A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies (MK-2140-006)

Sponsor: Merck Sharp & Dohme LLC

Sponsor score: 40

ClinicalTrials ID:NCT05458297

This study evaluates the safety and efficacy of zilovertamab vedotin, alone and with nemtabrutinib, in relapsed/refractory B-cell malignancies. Eligible participants have specific prior treatment histories and meet WHO classification criteria. Interventions include IV zilovertamab vedotin and oral nemtabrutinib. Participants must have an ECOG status of 0-2 and controlled HBV if applicable.

Patient Parameters

Program Overview

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)).

Eligibility Criteria

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.
  • Active HBV or hepatitis C virus (HCV) infection.
  • For Cohort C only: has any clinically significant gastrointestinal abnormalities that might alter absorption.

Locations

FACILITYZIPCITYSTATE
Alaska Oncology and Hematology ( Site 0037)99508AnchorageAlaska
Banner MD Anderson Cancer Center ( Site 0040)85234GilbertArizona
Banner MD Anderson Cancer Center - University Medical Center Phoenix-Medical Oncology ( Site 0036)85006PhoenixArizona
University of Colorado Anschutz Medical Campus-The Center for Cancer and Blood Disorders ( Site 000880045AuroraColorado
Cancer Care Specialists of Illinois ( Site 0031)62526DecaturIllinois
University of Kansas Medical Center-Division of Hematologic Malignancies and Cellular Therapeutics (66205FairwayKansas
Norton Women's and Children's Hospital-Norton Cancer Institute - St. Matthews ( Site 0007)40207Saint MatthewsKentucky
Greenebaum Comprehensive Cancer Center-Hematology & Multiple Myeloma ( Site 0010)21201BaltimoreMaryland
Tufts Medical Center ( Site 0024)02111BostonMassachusetts
Massachusetts General Hospital ( Site 0018)02114BostonMassachusetts

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