A Study of Zilovertamab Vedotin (MK-2140) in Combination With Cyclophosphamide, Doxorubicin, and Prednisone Plus Rituximab or Rituximab Biosimilar (Truxima) (R-CHP) in Participants With Diffuse Large B-Cell Lymphoma (DLBCL) (MK-2140-007)

Study Overview
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Brief Summary
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This study consists of a dose escalation/confirmation phase and an efficacy expansion phase. The dose escalation/confirmation phase is to determine the safety and tolerability and establish a preliminary recommended Phase 2 dose (RP2D) of zilovertamab vedotin when administered in combination with R-CHP in participants with DLBCL who have received no prior treatment for their disease. The efficacy expansion phase is to determine the efficacy of the RP2D of zilovertamab vedotin when administered in combination with R-CHP in participants with DLBCL who have received no prior treatment for their disease.

Official Title
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A Multicenter, Open-label, Phase 2 Dose Escalation and Confirmation, and Efficacy Expansion Study of Zilovertamab Vedotin (MK-2140) in Combination With R-CHP in Participants With DLBCL (waveLINE)

Conditions
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Lymphoma, Large B-Cell, Diffuse (DLBCL)

Intervention / Treatment
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* Biological: Zilovertamab Vedotin
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Biological: Rituximab
* Biological: Rituximab Biosimilar
* Drug: Prednisone
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion: Has histologically confirmed diagnosis of DLBCL by prior biopsy Has positron emission tomography (PET)-positive disease verified by blinded independent central review (BICR) at screening, defined as 4-5 on the Lugano response criteria 5-point scale Has received no prior treatment for DLBCL Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 7 days prior to the start of study intervention Exclusion: Has a history of transformation of indolent disease to DLBCL Has received solid organ transplant at any time Has received a diagnosis of primary mediastinal B-cell lymphoma (PMBCL) 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, 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 History of a second malignancy unless potentially curative treatment has been completed with no evidence of malignancy for 2 years with the exception of participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous-cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder Has received prior radiotherapy within 28 days of start of study intervention 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 received a strong inhibitor or inducer of CYP3A4 (including itraconazole, ketoconazole, posaconazole, or voriconazole) within 7 days prior to the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor until <30 days after the last dose Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days before the first dose of study intervention Has known active central nervous system (CNS) lymphoma Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known active hepatitis C virus infection Has a known active hepatitis B virus infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zilovertamab Vedotin + R-CHP: Dose Escalation/Confirmation<br>Participants in the dose escalation/confirmation phase receive a dose level of zilovertamab vedotin (from 1.5 mg/Kg up to 2.5 mg/Kg) plus 750 mg/m^2 cyclophosphamide, 50 mg/m^2 doxorubicin, and 375 mg/m^2 rituximab or rituximab biosimilar (truxima) administered by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 8 cycles (up to approximately 5.5 months). Participants also receive 100 mg prednisone or prednisolone per day during Days 1-5 of each 21-day cycle for up to 8 cycles (up to approximately 5.5 months). | Biological: Zilovertamab Vedotin<br>* IV infusion<br>* Other names: VLS-101;Drug: Cyclophosphamide<br>* IV infusion<br>* Other names: NEOSAR®;Drug: Doxorubicin<br>* IV infusion<br>* Other names: ADRIAMYCIN®;Biological: Rituximab<br>* IV infusion<br>* Other names: RITUXAN®;Biological: Rituximab Biosimilar<br>* IV infusion<br>* Other names: TRUXIMA®;Drug: Prednisone<br>* IV or oral administration (per local guidelines)<br>Drug: Prednisolone<br>* IV or oral administration (per local guidelines)<br>|
| Experimental: Zilovertamab Vedotin + R-CHP: Efficacy Expansion<br>Participants in the efficacy expansion phase receive the RP2D of zilovertamab vedotin plus 750 mg/m^2 cyclophosphamide, 50 mg/m^2 doxorubicin, and 375 mg/m^2 rituximab or rituximab biosimilar (truxima) administered by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 8 cycles (up to approximately 5.5 months). Participants also receive 100 mg prednisone or prednisolone per day during Days 1-5 of each 21-day cycle for up to 8 cycles (up to approximately 5.5 months). | Biological: Zilovertamab Vedotin<br>* IV infusion<br>* Other names: VLS-101;Drug: Cyclophosphamide<br>* IV infusion<br>* Other names: NEOSAR®;Drug: Doxorubicin<br>* IV infusion<br>* Other names: ADRIAMYCIN®;Biological: Rituximab<br>* IV infusion<br>* Other names: RITUXAN®;Biological: Rituximab Biosimilar<br>* IV infusion<br>* Other names: TRUXIMA®;Drug: Prednisone<br>* IV or oral administration (per local guidelines)<br>Drug: Prednisolone<br>* IV or oral administration (per local guidelines)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) in Cycle 1 | DLTs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and are defined as any drug-related adverse event (AE) observed during the DLT evaluation period (e.g. Cycle 1) that results in a change to a given dose or a delay in initiating the next cycle. The number of participants with DLTs in Cycle 1 will be reported. | Cycle 1 (up to 21 days) | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | 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 number of participants who experience an AE will be reported. | Up to approximately 42 months | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 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 number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 5.5 months | 
| Complete Response Rate (CRR) per Lugano Response Criteria | CRR is defined as the percentage of participants who achieve a Complete Response (CR) per Lugano response criteria [Cheson, B. D., et al 2014] for malignant lymphoma as assessed by the investigator. Assessment includes anatomic imaging with computed tomography (CT) or magnetic resonance imaging (MRI), metabolic imaging with positron emission tomography (PET), and clinical findings including physical examination and bone marrow biopsy results. The percentage of participants with CRR will be reported. | Up to approximately 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per Lugano Response Criteria | ORR is defined as the percentage of participants who achieve a Complete Response (CR) or Partial Response (PR) per Lugano response criteria [Cheson, B. D., et al 2014] for malignant lymphoma as assessed by the investigator. Assessment includes anatomic imaging with computed tomography (CT) or magnetic resonance imaging (MRI), metabolic imaging with positron emission tomography (PET), and clinical findings including physical examination and bone marrow biopsy results. The percentage of participants with ORR will be reported. | Up to approximately 42 months | 
| Duration of Response (DOR) per Lugano Response Criteria | For participants who demonstrate a confirmed Complete Response (CR) or Partial Response (PR) per Lugano response criteria [Cheson, B. D., et al 2014] for malignant lymphoma, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. CR and PR assessment includes anatomic imaging with computed tomography (CT) or magnetic resonance imaging (MRI), metabolic imaging with positron emission tomography (PET), and clinical findings including physical examination and bone marrow biopsy results. DOR as assessed by the investigator will be reported. | Up to approximately 42 months |