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Participants will be administered escalating doses of zilovertamab vedotin at 0.50, 1.00, 1.50, 2.25, 2.50, 2.75, and 3.00 mg/kg IV on Day 1 of repeated 21-day cycles (Q1/3W).

Participants will be administered escalating doses of zilovertamab vedotin at 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, and 2.25 mg/kg IV on Day 1 and 8 of repeated 21-day cycles (Q2/3W).

Participants will be administered escalating doses of zilovertamab vedotin at 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, and 2.25 mg/kg IV on Day 1, 8, and 15 of repeated 21-day cycles (Q3/4W).

Zilovertamab vedotin administered via IV infusion per Schedule 1, 2, or 3 according to participant allocation.

Zilovertamab vedotin

Medical Director

The purpose of this study is to evaluate the safety, pharmacokinetics, immunogenicity, and efficacy of zilovertamab vedotin given intravenously (IV) across a range of dose levels in participants with previously treated hematological cancers including acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), Burkitt lymphoma (BL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Richter transformation lymphoma (RTL), and T-cell non-Hodgkin lymphoma (NHL).

Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher dose levels within each dose schedule of zilovertamab vedotin using a 3+3 dose-escalation design.

A Study of Zilovertamab Vedotin (MK-2140) (VLS-101) in Participants With Hematologic Malignancies (MK-2140-001)

A Phase 1 Dose-Escalation and Cohort-Expansion Study of VLS-101 in Subjects With Hematological Malignancies (waveLINE-001)

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Participants will receive zilovertamab vedotin according to Schedule 1, 2, or 3. The MTD will be determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD will be defined as the highest tested dose level at which ≥6 participants have been treated and which is associated with a Cycle 1 DLT in ≤17% of the participants.

Selection of the RDR will be based on consideration of short- and long-term safety information together with available pharmacokinetic, pharmacodynamic, and efficacy data. The RDR may be the MTD or may be a lower dose within the tolerable dose range.

Zilovertamab vedotin drug administration will be assessed by prescribing records and the average number of zilovertamab vedotin infusions administered will be determined.

An AE is any untoward medical occurrence in a participant administered a medicinal product; the event does not necessarily have a causal relationship with study drug administration or usage. Laboratory abnormalities, vital sign/oxygen saturation abnormalities, and adverse electrocardiogram (ECG) findings will also be recorded as AEs. A TEAE is defined as an AE that occurs or worsens in the period from the first dose of study drug administration to 30 days after the final dose of study drug administration. The number of participants with a TEAE will be reported for each arm.

A DLT is defined as a protocol pre-specified TEAE that occurs in Cycle 1 of zilovertamab vedotin therapy and is considered drug-related. Failure to recover to baseline by ≥21 days from the last dose of study drug in the current cycle due to a drug-related TEAE is also considered a DLT. The number of participants with a DLT will be reported for each arm.

An SAE is defined as an untoward medical occurrence that results in any of the following outcomes: death, life-threatening situation, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or other medically significant event.

Prespecified AESIs for this study will include: Grade ≥3 infusion reactions, tumor lysis syndrome (TLS) of any grade, and Grade ≥3 peripheral neuropathy. The number of participants with an AESI will be reported for each arm.

An AE is any untoward medical occurrence in a participant administered a medicinal product; the event does not necessarily have a causal relationship with study drug administration or usage. The number of participants that discontinue study treatment due to an AE will be reported for each arm.

The number of participants that use supportive care or concomitant medications will be reported for each arm.

Plasma concentration of zilovertamab vedotin will be reported for each arm.

Plasma concentration of total UC-961 antibody will be reported for each arm.

Plasma concentration of MMAE will be reported for each arm.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Cmax of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Tmax of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine AUC of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Vd of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine CL of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine t1/2 of plasma concentration of zilovertamab vedotin.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Cmax of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Tmax of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine AUC of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Vd of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine CL of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine t1/2 of plasma concentration of total UC-961 antibody.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Cmax of MMAE.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Tmax of MMAE.

Blood samples collected predose and at multiple timepoints postdose will be used to determine AUC of MMAE.

Blood samples collected predose and at multiple timepoints postdose will be used to determine Vd of MMAE.

Blood samples collected predose and at multiple timepoints postdose will be used to determine CL of MMAE.

Blood samples collected predose and at multiple timepoints postdose will be used to determine t1/2 of plasma concentration of MMAE.

Number of participants with zilovertamab vedotin-reactive antibodies will be assessed.

OR will be defined by achievement of the following outcomes as indicated by disease type: CLL/SLL: Complete response (CR: disappearance of detectable disease per Cheson 2012 criteria), CR with incomplete blood count recovery (CRi: CR with ≥1 additional change in absolute neutrophil count, platelet count, or hemoglobin), partial response (PR: no evidence of new disease per Cheson 2012 criteria), or PR with lymphocytosis (PR except lack of decrease in peripheral blood absolute lymphocyte count); NHL: CR (disappearance of all detectable disease per Cheson 2014 criteria) or PR (≥50% decrease in the sum of the product of diameters of the index nodal and extranodal lesions); LPL/WM: CR, very good PR (CR with ≥90% decrease in M protein), PR, or minor response (criteria for PR or stable disease met per Cheson 2014); ALL: (CR, CRi, unconfirmed CR, or PR per National Comprehensive Cancer Network criteria); AML (CR, CRi, morphologic leukemia-free state \[MLFS\], or PR per Cheson 2003 criteria).

CRMRD- is defined as the achievement of ≤1 × 10\^-4 malignant cells in bone marrow (as assessed by flow cytometry) in a participant who meets all other criteria for CR.

Percent change in tumor dimensions is defined as the percent change from baseline in the sum of the products of the diameters (SPD) of index lesions.

TTR is defined as the interval from the start of study therapy to the first documentation of an objective response.

DOR is defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression/relapse or death from any cause.

PFS is defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression/relapse or death from any cause.

TTF failure is defined as the interval from start of study therapy to the earliest of the first documentation of disease progression/relapse, treatment failure (for participants with ALL or AML), the permanent cessation of study drug due to an AE, or death from any cause.

OS is defined as the interval from the start of study therapy to death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Zilovertamab Vedotin (MK-2140) (VLS-101) in Participants With Hematologic Malignancies (MK-2140-001)	NCT03833180	Chronic Lymphoc... Mantle Cell Lym... Follicular Lymp... Marginal Zone L... Diffuse Large B... Richter Transfo... Burkitt Lymphom... Lymphoplasmacyt... T-cell Non-Hodg... Acute Lymphoid ... Acute Myeloid L... Waldenstrom Mac...	Zilovertamab ve...	18 Years -	VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
A Study of Zilovertamab Vedotin (MK-2140) (VLS-101) in Participants With Hematologic Malignancies (MK-2140-001)	NCT03833180	Chronic Lymphoc... Mantle Cell Lym... Follicular Lymp... Marginal Zone L... Diffuse Large B... Richter Transfo... Burkitt Lymphom... Lymphoplasmacyt... T-cell Non-Hodg... Acute Lymphoid ... Acute Myeloid L... Waldenstrom Mac...	Zilovertamab ve...	18 Years -	VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

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