C911 Chronic lymphocytic leukaemia of B-cell type Chronic lymphocytic leukaemia of B-cell type
Conditions
Interventions
Nemtabrutinib as 5 mg and 20 mg tablets. 65 mg will be administered orally, every day, until disease progression, unacceptable toxicity or until discontinuation criteria are met. - Ibrutinib as 140 mg
Sponsors
Merck Sharp & Dohme LLC., (una subsidiaria de Merck & Co. Inc.)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Type of Participant and Disease Characteristics: Confirmed diagnosis of CLL/SLL and active disease clearly documented to have a need to initiate therapy. At least 1 of the following criteria should be met: - Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hb 1.5 cm in longest diameter when assessed by CT/MRI scan. - Absolute lymphocyte count >4 × 109/l. - Platelet count <100 × 109/l. - Hemoglobin <11 g/dL Type of Participant and Disease Characteristics: Provision of peripheral blood, bone marrow aspirate, and/or a lymph node sample as specified in the SoA (Section 1.3.1) and Appendix 13 for determination of del(17p) status and TP53 mutation status, both determined by central testing. This is required before randomization. - Del(17p) indeterminate is eligible only if TP53 mutation is present. - TP53 indeterminate is eligible only if del(17p) is detected. Type of Participant and Disease Characteristics: An ECOG PS of 0 to 2 within 7 days before randomization. Type of Participant and Disease Characteristics: The ability to swallow and retain oral medication. NOTE: Administration of nemtabrutinib is not permitted through a J-PEG tube. Type of Participant and Disease Characteristics: Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV DNA viral load before randomization. NOTE: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. Hepatitis B screening tests, including HBsAg and anti-HBc, are required for all participants. See Appendix 7 for country
Exclusion criteria
Exclusion criteria: Medical Conditions: History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder. Medical Conditions: Active HBV/HCV infection. See Inclusion Criteria 6 (HBV) and 7 (HCV) for requirements. Medical Conditions: Gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy). Medical Conditions: Diagnosis of Richter Transformation or active CNS involvement by CLL/SLL. Medical Conditions: AIDS-defining opportunistic infection in the past 12 months before screening. Medical Conditions: QTc prolongation (defined as a QTcF >450 msecs) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min). Medical Conditions: Hypersensitivity to nemtabrutinib or contraindication to ibrutinib or acalabrutinib (eg, Child-Pugh Class C hepatic impairment), or any of the excipients. NOTE: Refer to the IB for details regarding excipients for nemtabrutinib and the current prescribing information for ibrutinib or acalabrutinib. Medical Conditions: History of severe bleeding disorder. Prior/Concomitant Therapy: Has received any systemic anticancer therapy for CLL/SLL Prior/Concomitant Therapy: Currently being treated with the following drugs: a. P-gp substrates with a narrow therapeutic index b. CYP3A strong inducers c. CYP3A strong inhibitors - CYP3A moderate inhibitors are not excluded, but coadministration with ibrutinib or acalabrutinib may require dose modifications. - Consult the current version of the relevant prescribing information as stated in Section 6.6.2. NOTE: - A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment. - Refer to Section 6.5 and Appendix 8 regarding prohibited concomitant medications and potential drug interactions after participant randomization. Prior/Concomitant Therapy: Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention. Prior/Concomitant Therapy: Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Refer to Section 6.5 for information on COVID-19 vaccines. Prior/Concurrent Clinical Study Experience: Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. Diagnostic Assessments: History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. Diagnostic Assessments: Diagnosis of immunodeficiency or is receiving chronic systemic steroid th
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Testing: Stratified Wald method for NI Estimation: Stratified Mantel- Haenszel method NAME OF THE RESULT: Secondary Efficacy Endpoint: Objective response (OR) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Have CR (complete response), CRi, nPR or PR (partial response) according to the iwCLL 2018 criteria, as assessed by the BICR;Testing: Stratified log-rank test for superiority Estimation: Stratified Cox model with Efron’s tie handling method NAME OF THE RESULT: Secondary Efficacy Endpoint: Progression-free survival (PFS) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Time from randomization to first documented disease progression according to iwCLL criteria, as assessed by BICR, or death from any cause, whichever occurs first. | — |
Secondary
| Measure | Time frame |
|---|---|
| Testing: Stratified Wald method for NI Estimation: Stratified Mantel- Haenszel method NAME OF THE RESULT: Secondary Efficacy Endpoint: Objective response (OR) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Have CR (complete response), CRi, nPR or PR (partial response) according to the iwCLL 2018 criteria, as assessed by the BICR;Testing: Stratified log-rank test for superiority Estimation: Stratified Cox model with Efron’s tie handling method NAME OF THE RESULT: Secondary Efficacy Endpoint: Progression-free survival (PFS) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Time from randomization to first documented disease progression according to iwCLL criteria, as assessed by BICR, or death from any cause, whichever occurs first.;Testing: Stratified log-rank test Estimation: Stratified Cox model with Efron’s tie handling method NAME OF THE RESULT: Secondary Efficacy Endpoint: Overall survival (OS) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Time from randomization to death due to any cause.;Kaplan-Meier method NAME OF THE RESULT: Secondary Efficacy Endpoint: Duration of response (DOR) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Time from first documented evidence of CR, CRi, nPR, or PR leading to response until disease progression or death from any cause, whichever occurs first.;They will be evaluated by clinical review of all relevant parameters, including AEs, laboratory test results, ECGs, and vital signs. NAME OF THE RESULT: Secondary safety endpoints: Safety and tolerability PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: AEs are monitored for 30 days after the last dose; SAEs are monitored for 90 days after the last dose or 30 days after the last dose if the participant st | — |
Countries
Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Czech Republic, Denmark, Germany, Greece, Israel, Japan, Malasya, Mexico, Norway, Peru, Poland, Portugal, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United Kindgdom
Contacts
Public ContactNELVA GARCIA
MERCK SHARP & DOHME PERU S.R.L.
Outcome results
None listed