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Leukemia, Lymphocytic, Chronic, B-CellPhase 1NCT02454270

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

A Phase 1 study testing Part 1 (Dose Escalation): Duvortuxizumab and Part 2 (Dose Expansion): Duvortuxizumab in people with Leukemia, Lymphocytic, Chronic, B-Cell and Lymphoma, Large B-Cell, Diffuse, run by Janssen Research & Development, LLC at 20 sites in 5 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Part 1 (Dose Escalation): Duvortuxizumab and Part 2 (Dose Expansion): Duvortuxizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
59 participants
Where
20 sitesin 5 countries
Study dates
15 Jun 2015to 26 Jul 2018
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

20 sites in 5 countries.

20 sites in 5 countries

United States6 sites

  • Study site

    Columbus, Ohio

  • Study site

    Detroit, Michigan

  • Study site

    Houston, Texas

  • Study site

    Nashville, Tennessee

  • Study site

    New York, New York

  • Study site

    Philadelphia, Pennsylvania

Other trials in United States

France4 sites

  • Study site

    Lille

  • Study site

    Pierre-Bénite

  • Study site

    Rennes

  • Study site

    Tours

Other trials in France

Israel4 sites

  • Study site

    Haifa

  • Study site

    Jerusalem

  • Study site

    Ramat Gan

  • Study site

    Tel Aviv

Other trials in Israel

Belgium3 sites

  • Study site

    Edegem

  • Study site

    Leuven

  • Study site

    Wilrijk

Other trials in Belgium

Spain3 sites

  • Study site

    Barcelona

  • Study site

    Madrid

  • Study site

    Salamanca

Other trials in Spain

About this study

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

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)].

Read the detailed description

This first in human study consists of 2 parts: a) The dose escalation part and b) The dose expansion part. This is an openlabel (all participants know the identity of the intervention), multicenter (more than one study site) study to evaluate the safety, establish a recommended Phase 2 dose (RP2D), and to determine the preliminary efficacy of duvortuxizumab in participants with relapsed or refractory B cell malignancies. The dose escalation part of the trial (Part 1) will be comprised of 3 different patient groups based on disease indication: Group 1 (DLBCL, FL, MCL); Group 2 (CLL); Group 3 (ALL). The duvortuxizumab dosing will be done on biweekly and weekly basis. Duvortuxizumab weekly escalating dosing will be investigated. Dose escalation will begin with Group 1 and will initially follow an accelerated dose titration design, followed by a traditional 3+3 design. At each dose escalation level the treatment of the second participant should be initiated after at least 72 hours of observation after the start of the first duvortuxizumab dose of the first participant. Dose escalation in Groups 2 and 3 will follow a 3+3 design and will begin after the initial dose level in Group 1 is deemed safe. Participants [Group 1 (DLBCL, FL, MCL), Group 2 (CLL) Group 3 (ALL)] are enrolled into cohorts of increasing dose levels of duvortuxizumab administered in 28 day treatment cycles. Up to 3 RP2Ds may be determined in Part 1 (one RP2D for Group 1, one RP2D for Group 2, and one RP2D for Group 3). In the cohort expansion part of the trial (Part 2), participants with relapsed or refractory B cell malignancies (DLBCL, FL, MCL, CLL and ALL) will be enrolled according to tumor type in up to 5 cohorts and receive duvortuxizumab at the RP2D determined in Part 1 for their disease type. The study consists of 3 periods: Screening period (up to 28 days prior to the first dose of study drug); Treatment period [first dose of study drug until the End of Treatment Visit (within 30 days after the last dose)]; and follow up period [End of Treatment Visit and continue until death, lost to follow up, consent withdrawal, or study end (as determined by the sponsor), whichever occurs first]. Number of participants who achieve an overall response in each Dose Expansion cohort will be evaluated primarily. Participants' safety will be monitored throughout the study.

Being tested
Part 1 (Dose Escalation): Duvortuxizumab, Part 2 (Dose Expansion): Duvortuxizumab
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
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular, Lymphoma, Mantle-Cell, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Part 1 (Dose Escalation): DuvortuxizumabDrug

    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.

  • Part 2 (Dose Expansion): DuvortuxizumabDrug

    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.

Study groups in NCT02454270
Study groupRoleWhat they receive
Dose Escalation: Participants With Certain B-Cell MalignanciesExperimentalDuring 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.
Receives: Drug: Part 1 (Dose Escalation): Duvortuxizumab
Dose Expansion: Diffuse-Large B-Cell Lymphoma ParticipantsExperimentalParticipants 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.
Receives: Drug: Part 2 (Dose Expansion): Duvortuxizumab
Dose Expansion: Follicular Cell Lymphoma ParticipantsExperimentalParticipants 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.
Receives: Drug: Part 2 (Dose Expansion): Duvortuxizumab
Dose Expansion: Mantle Cell Lymphoma ParticipantsExperimentalParticipants 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.
Receives: Drug: Part 2 (Dose Expansion): Duvortuxizumab
Dose Expansion: Chronic Lymphocytic Leukemia ParticipantsExperimentalParticipants 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.
Receives: Drug: Part 2 (Dose Expansion): Duvortuxizumab
Dose Expansion: Acute Lymphoblastic Leukemia ParticipantsExperimentalParticipants 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.
Receives: Drug: Part 2 (Dose Expansion): Duvortuxizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)].

    Measured: Approximately 15 months

  2. 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).

    Measured: Approximately 2 Years

Secondary outcomes (12)

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

    The AUC tau is the area under the serum concentration versus time curve during a dose interval time period (tau).

    Measured: Approximately 2 Years

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

    The Cmax is the maximum observed serum concentration of duvortuxizumab.

    Measured: Approximately 2 Years

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

    The t(1/2) is defined as 0.693/Lambda (z)

    Measured: Approximately 2 Years

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

    The CL is a quantitative measure of the rate at which a drug substance is removed from the body.

    Measured: Approximately 2 Years

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

    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.

    Measured: Approximately 2 Years

  6. Part 1 and 2: Immunogenicity of Duvortuxizumab

    Plasma levels of antibodies to duvortuxizumab for evaluation of potential immunogenicity.

    Measured: Approximately 2 Years

  7. Part 2: Duration of Response (DoR)

    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.

    Measured: Approximately 2 Years

  8. Part 2: Progression Free Survival (PFS) for DLBCL, FL, MCL, and CLL

    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.

    Measured: Approximately 2 Years

  9. Part 2: Percentage of Participants With Complete Response (CR)

    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).

    Measured: Approximately 2 Years

  10. Part 2: Percentage of Participants with Overall Survival

    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.

    Measured: Up to followup (Approximately 2 Years)

  11. Part 1 and 2: Number of Participants with Adverse Events (AEs) and Serious AEs

    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.

    Measured: Screening up to follow-up (Approximately 2 Years)

  12. Part 2: Relapse-Free survival for Acute Lymphoblastic Leukemia (RFS for ALL)

    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.

    Measured: Approximately 2 Years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 May 2015 (estimated)
  2. Study start15 Jun 2015
  3. Primary completion26 Jul 2018
  4. Study completion26 Jul 2018

Why it stopped: Recent advances in the treatment of B cell malignancies resulting in new treatments being approved for marketing and many others in late stage development

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
59 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02454270
Sponsor's protocol ID
CR107241
Other IDs
2015-000485-63, 64052781LYM1001, 2015
Status last verified
Dec 2018
First submitted
6 May 2015
Last updated
20 Dec 2018
Results posted
No
Data monitoring committee
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Part 1 (Dose Escalation): Duvortuxizumab and Part 2 (Dose Expansion): Duvortuxizumab in people with Leukemia, Lymphocytic, Chronic, B-Cell and Lymphoma, Large B-Cell, Diffuse, run by Janssen Research & Development, LLC at 20 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 20 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites in United States, France, Israel, Belgium, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Recent advances in the treatment of B cell malignancies resulting in new treatments being approved for marketing and many others in late stage development). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 1: Recommended Phase 2 Dose (RP2D) of Duvortuxizumab (time frame: Approximately 15 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02454270.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2018.

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