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).
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.
Primary outcome:
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
Secondary outcome:
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
- Experimental: Cohort A
Participants will receive zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) until
disease progression or discontinuation. - Experimental: Cohort B
Participants will receive zilovertamab vedotin 2.5 mg/kg every 3 weeks (Q3W) until
disease progression or discontinuation. - Experimental: Cohort C
Participants will receive zilovertamab vedotin every 3 weeks (Q3W) combined with
nemtabrutinib daily until disease progression or discontinuation. - 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. - 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. - 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.
- Zilovertamab vedotin (MK-2140):
IV infusion - Nemtabrutinib (MK-1026):
65 mg once daily (QD) orally
Quelle: ClinicalTrials.gov
