Aggressive and Indolent B-cell Malignancies MedDRA version: 20.0 Level: PT Classification code 10061275 Term: Mantle cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 24.0 Level: PT Classification code 10085128 Term: Follic
Conditions
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. For aggressive B-cell malignancies: • Cohort A: a. Has biopsy proven histologically confirmed MCL. AND b. Has relapsed or refractory disease after at least 2 prior systemic therapies • Cohort B: a. Has biopsy proven histologically confirmed RT AND b. Has relapsed or refractory disease after at least 1 prior systemic therapy. • Cohort C: a. Has biopsy proven histologically confirmed MCL AND b. Has relapsed or refractory disease after at least 1 prior systemic therapy, has no prior exposure to a non-covalent BTKi. 2. For indolent B-cell malignancies, Part 1: • Cohort D: a. Has biopsy proven histologically confirmed FL Grade 1-3A AND b. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy. OR c. Has histologically confirmed CLL AND d. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy. 3. For indolent B-cell malignancies, Part 2: • Cohort E: a. Has biopsy proven histologically confirmed FL Grade 1-3A AND b. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy. • Cohort F: a. Has histologically confirmed CLL AND b. Has relapsed c or refractory d disease after at least 2 prior systemic therapies and no other available therapy. 4. Disease status requirements: • For Cohorts A and B: a. Has PET positive disease verified by BICR at Screening b. Has radiographically measurable disease per the Lugano Response Criteria, as assessed locally by the investigator and confirmed by BICR. • For Cohort C: a. Has PET positive assessed locally by investigator at Screening, defined as 4-5 on the Lugano 5-point scale. b. Has radiographically measurable disease per the Lugano Response Criteria • For Cohort D and E: a. Has radiographically measurable disease per the Lugano Response Criteria, OR b. Has PET positive disease verified by BICR at Screening defined as 4-5 on a 5-point scale. • For Cohorts D, and F: symptomatic disease that mandates treatment • For Cohorts D (FL) and E: clinical features that mandate treatment such as high tumor burden according to the modified GELF criteria. 5. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. 6. Participants with history of HCV infection are eligible if HCV viral load is undetectable at Screening. 7. Is male or female, from 18 years of age inclusive, at the time of providing informed consent. 8. If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: - Zilovertamab vedotin: 110 days - Nemtabrutinib: 12 days • Refrains from donating sperm PLUS either: • Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent OR • Uses contraception unless confirmed to be azoospermic 9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Not a WOCBP OR • A WOCBP and: - Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle. The length of time required to continue contrac
Exclusion criteria
Exclusion criteria: 1. Has received solid organ transplant at any time. 2. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (1 peripheral neuropathy. 6. Has a demyelinating form of Charcot-Marie-Tooth disease. 7. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. 8. Participants with FL who have transformed to a more aggressive type of lymphoma. 9. Has received prior therapy with a ROR1-directed therapy. 10. Has contraindication to any of the study intervention components. 11. Has received prior systemic anticancer therapy, including investigational agents, within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibodies) or 2 weeks (small molecules like kinase inhibitors) prior to the first dose of study intervention. 12. Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease. 13. Has ongoing corticosteroid therapy exceeding 30 mg daily of prednisone equivalent. If taken, prednisone equivalent dosing of =30 mg daily must have been stable for at least 4 weeks prior to C1D1 unless corticosteroid treatment is required for lymphoma symptom control prior to C1D1. In that case, up to 100 mg per day of prednisone equivalent can be given for up to 5 days, and tumor assessments must have been completed prior to the start of corticosteroid treatment. 14. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. 15. Has received a strong inhibitor or inducer of CYP3A4 (including itraconazole, ketoconazole, posaconazole, or voriconazole) within 7 days prior to C1D1 or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer until <30 days after the last IMP dose. 16. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. 17. Has known active CNS lymphoma involvement or active CNS involvement by lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease) and clinical remission. 18. Has an active infection requiring systemic therapy. 19. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority. 20. Active HBV or HCV infection. 21. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): 1. Percentage of participants with =1 adverse event (AE) [Cohorts C and D] 2. Percentage of participants discontinuing from study therapy due to AE (Cohorts C and D) 3. Percentage of participants with dose-limiting toxicity (DLT) [Cohort C] 4. Objective response rate (ORR) per Lugano Response Criteria as assessed by blinded independent central review (BICR) 5. ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as assessed by investigator;Main Objective: 1. To evaluate the safety and tolerability of zilovertamab vedotin 2. To evaluate the safety and tolerability of zilovertamab vedotin in combination with nemtabrutinib 3. To evaluate zilovertamab vedotin with respect to objective response rate 4. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to objective response rate ;Secondary Objective: 1. To evaluate zilovertamab vedotin with respect to duration of response 2. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to duration of response 3. To evaluate the safety and tolerability of zilovertamab vedotin ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 57 months 2. Up to approximately 57 months 3. Up to approximately 57 months 4. Up to approximately 57 months 5. Up to approximately 57 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Duration of response (DOR) per Lugano Response Criteria as assessed by BICR 2. DOR per iwCLL Criteria as assessed by investigator 3. Percentage of participants with =1 AE (Cohorts A, B, E, and F) 4. Percentage of participants discontinuing from study therapy due to AE (Cohorts A, B, E, and F);Timepoint(s) of evaluation of this end point: 1. Up to approximately 57 months 2. Up to approximately 57 months 3. Up to approximately 57 months 4. Up to approximately 57 months | — |
Countries
Brazil, Canada, Chile, Czechia, Czech Republic, Estonia, Germany, Ireland, Israel, Italy, Korea, Republic of, Malaysia, Peru, Poland, Portugal, Russian Federation, Singapore, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactSónia Cândido
Merck Sharp & Dohme, Lda
Outcome results
None listed