A Dose Escalation Study of Duvortuxizumab in Participants With Relapsed or Refractory B-cell Malignancies
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ClinicalTrials.gov Identifier: NCT02454270 |
Recruitment Status :
Terminated
(Recent advances in the treatment of B cell malignancies resulting in new treatments being approved for marketing and many others in late stage development)
First Posted : May 27, 2015
Last Update Posted : December 20, 2018
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Condition or disease | Intervention/treatment | Phase |
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Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular Lymphoma, Mantle-Cell Precursor Cell Lymphoblastic Leukemia-Lymphoma | Drug: Part 1 (Dose Escalation): Duvortuxizumab Drug: Part 2 (Dose Expansion): Duvortuxizumab | Phase 1 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 59 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of Duvortuxizumab, A Humanized CD19 x CD3 Dual-Affinity Re-Targeting (DART®) Protein in Subjects With Relapsed or Refractory B-cell Malignancies |
Actual Study Start Date : | June 15, 2015 |
Actual Primary Completion Date : | July 26, 2018 |
Actual Study Completion Date : | July 26, 2018 |

Arm | Intervention/treatment |
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Experimental: Dose Escalation: Participants With Certain B-Cell Malignancies
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.
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Drug: Part 1 (Dose Escalation): Duvortuxizumab
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. |
Experimental: Dose Expansion: Diffuse-Large B-Cell Lymphoma Participants
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.
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Drug: Part 2 (Dose Expansion): Duvortuxizumab
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. |
Experimental: Dose Expansion: Follicular Cell Lymphoma Participants
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.
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Drug: Part 2 (Dose Expansion): Duvortuxizumab
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. |
Experimental: Dose Expansion: Mantle Cell Lymphoma Participants
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.
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Drug: Part 2 (Dose Expansion): Duvortuxizumab
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. |
Experimental: Dose Expansion: Chronic Lymphocytic Leukemia Participants
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.
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Drug: Part 2 (Dose Expansion): Duvortuxizumab
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. |
Experimental: Dose Expansion: Acute Lymphoblastic Leukemia Participants
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.
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Drug: Part 2 (Dose Expansion): Duvortuxizumab
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. |
- Part 1: Recommended Phase 2 Dose (RP2D) of Duvortuxizumab [ Time Frame: Approximately 15 months ]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)].
- Part 2: Number of Participants With Overall Response Rate (ORR) [ Time Frame: Approximately 2 Years ]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).
- Part 1 and 2: Area Under the Curve From Time Zero to End of Dosing Interval (AUC tau) of Duvortuxizumab [ Time Frame: Approximately 2 Years ]The AUC tau is the area under the serum concentration versus time curve during a dose interval time period (tau).
- Part 1 and 2: Maximum Serum Concentration (Cmax) of Duvortuxizumab [ Time Frame: Approximately 2 Years ]The Cmax is the maximum observed serum concentration of duvortuxizumab.
- Part 1 and 2: Half-Life (t1/2) of Duvortuxizumab [ Time Frame: Approximately 2 Years ]The t(1/2) is defined as 0.693/Lambda (z)
- Part 1 and 2: Total Systemic Clearance (CL) of Duvortuxizumab [ Time Frame: Approximately 2 Years ]The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
- Part 1 and 2: Volume of Distribution at Steady-State (Vss) of Duvortuxizumab [ Time Frame: Approximately 2 Years ]The Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of duvortuxizumab at steady state.
- Part 1 and 2: Immunogenicity of Duvortuxizumab [ Time Frame: Approximately 2 Years ]Plasma levels of antibodies to duvortuxizumab for evaluation of potential immunogenicity.
- Part 2: Duration of Response (DoR) [ Time Frame: Approximately 2 Years ]The DoR is defined as the time from the first observed response (CR or PR) to documented disease progression or death due to any cause.
- Part 2: Progression Free Survival (PFS) for DLBCL, FL, MCL, and CLL [ Time Frame: Approximately 2 Years ]The PFS is defined as the time from date of the first dose of study drug to documented disease progression or death due to any cause.
- Part 2: Percentage of Participants With Complete Response (CR) [ Time Frame: Approximately 2 Years ]The CR is defined as a best response of CR according to the Criteria for Response Assessment of Non-Hodgkin Lymphomas (NHL), International Workshop on Chronic Lymphocytic Leukemia (CLL) or Response Criteria for acute lymphoblastic leukemia (ALL).
- Part 2: Percentage of Participants with Overall Survival [ Time Frame: Up to followup (Approximately 2 Years) ]Overall survival is defined as the duration from the date of the first dose of the study drug to the date of death for DLBCL, FL, MCL, CLL, and ALL.
- Part 1 and 2: Number of Participants with Adverse Events (AEs) and Serious AEs [ Time Frame: Screening up to follow-up (Approximately 2 Years) ]An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
- Part 2: Relapse-Free survival for Acute Lymphoblastic Leukemia (RFS for ALL) [ Time Frame: Approximately 2 Years ]Relapse free survival (RFS) is defined as time from the date of the first dose of the study drug to relapse from CR, progressive disease, or death due to any cause for ALL.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02454270
United States, Michigan | |
Detroit, Michigan, United States | |
United States, New York | |
New York, New York, United States | |
United States, Ohio | |
Columbus, Ohio, United States | |
United States, Pennsylvania | |
Philadelphia, Pennsylvania, United States | |
United States, Tennessee | |
Nashville, Tennessee, United States | |
United States, Texas | |
Houston, Texas, United States | |
Belgium | |
Edegem, Belgium | |
Leuven, Belgium | |
Wilrijk, Belgium | |
France | |
Lille, France | |
Pierre Benite, France | |
Rennes, France | |
Tours Cedex, France | |
Israel | |
Haifa, Israel | |
Jerusalem, Israel | |
Ramat Gan, Israel | |
Tel Aviv, Israel | |
Spain | |
Barcelona, Spain | |
Madrid, Spain | |
Salamanca, Spain |
Study Director: | Janssen Research & Development, LLC Clinical Trial | Janssen Research & Development, LLC |
Responsible Party: | Janssen Research & Development, LLC |
ClinicalTrials.gov Identifier: | NCT02454270 |
Other Study ID Numbers: |
CR107241 2015-000485-63 ( EudraCT Number ) 64052781LYM1001 ( Other Identifier: Janssen Research & Development, LLC ) |
First Posted: | May 27, 2015 Key Record Dates |
Last Update Posted: | December 20, 2018 |
Last Verified: | December 2018 |
Studies a U.S. FDA-regulated Device Product: | No |
First-in-Human B-Cell Chronic Lymphocytic Leukemia Diffuse Large-Cell Lymphoma Follicular Lymphoma |
Mantle-Cell Lymphoma Acute Lymphoid Leukemia Dose Escalation Study Duvortuxizumab |
Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Large B-Cell, Diffuse Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Follicular Lymphoma, Mantle-Cell Neoplasms by Histologic Type |
Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, B-Cell Lymphoma, Non-Hodgkin Leukemia, B-Cell |