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

VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)14 sites in 1 country91 target enrollmentMarch 14, 2019

ConditionsChronic 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

InterventionsZilovertamab vedotin

DrugsZilovertamab vedotin

Overview

Phase: Phase 1
Intervention: Zilovertamab vedotin
Conditions: Chronic Lymphocytic Leukemia
Sponsor: VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Enrollment: 91
Locations: 14
Primary Endpoint: Maximum tolerated dose (MTD) of zilovertamab vedotin
Status: Completed
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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).

Registry

clinicaltrials.gov

Start Date

March 14, 2019

End Date

December 18, 2023

Last Updated

2 years ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Men or women of age ≥18 years.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
•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.

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.

Arms & Interventions

Zilovertamab vedotin Schedule 1: Q1/3W

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).

Intervention: Zilovertamab vedotin

Zilovertamab vedotin Schedule 2: 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 and 8 of repeated 21-day cycles (Q2/3W).

Intervention: Zilovertamab vedotin

Zilovertamab vedotin Schedule 3: Q3/4W

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).

Intervention: Zilovertamab vedotin

Outcomes

Primary Outcomes

Maximum tolerated dose (MTD) of zilovertamab vedotin

Time Frame: Cycle 1 (Up to 21 Days)

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.

Recommended Dosing Regimen (RDR)

Time Frame: Cycle 1 (Up to 21 Days)

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.

Secondary Outcomes

Number of participants that use supportive care or concomitant medications(Up to approximately 3.5 years)
Plasma concentration of monomethyl auristatin E (MMAE)(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)
Number of participants with a treatment-emergent adverse event (TEAE)(Up to approximately 3.5 years)
Number of participants with an adverse event of special interest (AESI)(Up to approximately 3.5 years)
Number of participants with a DLT(Cycle 1 (Up to 21 Days))
Plasma concentration of zilovertamab vedotin(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)
Maximum plasma concentration (Cmax) of zilovertamab vedotin(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)
Cmax of total UC-961 antibody(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)
Number of participants with a serious adverse event (SAE)(Up to approximately 3.5 years)
Overall Response (OR)(Up to approximately 3.5 years)
Average number of zilovertamab vedotin infusions administered(Up to 5 months)
Plasma concentration of total UC-961 antibody(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)
Volume of distribution (Vd) of zilovertamab vedotin(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)
Vd of total UC-961 antibody(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)
t1/2 of plasma concentration of MMAE(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)
Number of participants that discontinue study treatment due to an AE(Up to approximately 3.5 years)
Time to maximum plasma concentration (Tmax) of zilovertamab vedotin(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)
Area under the plasma concentration time curve (AUC) of zilovertamab vedotin(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)
Tmax of total UC-961 antibody(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)
CL of total UC-961 antibody(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)
Number of participants with zilovertamab vedotin-reactive antibodies(Day 1 of Cycles 1 through end of therapy (up to approximately 3.5 years): predose and end of infusion (up to ~30 minutes))
Duration of Response (DOR)(Up to approximately 3.5 years)
Overall Survival (OS)(Up to approximately 3.5 years)
Clearance (CL) of zilovertamab vedotin(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)
Apparent terminal half-life (t½) of plasma concentration of zilovertamab vedotin(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)
AUC of total UC-961 antibody(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)
Cmax of MMAE(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)
Tmax of MMAE(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)
AUC of MMAE(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)
Vd of MMAE(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)
Complete Response without measurable residual disease (CRMRD-)(Up to approximately 3.5 years)
Time to Treatment Failure (TTF)(Up to approximately 3.5 years)
t1/2 of plasma concentration of total UC-961 antibody(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)
CL of MMAE(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)
Percent change from baseline in tumor dimension(Up to approximately 3.5 years)
Time to Response (TTR)(Up to approximately 3.5 years)
Progression free survival (PFS)(Up to approximately 3.5 years)