Clinical trial NCT03833180: A Study of Zilovertamab Vedotin (MK-2140) (VLS-101) in Participants With Hematologic Malignancies (MK-2140-001)
Official title: A Phase 1 Dose-Escalation and Cohort-Expansion Study of VLS-101 in Subjects With Hematological Malignancies (waveLINE-001)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Mantle Cell Lymphoma
Follicular Lymphoma
Marginal Zone Lymphoma
Diffuse Large B-cell Lymphoma
Richter Transformation Lymphoma
Burkitt Lymphoma
Lymphoplasmacytoid Lymphoma
T-cell Non-Hodgkin Lymphoma
Acute Lymphoid Leukemia
Acute Myeloid Leukemia
Waldenstrom Macroglobulinemia
Keywords: Lymphoma
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Leukemia, Lymphoid
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Burkitt Lymphoma
Lymphoma, Lymphoplasmacytoid
Waldenström Macroglobulinemia
Lymphoma, T-cell
Leukemia, Lymphoid, Acute
Leukemia, Myeloid, Acute
Lead sponsor: VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2019-02-06
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: Inclusion Criteria:

* Men or women of age ≥18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Histological diagnosis of CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T-cell NHL, ALL, or AML as documented in medical records.
* Hematological cancer under study has been previously treated and has progressed during or relapsed after prior systemic therapy.
* Hematological cancer is unlikely to be responsive to established therapies known to provide clinical benefit or the study candidate has developed an intolerance to established therapies known to provide clinical benefit.
* Presence of measurable cancer including CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T-cell NHL, ALL, and AML.
* Current medical need for therapy due to disease-related symptoms or complications, cytopenias, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease.
* Availability of pretreatment tumor tissue.
* Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week before the start of study therapy.
* All acute toxic effects of any prior antitumor therapy (not including hydroxyurea, cytarabine, and/or cyclophosphamide used in subjects with acute leukemia) resolved to ≤Grade 1 before the start of study therapy (with the exception of alopecia \[Grade 1 or 2 permitted\] or selected laboratory parameters \[Grade 1 or Grade 2 permitted with exceptions.
* Adequate bone marrow function.
* Adequate hepatic profile.
* Adequate renal function.
* Adequate coagulation profile.
* Negative antiviral serology.
* For female participants of childbearing potential, a negative serum pregnancy test.
* For both male and female participants, willingness to use protocol-recommended method of contraception from the start of the screening period until ≥6 months after the final dose of study therapy.
* Willingness and ability of the participant to comply with study activities.
* Evidence of a personally signed informed consent document.
* Previous treatment with an MMAE-containing drug is allowed.

Exclusion Criteria:

* Presence of malignancy involving the central nervous system.
* Presence of another cancer with disease manifestations or therapy that could adversely affect participant safety or longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results.
* Significant cardiovascular disease within 3 months prior to start of study therapy.
* Significant screening electrocardiogram (ECG) abnormalities.
* Uncontrolled ongoing systemic bacterial, fungal, or viral infection.
* Known diagnosis of liver cirrhosis.
* Pregnancy or breastfeeding.
* Candidacy for hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor (CAR)-T-cell therapy with access to HSCT or CAR-T cells and a willingness to undergo such therapy.
* In participants with prior HSCT, evidence of graft-versus-host disease (GVHD) with Grade ≥2 serum bilirubin, Grade ≥3 skin involvement, or Grade ≥3 diarrhea.
* Prior solid organ transplantation.
* Major surgery within 4 weeks before the start of study therapy.
* Prior therapy with a receptor tyrosine kinase-like orphan receptor 1 (ROR1)-directed therapy.
* Has ongoing corticosteroid therapy (exceeding 30 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks prior to Cycle 1 Day 1 (C1D1). If corticosteroid treatment is required for lymphoma symptom control prior to C1D1, up to 100 mg per day of prednisone equivalent can be given for up to 5 days. In that case, all tumor assessments must have been completed prior to the start of corticosteroid treatment.
* Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4.
* Use within 7 days prior to the start of study therapy of a drug known to prolong the QT interval.
* Concurrent participation in another therapeutic or imaging clinical trial.
* Presence of a medical condition that (in the judgement of the investigator) interferes with the ability of the participant to participate in the study.
* Has baseline peripheral neuropathy \>Grade 1.

Primary outcomes:
measure: Maximum tolerated dose (MTD) of zilovertamab vedotin
timeFrame: Cycle 1 (Up to 21 Days)
measure: Recommended Dosing Regimen (RDR)
timeFrame: Cycle 1 (Up to 21 Days)
Secondary outcomes:
measure: Average number of zilovertamab vedotin infusions administered
timeFrame: Up to 5 months
measure: Number of participants with a treatment-emergent adverse event (TEAE)
timeFrame: Up to approximately 3.5 years
measure: Number of participants with a DLT
timeFrame: Cycle 1 (Up to 21 Days)
measure: Number of participants with a serious adverse event (SAE)
timeFrame: Up to approximately 3.5 years
measure: Number of participants with an adverse event of special interest (AESI)
timeFrame: Up to approximately 3.5 years
measure: Number of participants that discontinue study treatment due to an AE
timeFrame: Up to approximately 3.5 years
measure: Number of participants that use supportive care or concomitant medications
timeFrame: Up to approximately 3.5 years
measure: Plasma concentration of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Plasma concentration of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Plasma concentration of monomethyl auristatin E (MMAE)
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Maximum plasma concentration (Cmax) of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Time to maximum plasma concentration (Tmax) of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Area under the plasma concentration time curve (AUC) of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Volume of distribution (Vd) of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Clearance (CL) of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Apparent terminal half-life (t½) of plasma concentration of zilovertamab vedotin
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Cmax of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Tmax of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: AUC of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Vd of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: CL of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: t1/2 of plasma concentration of total UC-961 antibody
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Cmax of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Tmax of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: AUC of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Vd of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: CL of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: t1/2 of plasma concentration of MMAE
timeFrame: Cycle 1 Day 1, 2, 3, 8, 15: predose, end of infusion (up to 4 hours); Day 1, Day 8 (Schedule 2, 3), Day 15 (Schedule 3) of Cycles 2 through end of therapy (up to ~3.5 years): predose, end of infusion
measure: Number of participants with zilovertamab vedotin-reactive antibodies
timeFrame: Day 1 of Cycles 1 through end of therapy (up to approximately 3.5 years): predose and end of infusion (up to ~30 minutes)
measure: Overall Response (OR)
timeFrame: Up to approximately 3.5 years
measure: Complete Response without measurable residual disease (CRMRD-)
timeFrame: Up to approximately 3.5 years
measure: Percent change from baseline in tumor dimension
timeFrame: Up to approximately 3.5 years
measure: Time to Response (TTR)
timeFrame: Up to approximately 3.5 years
measure: Duration of Response (DOR)
timeFrame: Up to approximately 3.5 years
measure: Progression free survival (PFS)
timeFrame: Up to approximately 3.5 years
measure: Time to Treatment Failure (TTF)
timeFrame: Up to approximately 3.5 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 3.5 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope ( Site 0010)
state: California
city: La Jolla
country: United States
facility: University of California - San Diego ( Site 0003)
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology ( Site 0007)
state: California
city: Omaha
country: United States
facility: University of Nebraska Medical Center ( Site 0006)
state: Nebraska
city: New Hyde Park
country: United States
facility: Northwell Health ( Site 0009)
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College ( Site 0005)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 0014)
state: New York
city: Rochester
country: United States
facility: University of Rochester ( Site 0008)
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan-Kettering Cancer Center ( Site 0019)
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University ( Site 0004)
state: Oregon
city: Houston
country: United States
facility: MD Anderson Cancer Center ( Site 0001)
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center ( Site 0011)
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center ( Site 0012)
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center ( Site 0002)
state: Washington
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Wang ML, Barrientos JC, Furman RR, Mei M, Barr PM, Choi MY, de Vos S, Kallam A, Patel K, Kipps TJ, Rule S, Flanders K, Jessen KA, Ren H, Riebling PC, Graham P, King L, Thurston AW, Sun M, Schmidt EM, Lannutti BJ, Johnson DM, Miller LL, Spurgeon SE. Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers. NEJM Evid. 2022 Jan;1(1):EVIDoa2100001. doi: 10.1056/EVIDoa2100001. Epub 2021 Oct 12.
citation: Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.