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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Sep 2022 → ongoing

Decision date (initial)

2024-02-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501374-19-00

EudraCT number

2021-004450-36

WHO UTN

U1111-1280-1849

ClinicalTrials.gov

NCT05458297

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacogenetic, Therapy, Pharmacokinetic, Efficacy, Pharmacodynamic, Dose response

1. (Cohort D): To evaluate the safety and tolerability of zilovertamab vedotin
2. (Cohort C): To evaluate the safety and tolerability of zilovertamab vedotin in combination with nemtabrutinib
3. To evaluate zilovertamabvedotin with respect to objective response rate: Cohorts A, B, D (FL), and E per Lugano Response Criteria as assessed by BICR; Cohort D (CLL): per iwCLL Criteria as assessed by investigator
4. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to objective response rate: Cohort C: per Lugano Response Criteria as assessed by investigator

Secondary objectives 3

1. To evaluate zilovertamab vedotin with respect to duration of response: Cohorts A, B, D (FL) and E: per Lugano Response Criteria as assessed by BICR; Cohort D (CLL): per iwCLL Criteria as assessed by investigator
2. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to duration of response: Cohort C: per Lugano Response Criteria as assessed by investigator
3. (Cohorts A, B, and E): To evaluate the safety and tolerability of zilovertamab vedotin

Conditions and MedDRA coding

Aggressive and Indolent B-cell Malignancies (mantle cell lymphoma; chronic lymphocytic leukemia; follicular lymphoma; Richter’s syndrome)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. For aggressive B-cell malignancies mantle cell lymphoma (MCL) Cohort A: 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
2. For aggressive B-cell malignancies MCL Cohort A: 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.
3. 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.
4. 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.
5. 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.
6. Have an ECOG performance status of 0 to 2 assessed within 7 days before cycle 1 day 1.

Exclusion criteria 16

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. Has pericardial effusion or clinically significant pleural effusion.
4. Has ongoing Grade >1 peripheral neuropathy.
5. Has a demyelinating form of Charcot-Marie-Tooth disease.
6. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
7. Participants with FL who have transformed to a more aggressive type of lymphoma.
8. Has received prior systemic anticancer therapy, including investigational agents, within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibodies) or 2 weeks (small molecules like kinase inhibitors) prior to the first dose of study intervention.
9. Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities.
10. Has ongoing corticosteroid therapy exceeding 30 mg daily of prednisone equivalent.
11. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
12. Has known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma.
13. Has an active infection requiring systemic therapy.
14. Has a known history of human immunodeficiency virus (HIV) infection not well controlled on antiretroviral therapy (ART)
15. Active HBV or hepatitis C virus (HCV) infection.
16. For Cohort C only: has any clinically significant gastrointestinal abnormalities that might alter absorption.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Percentage of Participants with MCL (Cohort C), FL (Cohort D), and CLL with ≥1 Adverse Event (AE)
2. Percentage of Participants with MCL (Cohort C), FL (Cohort D), and CLL who Discontinue from Study Therapy Due to AE
3. Percentage of Participants with MCL (Cohort C) who Experience a Dose-Limiting Toxicity (DLT)
4. 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))
5. ORR per Lugano Response Criteria as Assessed by Investigator in Participants with MCL (Cohort C)
6. ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Investigator in Participants with CLL

Secondary endpoints 5

1. Duration of Response (DOR) per Lugano Response Criteria as Assessed by BICR in Participants with MCL (Cohort A), RT, and FL (Cohorts D & E)
2. DOR per Lugano Response Criteria as Assessed by Investigator in Participants with MCL (Cohort C)
3. DOR per iwCLL Criteria as Assessed by Investigator in Participants with CLL
4. Percentage of Participants with ≥1 AE in Participants with MCL (Cohort A), RT, and FL (Cohort E)
5. Percentage of Participants Discontinuing from Study Therapy Due to AE in Participants with MCL (Cohort A), RT, and FL (Cohort E)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Katherine Ryland

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Katherine Ryland

Third parties 6

Locations

9 EU/EEA countries · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 6 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 72 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications