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Ibrutinib

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Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Participants with certain B-cell malignancies (diffuse large B-cell lymphoma \[DLBCL\], mantle cell lymphoma \[MCL\], or follicular lymphoma \[FL\]) will receive rising doses of intravenous infusions of duvortuxizumab either with or without a priming dose in combination with oral ibrutinib until disease progression, unacceptable toxicity, or other protocol-specified withdrawal criteria are met. Dose escalation will continue until the recommended phase 2 dose or maximum tolerated dose is reached.

Participants with DLBCL will receive intravenous infusions of duvortuxizumab either with or without a priming dose in combination with oral ibrutinib at the recommended phase 2 dose until disease progression, unacceptable toxicity, or other protocol-specified withdrawal criteria are met.

Participants with FL will receive intravenous infusions of duvortuxizumab either with or without a priming dose in combination with oral ibrutinib at the recommended phase 2 dose until disease progression, unacceptable toxicity, or other protocol-specified withdrawal criteria are met.

Participants with MCL will receive intravenous infusions of duvortuxizumab either with or without a priming dose in combination with oral ibrutinib at the recommended phase 2 dose until disease progression, unacceptable toxicity, or other protocol-specified withdrawal criteria are met.

Participants with chronic lymphocytic leukemia (CLL) will receive intravenous infusions of duvortuxizumab either with or without a priming dose in combination with oral ibrutinib at the recommended phase 2 dose until disease progression, unacceptable toxicity, or other protocol-specified withdrawal criteria are met.

Duvortuxizumab will be administered at starting dose of 15 nanogram per kilogram (ng/kg) as an intravenous (IV) infusion during Part 1 (Dose Optimization) and at RP2D level determined in Part 1 during Part 2 (Dose Expansion). Participants will receive duvortuxizumab either with or without a priming dose. Participants who receive a priming dose will have infusions on Days 1, 8, and 22 of an initial 35-day cycle and then on Days 1 and 15 of 28-day cycles thereafter. Participants who do not receive a priming dose will have infusions on Days 1 and 15 of 28-day cycles.

Duvortuxizumab

Ibrutinib will be administered at 560 milligram per day (mg/day) orally once daily during Part 1 (Dose Optimization) and at a dose of 420 mg/day (for participants with CLL) or 560 mg/day (for participants with DLBCL, FL, or MCL) during Part 2 (Dose Expansion). In Part 1, ibrutinib will be initiated on Day 1 of the initial treatment cycle. In Part 2, ibrutinib will be initiated on Day -7 prior to the initial treatment cycle.

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is to determine whether duvortuxizumab and ibrutinib can be combined safely and to establish the maximum tolerated dose (MTD) in Part 1 and the recommended Phase 2 dose (RP2D) and to further explore the safety of duvortuxizumab in combination with ibrutinib at the RP2D in participants with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL) in Part 2.

This is an open-label (identity of study drug will be known to participant and study staff), multicenter (when more than one hospital or medical school team work on a medical research study), Phase 1b study. The purpose of this study is to see if duvortuxizumab in combination with ibrutinib is safe and useful for treating participants with B-cell malignancies. This study will be conducted in 2 parts: Part 1: Dose Optimization and Part 2: Dose Expansion. Part 1 will determine what dose of duvortuxizumab can be given safely with the standard dose of ibrutinib to participants with previously treated B-cell malignancies. Part 2 will look at how previously treated DLBCL, FL, MCL, and CLL participants respond to a safe dose of duvortuxizumab in combination with ibrutinib. Part 2 will also test whether the dose from Part 1 is an effective cancer therapy. The study consists of a Screening Phase, an ibrutinib Run-In Phase (Part 2 only), a combination (duvortuxizumab plus ibrutinib) Treatment Phase (Day 1, Cycle 1 and continues until the completion of the End-of-Treatment Visit), End-of-Treatment Visit (30 days (+7 days) after the last dose of study drug), and Post-treatment Follow-up Phase. The end of the study will be defined as 12 months after the last participant has received the first dose of study treatment. Participants' safety will be monitored throughout the study.

Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Duvortuxizumab (JNJ-64052781) Plus Ibrutinib in Lymphoma

A Phase 1b Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of the Combination of Duvortuxizumab With Ibrutinib in Subjects With B-Cell Malignancies

Dose limiting toxicity is based on adverse events and includes unacceptable hematologic toxicity, unacceptable non-hematologic toxicity, and laboratory abnormalities of Grade 4 or higher.

An adverse event (AE) is any untoward medical occurrence in a participant who received study treatment 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 abnormality.

Standard clinical chemistry and hematology panels will be used to evaluate changes in laboratory parameters in blood samples collected pre- and post-treatment.

The AUC\[0-t\] is the area under the duvortuxizumab serum concentration-time curve from time \[0 to t\].

The AUC\[0-t\] is the area under the ibrutinib serum concentration-time curve from time \[0 to t\].

The Cmax is the maximum observed serum concentration of duvortuxizumab.

The Cmax is the maximum observed serum concentration of ibrutinib.

The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration.

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

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

The Vss is defined as the theoretical volume in which the total amount of duvortuxizumab would be uniformly distributed to produce the desired serum concentration of duvortuxizumab at steady state.

The Vss is defined as the theoretical volume in which the total amount of ibrutinib would be uniformly distributed to produce the desired serum concentration of Ibrutinib at steady state.

Plasma levels of antibodies to duvortuxizumab will be assessed for evaluation of potential immunogenicity.

Objective tumor response is represented by participants who achieve a complete response (CR) or partial response (PR) to study treatment per the criteria for response assessment of Non-Hodgkin's Lymphoma (participants with diffuse large B-cell lymphoma \[DLBCL\], follicular lymphoma \[FL\], and mantle cell lymphoma \[MCL\]) or the International Workshop on chronic lymphocytic leukemia Criteria (IWCLL) (participants with CLL)

The CR rate is frequency of participants who achieve a complete response to study treatment according to the Criteria for Response Assessment of Non-Hodgkin's Lymphoma (participants with DLBCL, FL, and MCL) or the IWCLL Criteria (for participants with CLL).

The Duration of Response is defined as the time from the first observed response (CR or partial response \[PR\]) to documented disease progression or death due to any cause.

Progression free survival is defined as the time from first enrollment into the study to documented disease progression or death due to any cause.

One-year survival is defined as the percentage of participants surviving 1 year after entering into the study.

Janssen Research & Development, LLC

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Diffuse Large B-Cell Lymphoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Tin Fluorides

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.

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.

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.

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.

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.

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.

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 1 (Dose Escalation): 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 2 (Dose Expansion): Duvortuxizumab

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 \[diffuse-large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL)\].

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.

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

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

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).

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

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

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

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.

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

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.

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.

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).

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Duvortuxizumab (JNJ-64052781) Plus Ibrutinib in Lymphoma	NCT02743546	Leukemia, Lymph... Lymphoma, Large... Lymphoma, Folli... Lymphoma, Mantl...	Duvortuxizumab Ibrutinib	18 Years -	Janssen Research & Development, LLC
A Dose Escalation Study of Duvortuxizumab in Participants With Relapsed or Refractory B-cell Malignancies	NCT02454270	Leukemia, Lymph... Lymphoma, Large... Lymphoma, Folli... Lymphoma, Mantl... Precursor Cell ...	Part 1 (Dose Es... Part 2 (Dose Ex...	18 Years -	Janssen Research & Development, LLC
Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Duvortuxizumab (JNJ-64052781) Plus Ibrutinib in Lymphoma	NCT02743546	Leukemia, Lymph... Lymphoma, Large... Lymphoma, Folli... Lymphoma, Mantl...	Duvortuxizumab Ibrutinib	18 Years -	Janssen Research & Development, LLC
Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Duvortuxizumab (JNJ-64052781) Plus Ibrutinib in Lymphoma	NCT02743546	Leukemia, Lymph... Lymphoma, Large... Lymphoma, Folli... Lymphoma, Mantl...	Duvortuxizumab Ibrutinib	18 Years -	Janssen Research & Development, LLC

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