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

• ClinicalTrials.gov Identifier: NCT05458297
• Recruitment Status: Recruiting
• First Posted: July 14, 2022
• Last Update Posted: May 10, 2024
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 11, 2022
• First Posted Date: July 14, 2022
• Last Update Posted Date: May 10, 2024
• Actual Study Start Date: July 21, 2022
• Estimated Primary Completion Date: March 13, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 10, 2022)

• Percentage of Participants with ≥1 Adverse Event (AE) [cohort C and D] [ Time Frame: Up to approximately 57 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, FL, and CLL who experienced an AE will be reported.
• Percentage of Participants Discontinuing from Study Therapy Due to AE (cohort C and D) [ Time Frame: Up to approximately 57 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, FL, and CLL who discontinued study treatment due to an AE will be reported.
• Percentage of Participants with Dose-Limiting Toxicity (DLT) [cohort C] [ Time Frame: Up to approximately 57 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 as assessed by investigator will be reported.
• Objective Response Rate (ORR) per Lugano Response Criteria as Assessed by Blinded Independent Central Review (BICR) [cohorts A, B, E and FL participants in D] [ Time Frame: Up to approximately 57 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 will be reported.
• ORR per Lugano Response Criteria as Assessed by Investigator (cohort C) [ Time Frame: Up to approximately 57 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 will be reported.
• ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Investigator [ Time Frame: Up to approximately 57 months ]
  ORR, defined as the percentage of participants who achieve a CR or PR per iwCLL criteria as assessed by investigator will be reported.

Original Primary Outcome Measures (submitted: July 11, 2022)

• Percentage of Participants with ≥1 Adverse Event (AE) [MCL, FL, and CLL] [ Time Frame: Up to approximately 57 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, FL, and CLL who experienced an AE will be reported.
• Percentage of Participants Discontinuing from Study Therapy Due to AE (MCL, FL, and CLL) [ Time Frame: Up to approximately 57 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, FL, and CLL who discontinued study treatment due to an AE will be reported.
• Percentage of Participants with Dose-Limiting Toxicity (DLT) [ Time Frame: Up to approximately 57 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 as assessed by investigator will be reported.
• Objective Response Rate (ORR) per Lugano Response Criteria as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 57 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 will be reported.
• ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Investigator [ Time Frame: Up to approximately 57 months ]
  ORR, defined as the percentage of participants who achieve a CR or PR per iwCLL criteria as assessed by investigator will be reported.

Current Secondary Outcome Measures (submitted: November 10, 2022)

• Duration of Response (DOR) per Lugano Response Criteria as Assessed by BICR (cohorts A, B, D (FL), and E) [ Time Frame: Up to approximately 57 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, will be reported.
• DOR per Lugano Response Criteria as Assessed by Investigator (cohort C) [ Time Frame: Up to approximately 57 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, will be reported.
• DOR per iwCLL Criteria as Assessed by Investigator (cohorts D [CLL] and F) [ Time Frame: Up to approximately 57 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, will be reported.
• Percentage of Participants with ≥1 AE (cohorts A, B, E, and F) [ Time Frame: Up to approximately 57 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, RTL, FL, and CLL who experienced an AE will be reported.
• Percentage of Participants Discontinuing from Study Therapy Due to AE (cohorts A, B, E, and F) [ Time Frame: Up to approximately 57 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, RTL, FL, and CLL who discontinued study treatment due to an AE will be reported.

Original Secondary Outcome Measures (submitted: July 11, 2022)

• Duration of Response (DOR) per Lugano Response Criteria as Assessed by BICR [ Time Frame: Up to approximately 57 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, will be reported.
• DOR per iwCLL Criteria as Assessed by Investigator [ Time Frame: Up to approximately 57 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, will be reported.
• Percentage of Participants with ≥1 AE (MCL, RTL, FL, and CLL) [ Time Frame: Up to approximately 57 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, RTL, FL, and CLL who experienced an AE will be reported.
• Percentage of Participants Discontinuing from Study Therapy Due to AE (MCL, RTL, FL, and CLL) [ Time Frame: Up to approximately 57 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, RTL, FL, and CLL who discontinued study treatment due to an AE will be reported.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies (MK-2140-006)
• Official Title: A Multicenter, Open-label, Phase 2 Basket Study to Evaluate the Safety and Efficacy of MK-2140 as a Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies

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
• Cohort F: Participants with relapsed or refractory CLL 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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Lymphocytic Leukemia
• Mantle Cell Lymphoma
• Follicular Lymphoma
• Richter Transformation Lymphoma

Intervention

• Biological: Zilovertamab vedotin
  IV infusion
  Other Name: MK-2140
• Drug: Nemtabrutinib
  65 mg once daily (QD) orally
  Other Name: MK-1026

Study Arms

• Experimental: Cohort A
  Participants will receive zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) until disease progression or discontinuation.
  Intervention: Biological: Zilovertamab vedotin
• Experimental: Cohort B
  Participants will receive zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) until disease progression or discontinuation.
  Intervention: Biological: Zilovertamab vedotin
• Experimental: Cohort C
  Participants will receive zilovertamab vedotin every 3 weeks (Q3W) combined with nemtabrutinib daily until disease progression or discontinuation.
  Interventions:

  • Biological: Zilovertamab vedotin
  • Drug: Nemtabrutinib
• Experimental: Cohort D
  Participants will receive either zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) or 2.0 mg/kg with infusions on Days 1 and 8 of each 3 week cycle (Q2/3W) until disease progression or discontinuation.
  Intervention: Biological: Zilovertamab vedotin
• Experimental: Cohort E
  Participants will receive either zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) or 2.0 mg/kg with infusions on Days 1 and 8 of each 3 week cycle (Q2/3W) until disease progression or discontinuation.
  Intervention: Biological: Zilovertamab vedotin
• Experimental: Cohort F
  Participants will receive either zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) or 2.0 mg/kg with infusions on Days 1 and 8 of each 3 week cycle (Q2/3W) until disease progression or discontinuation.
  Intervention: Biological: Zilovertamab vedotin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 10, 2022): 275
• Original Estimated Enrollment (submitted: July 11, 2022): 260
• Estimated Study Completion Date: April 26, 2027
• Estimated Primary Completion Date: March 13, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

The main inclusion criteria include, but are not limited to the following:

Inclusion Criteria:

• For aggressive B-cell malignancies 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 FL and 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Brazil, Canada, Chile, China, Czechia, Estonia, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Peru, Poland, Portugal, Singapore, Spain, Sweden, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05458297
• Other Study ID Numbers: 2140-006; MK-2140-006 ( Other Identifier: Merck ); jRCT2011230019 ( Registry Identifier: Japan Registry of Clinical Trials (jRCT) ); 2021-004450-36 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: May 2024