Patients received 4-6 cycles depending on number of prior therapies, as long as well-tolerated or until progression. Of 10 patients enrolled, the ORR was 40% and complete response rate was 20%. The median progression-free and overall survivals were 8.1 months and 16.2 months. Three patients developed Richter transformation. The study was closed early due to unexpected adverse events including infusion-related reactions, infection and neurotoxicity.
Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. [2019]The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.
Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. [2022]This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P
Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. [2015]Bendamustine (Treanda(®); Pharmachemie BV, The Netherlands for Cephalon, Inc., PA, USA) is a unique cytotoxic agent with both alkylating and antimetabolite properties. A growing body of evidence demonstrates its efficacy in a number of hematologic malignancies, and as such, it has been US FDA approved for the treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma that has not responded to, or progressed within 6 months of, a rituximab-based regimen. Bendamustine has efficacy both as a single agent as well as in combination with other chemotherapeutics and immunotherapeutics. Here, we will discuss in the detail the molecular properties, clinical efficacy and safety profile of bendamustine.
Description of late onset neutropenia in indolent lymphoma patients treated with bendamustine plus rituximab. [2018]Bendamustine (B) associated with rituximab (R) is widely described in literature for the management of patients with chronic lymphoid leukaemia (CLL) and indolent non-Hodgkin lymphoma. Safety data regarding late hematotoxicity such as late onset neutropenia (LON) are scarce. The aim of our study was to assess the incidence and to identify risk factors for LON in patients with indolent non-Hodgkin lymphoma and CLL treated with B and R (B-R). One hundred forty five patients were treated with B-R as first or second line. Patients with neutropenia prior induction treatment, treated beyond second line and relapsing within 3 months after the end of induction treatment, were excluded. Patients receiving at least 1 cycle of B-R and having LON during follow-up period were included and considered as eligible for toxicity assessment. A complete blood count was performed 4 weeks after the last cycle of induction treatment and thereafter every 3 months for 1 year. Thirty six patients were identified in our cohort (incidence of 25%), mostly affected by CLL (n = 11) and follicular lymphoma (FL) (n = 15). During follow-up, 84 events of LON were recorded, 61% and 39% were of grades 1/2 and 3/4, respectively. No episode of febrile neutropenia was documented. Amongst 13 of the 15 patients with FL undergoing R maintenance, 8 had treatment discontinuation because of LON. Median time for LON (grade > 2) and time to recovery (grade 1. The LON in B-R treated patients is clinically relevant. Close clinical and biological follow-up and treatment prophylaxis (eg, valaciclovir and cotrimoxazole) especially for FL patients undergoing maintenance with R monotherapy seems relevant.
Bendamustine. [2018]Bendamustine is a bifunctional alkylating agent with cytotoxic activity against human ovarian and breast cancers in vitro. It shows only partial in vitro cross-resistance with cyclophosphamide, melphalan, carmustine and cisplatin. Bendamustine as monotherapy or as part of combination chemotherapy protocols for first-line or subsequent treatment produced objective response rates of 61 to 97% in patients with Hodgkin's disease or non-Hodgkin's lymphoma (NHL) [41 to 48% in high grade NHL]. In patients with multiple myeloma, a bendamustine/prednisone regimen produced a higher rate of complete response (32 vs 11%) and more durable responses than a melphalan/prednisone regimen. Substitution of bendamustine for cyclophosphamide in a standard first-line COP regimen (cyclophosphamide, vincristine and prednisolone) yielded similar response rates in patients with advanced low grade NHL. Substituting bendamustine for cyclophosphamide in the CMF protocol (cyclophosphamide, methotrexate and fluorouracil) prolonged remission from 6.2 to 15.2 months in patients with metastatic breast cancer. The most common adverse events in patients receiving bendamustine are haematological events and gastrointestinal disturbances. Bendamustine has a relatively low propensity to induce alopecia.
Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma. [2021]Exposure-response relationships were investigated to assess the risk/benefit of polatuzumab vedotin (pola) + bendamustine-rituximab (pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Analyses were conducted in pivotal study GO29365 (NCT02257567; BR/pola + BR/pola + BG [BG: bendamustine-obinutuzumab]; 1.8 mg/kg pola, every 3 weeks [Q3W], six cycles), and supportive studies DCS4968g (NCT01290549) and GO27834 (NCT01691898) (pola/pola + R/pola + G; 0.1-2.4 mg/kg pola Q3W; eight-cycle landmark), separately. Exposure was characterized as simulated cycle-6 AUC and Cmax for antibody-conjugated mono-methyl auristatin E (acMMAE) and unconjugated MMAE. Supportive studies showed response rate and safety risk (grade ≥2 peripheral neuropathy; grade ≥3 anemia) increased with exposure, suggesting not to dose below 1.8 mg/kg (up to eight-cycle) for balancing safety and efficacy. Pivotal study with limited exposure range showed no exposure-safety relationship and slightly positive exposure (acMMAE)-efficacy relationship for overall survival. The exposure-response analyses and the observed risk/benefit characteristics in pivotal study supported pola (1.8 mg/kg) +BR Q3W for six cycles in R/R DLBCL patients.
[Chronic lymphocytic leukemia: current standards and novel approaches]. [2018]Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world and affects mainly elderly patients. In current phase III trials, standard treatment options were established that differ mainly based on the fitness and age of the patient. The combination of fludarabine, cyclophosphamide, and the CD20 antibody rituximab (FCR) is recommended for young patients without relevant comorbidity, while bendamustine and rituximab (BR) should be favored for elderly (ca. >65 years) fit individuals. Bendamustine plus ofatumumab is another option in this situation. Patients with major comorbidities should receive chlorambucil combined with CD20 antibody (obinutuzumab or ofatumumab). In 2014, several new compounds were approved for patients with ultrahigh risk genetic factors (17p-, TP53mut) and for relapsed/refractory CLL: both idelalisib and ibrutinib are orally bioavailable kinase inhibitors that block key regulators of central pathways. For both agents, very impressive data are available with regard to tolerability and efficacy that will change the treatment paradigm in CLL. With ABT-199, a direct apoptosis inducer is being developed that in early clinical trials produced high remission rates combined with good tolerability. Combinations and sequences of the "novel" compounds obinutuzumab, ofatumumab, idelalisib, ibrutinib, and ABT-199 will be studied in coming years in clinical trials in order to prolong remission duration and reduce side effects with the eventual aim of curing CLL.
Novel agents for chronic lymphocytic leukemia. [2021]Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL.