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

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 2

Conditions: Follicular Lymphoma; Mantle Cell Lymphoma; Chronic Lymphocytic Leukemia; Richter Transformation Lymphoma

Treatments: Biological: Zilovertamab vedotin; Drug: Nemtabrutinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT05458297

jRCT2011230019 (Registry Identifier)

U1111-1280-1849 (Registry Identifier)

2140-006

2022-501374-19-00 (Registry Identifier)

MK-2140-006 (Other Identifier)

2021-004450-36 (EudraCT Number)

Details and patient eligibility

About

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)).

Enrollment: 223 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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223 participants in 5 patient groups

Cohort A, Relapsed or Refractory MCL with 2 Prior Lines of Therapy

Experimental group

Description:

Participants will receive zilovertamab vedotin intravenous (IV) infusion at Dose 1 every 3 weeks (Q3W) until disease progression or discontinuation.

Treatment:

Biological: Zilovertamab vedotin

Cohort B, Relapsed or Refractory RT with 1 Prior Line of Therapy

Experimental group

Description:

Participants will receive zilovertamab vedotin IV infusion at Dose 1 every 3 weeks (Q3W) until disease progression or discontinuation.

Treatment:

Biological: Zilovertamab vedotin

Cohort C, Relapsed or Refractory MCL with 1 Prior Line of Therapy

Experimental group

Description:

Participants will receive zilovertamab vedotin IV infusion at Dose 2 every 3 weeks (Q3W) combined with nemtabrutinib oral dose daily until disease progression or discontinuation.

Treatment:

Drug: Nemtabrutinib

Biological: Zilovertamab vedotin

Cohort D, Relapsed or Refractory FL and CLL with 2 Prior Lines of Therapy

Experimental group

Description:

Participants will receive either zilovertamab vedotin IV infusion Dose 1 every 3 weeks (Q3W) until disease progression or discontinuation.

Treatment:

Biological: Zilovertamab vedotin

Cohort E, Relapsed or Refractory FL with 2 Prior Lines of Therapy

Experimental group

Description:

Participants will receive either zilovertamab vedotin IV infuison Dose 1 every 3 weeks (Q3W) until disease progression or discontinuation.

Treatment:

Biological: Zilovertamab vedotin