A research study to evaluate the safety and effectiveness of Zilovertamab Vedotin with or without Nemtabrutinib in adults with B-cell Malignancies

Phase 1

• Conditions: Aggressive and Indolent B-cell Malignancies; MedDRA version: 20.0Level: PTClassification code 10061275Term: Mantle cell lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 27.0Level: PTClassification code 10085128Term: Follicular lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10058728Term: Richter's syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-004450-36-PL
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2022-05-23
• Last Update Posted: 24 June 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 275

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 verified 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 contrace

Exclusion Criteria

1. Has received solid organ transplant at any time.
2. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina (<6 months prior to enrollment), congestive heart failure (New York Heart Association Classification Class = II), or serious cardiac arrhythmia requiring medication.
3. In participants with prior allo-SCT, acute GVHD or ongoing evidence of chronic GVHD manifesting as Grade =2 serum bilirubin, Grade =3 skin involvement, or Grade =3 diarrhea or requiring systemic immunosuppression for treatment/prophylaxis for their GVHD.
4. Has pericardial effusion or clinically significant pleural effusion.
5. Has ongoing Grade >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, within 5 half-lives or 4 weeks if prior therapy was a monoclonal antibodies or 2 weeks if prior therapy was 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 during the study intervention period and for 30 days after the last dose of study intervention.
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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified