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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

Janssen Research & Development, LLC Clinical Trial

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 Cmax is the maximum observed serum concentration of duvortuxizumab.

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.

Spots Global Cancer Trial Database for part 1 (dose escalation): duvortuxizumab