Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Follicular Lymphoma, Richter Transformation Lymphoma
Conditions
Brief summary
The purpose of this study is to assess the safety and tolerability of zilovertamab vedotin as monotherapy and in combination in participants with select B-cell lymphomas including mantle cell lymphoma (MCL), Richter's transformation lymphoma (RTL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). This study will also evaluate zilovertamab vedotin as monotherapy and in combination with respect to objective response rate. * Cohort A: Participants with relapsed or refractory MCL relapsed or refractory disease after at least 2 prior systemic therapies including a Bruton's tyrosine kinase inhibition/inhibitor (BTKi), and post therapy chimeric antigen receptor T (CAR-T) cell therapy or ineligible for CAR-T cell therapy * Cohort B: Participants with relapsed or refractory RT disease after at least 1 prior systemic therapy * Cohort C: Participants with relapsed or refractory MCL relapsed or refractory disease after at least 1 prior systemic therapy and no prior exposure to a non-covalent BTKi * Cohort D: Participants with relapsed or refractory FL and CLL relapsed or refractory disease after at least 2 prior systemic therapies and have no other available therapy * Cohort E: Participants with relapsed or refractory FL after at least 2 prior systemic therapies and have no other available therapy The primary study hypothesis is that zilovertamab vedotin monotherapy has an increased Objective Response Rate (ORR) per Lugano Response Criteria as assessed by blinded independent central review (BICR). As of Amendment 07, Cohort D is closed to enrollment of participants with CLL and enrollment of participants into Arm 2 (zilovertamab vedotin at Dose 2 on Days 1 & 8 of each 3 Week Cycle (Q2/3W)).
Interventions
BIOLOGICALZilovertamab vedotin
IV infusion
DRUGNemtabrutinib
Oral tablet
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The main inclusion criteria include, but are not limited to the following: Inclusion Criteria: * For aggressive B-cell malignancies mantle cell lymphoma (MCL): Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease after at least 2 prior systemic therapies including a Bruton's tyrosine kinase inhibition/inhibitor(s) (BTKi), and is post chimeric antigen receptor T (CAR-T) cell therapy or is ineligible for CAR-T cell therapy. * For aggressive B-cell malignancies MCL Cohort C: Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease after at least 1 prior systemic therapy and has no prior exposure to a non-covalent BTKi. * For aggressive B-cell malignancies Richter transformation lymphoma (RTL): Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease. * For indolent B-cell malignancies follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL): Has histologically confirmed biopsy and has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy. * Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization/allocation. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 assessed within 7 days before cycle 1 day 1.
Exclusion criteria
* Has received solid organ transplant at any time. * 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. * Has pericardial effusion or clinically significant pleural effusion. * Has ongoing Grade \>1 peripheral neuropathy. * Has a demyelinating form of Charcot-Marie-Tooth disease. * Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. * Participants with FL who have transformed to a more aggressive type of lymphoma. * 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. * Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities. * Has ongoing corticosteroid therapy exceeding 30 mg daily of prednisone equivalent. * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. * Has known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma. * Has an active infection requiring systemic therapy. * Has a known history of human immunodeficiency virus (HIV) infection not well controlled on antiretroviral therapy (ART) * Active HBV or hepatitis C virus (HCV) infection. * For Cohort C only: has any clinically significant gastrointestinal abnormalities that might alter absorption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants with MCL (Cohort C), FL (Cohort D), and CLL with ≥1 Adverse Event (AE) | Up to approximately 81 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants with MCL (Cohort C), FL (Cohort D), and CLL who experienced an AE will be reported. |
| Percentage of Participants with MCL (Cohort C), FL (Cohort D), and CLL who Discontinue from Study Therapy Due to AE | Up to approximately 81 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants with MCL (Cohort C), FL (Cohort D), and CLL who discontinued study treatment due to an AE will be reported. |
| Percentage of Participants with MCL (Cohort C) who Experience a Dose-Limiting Toxicity (DLT) | Up to approximately 81 months | The Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 will be used to grade the severity of AEs. DLTs for participants with MCL (Cohort C) as assessed by investigator will be reported. |
| Objective Response Rate (ORR) per Lugano Response Criteria as Assessed by Blinded Independent Central Review (BICR) in Participants with MCL (Cohort A), RT, and FL (Cohorts D & E) | Up to approximately 81 months | ORR, defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) per Lugano Response Criteria as assessed by BICR in Participants with MCL (Cohort A), RT, and FL (Cohorts D \& E) will be reported. |
| ORR per Lugano Response Criteria as Assessed by Investigator in Participants with MCL (Cohort C) | Up to approximately 81 months | ORR, defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) per Lugano Response Criteria as assessed by investigator in Participants with MCL (Cohort C) will be reported. |
| ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Investigator in Participants with CLL | Up to approximately 81 months | ORR, defined as the percentage of participants who achieve a CR or PR per iwCLL criteria as assessed by investigator in participants with CLL will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) per Lugano Response Criteria as Assessed by BICR in Participants with MCL (Cohort A), RT, and FL (Cohorts D & E) | Up to approximately 81 months | DOR, defined as the time from the first documented evidence of CR or PR per Lugano Response Criteria as assessed by BICR, until disease progression or death due to any cause, whichever occurs first, in Participants with MCL (Cohort A), RT, and FL (Cohorts D \& E) will be reported. |
| DOR per Lugano Response Criteria as Assessed by Investigator in Participants with MCL (Cohort C) | Up to approximately 81 months | DOR, defined as the time from the first documented evidence of CR or PR per Lugano Response Criteria as assessed by investigator, until disease progression or death due to any cause, whichever occurs first, in participants with MCL (Cohort C) will be reported. |
| DOR per iwCLL Criteria as Assessed by Investigator in Participants with CLL | Up to approximately 81 months | DOR, defined as the time from the first documented evidence of CR or PR per iwCLL criteria as assessed by investigator, until disease progression or death due to any cause, whichever occurs first, in participants with CLL will be reported. |
| Percentage of Participants with ≥1 AE in Participants with MCL (Cohort A), RT, and FL (Cohort E) | Up to approximately 81 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants with MCL (Cohort A), RTL, and FL (Cohort E) who experienced an AE will be reported. |
| Percentage of Participants Discontinuing from Study Therapy Due to AE in Participants with MCL (Cohort A), RT, and FL (Cohort E) | Up to approximately 81 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants with MCL (Cohort A), RT, and FL (Cohort E) who discontinued study treatment due to an AE will be reported. |
Countries
Brazil, Canada, Chile, China, Czechia, Estonia, Germany, Ireland, Israel, Italy, Japan, Peru, Poland, Portugal, Singapore, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed