A Dose Escalation Study of Duvortuxizumab in Participants With Relapsed or Refractory B-cell Malignancies

NCT02454270 | Terminated Phase 1

• 3 other identifiers: CR1072412015-000485-6364052781LYM1001
• Study Type: interventional
• Target: 59
• Locations: 5 countries
• Sites: 20

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, dose-limiting toxicities (any harmful effect of a drug) (DLT), maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) and preliminary clinical activity of duvortuxizumab when administered intravenously to participants with relapsed or refractory B-cell malignancies \[diffuse-large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL)\].

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Keywords

First-in-Human; B-Cell Chronic Lymphocytic Leukemia; Diffuse Large-Cell Lymphoma; Follicular Lymphoma; Mantle-Cell Lymphoma; Acute Lymphoid Leukemia; Dose Escalation Study; Duvortuxizumab

Outcome Measures

Primary Outcomes (2)

• Part 1: Recommended Phase 2 Dose (RP2D) of Duvortuxizumab

  The RP2D will be determined based on safety, clinical activity, pharmacokinetics, and pharmacodynamics in participants with relapsed or refractory B cell malignancies \[diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL)\].

  Approximately 15 months

• Part 2: Number of Participants With Overall Response Rate (ORR)

  The ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) per criteria for response assessment of Non Hodgkin Lymphomas (NHL) or International Workshop on Chronic Lymphocytic Leukemia (IWCLL), or complete response (CR), complete response with partial hematologic recovery (CRp), or complete response with incomplete recovery of counts (CRi) per response criteria for acute lymphoblastic leukemia (ALL).

  Approximately 2 Years

Secondary Outcomes (12)

• Part 1 and 2: Area Under the Curve From Time Zero to End of Dosing Interval (AUC tau) of Duvortuxizumab

  Approximately 2 Years

• Part 1 and 2: Maximum Serum Concentration (Cmax) of Duvortuxizumab

  Approximately 2 Years

• Part 1 and 2: Half-Life (t1/2) of Duvortuxizumab

  Approximately 2 Years

• Part 1 and 2: Total Systemic Clearance (CL) of Duvortuxizumab

  Approximately 2 Years

• Part 1 and 2: Volume of Distribution at Steady-State (Vss) of Duvortuxizumab

  Approximately 2 Years

Study Arms (6)

Dose Escalation: Participants With Certain B-Cell Malignancies

EXPERIMENTAL

During accelerated dose titration in Group 1, participant will receive duvortuxizumab starting at 0.5 nanogram per kilogram (ng/kg) for biweekly dosing. Dose will be increased by half logarithmic steps in subsequent Dose Level (DL). After safety stopping criteria are met, Dose Escalation (DE) in Group 1 will transition to 3+3 design, and will continue until the Maximum tolerated Dose (MTD) is defined. DE in Groups 2 and 3 will follow 3+3 design, begin after initial dose level in Group 1 is deemed safe and recommended phase 2 doses (RP2D) for Part 1 of study can be decided. Duvortuxizumab at a starting dose of 50 ng/kg weekly will also be investigated in Group 1 and will follow 3+3 study design continue until the MTD or Maximum administered dose (MAD) is reached. Disease-specific dose escalation in Group 2 and 3 will not be initiated until dose in Group 1 is determined safe.

Drug: Part 1 (Dose Escalation): Duvortuxizumab

Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants

EXPERIMENTAL

Participants with Diffuse-Large B-Cell Lymphoma (DLBCL) will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) either with or without a priming dose.

Drug: Part 2 (Dose Expansion): Duvortuxizumab

Dose Expansion: Follicular Cell Lymphoma Participants

EXPERIMENTAL

Participants with Follicular Cell Lymphoma (FL) will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) either with or without a priming dose.

Drug: Part 2 (Dose Expansion): Duvortuxizumab

Dose Expansion: Mantle Cell Lymphoma Participants

EXPERIMENTAL

Participants with Mantle Cell Lymphoma (MCL) will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) either with or without a priming dose.

Drug: Part 2 (Dose Expansion): Duvortuxizumab

Dose Expansion: Chronic Lymphocytic Leukemia Participants

EXPERIMENTAL

Participants with Chronic Lymphocytic Leukemia (CLL) will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) either with or without a priming dose.

Drug: Part 2 (Dose Expansion): Duvortuxizumab

Dose Expansion: Acute Lymphoblastic Leukemia Participants

EXPERIMENTAL

Participants with Acute Lymphoblastic Leukemia (ALL) will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) either with or without a priming dose.

Drug: Part 2 (Dose Expansion): Duvortuxizumab

Interventions

Part 1 (Dose Escalation): Duvortuxizumab DRUG

Participants currently enrolled in the study will continue to receive duvortuxizumab every 14 days (biweekly dosing) in each 28 -day cycle as an intravenous infusion. In the priming dose regimen, a priming dose will be administered on Day 1 followed by full doses on Day 8 and Day 22, of a 35-day Cycle 1, and then every 14 days in each subsequent 28-day cycle. The cohorts will be opened where participants will receive duvortuxizumab every 7 days (for investigating weekly dosing schedule) in each 28-day cycle as an intravenous infusion. In the priming dose regimen, a priming dose will be administered on Day 1 followed by full doses on Day 8, Day 15, Day 22, and Day 28 of a 35-day Cycle 1, and then every 7 days in each subsequent 28-day cycle.

Dose Escalation: Participants With Certain B-Cell Malignancies

Part 2 (Dose Expansion): Duvortuxizumab DRUG

Participants will receive intravenous infusion of duvortuxizumab at the recommended Phase 2 dose (RP2D) defined in Part 1 for their disease type either with or without a priming dose.

Dose Expansion: Acute Lymphoblastic Leukemia Participants; Dose Expansion: Chronic Lymphocytic Leukemia Participants; Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants; Dose Expansion: Follicular Cell Lymphoma Participants; Dose Expansion: Mantle Cell Lymphoma Participants

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Participants must meet protocol specified hematology and chemistry lab parameters criteria
• Histological confirmation of disease with documented disease relapse after the last therapy requiring treatment per the treating physician. Participants with lymphoma must have at least 1 measurable site of disease (Part 2 only). In addition, B-cell malignancy disease-specific criteria specified in the protocol must also be met
• A woman of childbearing potential must have a negative highly sensitive serum \[beta-human chorionic gonadotropin (β-hCG)\] or urine pregnancy test at (minimum sensitivity 25 International units (IU)/ liter (L) or equivalent units of HCG) within 7 days prior to the first dose of study drug
• A woman must agree to use an effective method of birth control and agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study drug
• A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository), man who is sexually active with a woman who is pregnant must use a condom and men must agree not to donate sperm for 90 days after the last dose of study drug
• Each participant (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Consent is to be obtained prior to the initiation of any study related tests or procedures that are not part of standard of care for the participant's disease

You may not qualify if:

• History of, or known central nervous system (CNS) involvement caused by the underlying B-cell malignancy or prior history of National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) Grade greater than or equal to \>= 3 drug-related CNS toxicity. Participants with signs or symptoms of CNS involvement should have a computed tomography (CT) or magnetic resonance imaging (MRI)
• History of or known or suspected autoimmune disease (exception: vitiligo, resolved childhood atopic dermatitis, and history of Grave's disease that is euthyroid clinically and by laboratory testing at Screening)
• Prior allogeneic hematopoietic stem-cell transplant for participants with DLBCL, FL, MCL, and CLL only. Prior allogenic hematopoietic stem-cell transplant is permitted for participants with ALL
• Prior solid organ transplantation
• Prior treatment with a therapeutic agent targeting CD19 and/or CD3

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (20)

Unknown Facility

Detroit, Michigan, United States

Location

Unknown Facility

New York, New York, United States

Location

Unknown Facility

Columbus, Ohio, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, United States

Location

Unknown Facility

Nashville, Tennessee, United States

Location

Unknown Facility

Houston, Texas, United States

Location

Unknown Facility

Edegem, Belgium

Location

Unknown Facility

Leuven, Belgium

Location

Unknown Facility

Wilrijk, Belgium

Location

Unknown Facility

Lille, France

Location

Unknown Facility

Pierre-Bénite, France

Location

Unknown Facility

Rennes, France

Location

Unknown Facility

Tours, France

Location

Unknown Facility

Haifa, Israel

Location

Unknown Facility

Jerusalem, Israel

Location

Unknown Facility

Ramat Gan, Israel

Location

Unknown Facility

Tel Aviv, Israel

Location

Unknown Facility

Barcelona, Spain

Location

Unknown Facility

Madrid, Spain

Location

Unknown Facility

Salamanca, Spain

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2015
• First Posted: May 27, 2015
• Study Start: June 15, 2015
• Primary Completion: July 26, 2018
• Study Completion: July 26, 2018
• Last Updated: December 20, 2018

Record last verified: 2018-12

Locations

US (6); BE (3); FR (4); ES (3); IL (4)