Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Mantle-Cell

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Mantle Cell Lymphoma

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Ibrutinib

Loncastuximab tesirine

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Tyrosine

A standard 3+3 dose escalation design will be used. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for Cycle 1 and 2 (3 weeks each) with concurrent ibrutinib (concomitant therapy) daily. Participants may continue to receive ibrutinib therapy up to 1 year after Cycle 1 Day 1 (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered intravenously (IV).

Participants with non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV.

Participants with germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV.

Participants with mantle cell lymphoma (MCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV.

Loncastuximab Tesirine

The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.

The Phase 1 portion of the study will cover the dose escalation portion of the study. This will then be followed by the Phase 2 portion of the study, which will treat participants with the dose of loncastuximab tesirine determined in the Phase 1 portion of the study. The ibrutinib dose of 560 mg daily, will remain the same throughout both phases of the study.

A standard 3+3 dose escalation design will be used for the Phase 1 portion of the study. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year.

The Phase 2 portion of the study will involve 3 cohorts:

* Non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) cohort
* Germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) cohort
* Mantle cell lymphoma (MCL) cohort

Each of the cohorts will be treated with the recommended dose of loncastuximab tesirine determined in the Phase 1 portion of the study.

The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).

Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients With Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead electrocardiograms (ECGs) which occurred after first dose of study drug were recorded as TEAEs.

A serious TEAE was defined as any AE which occurred after the first dose of study drug that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance was not considered a serious adverse event), resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or important medical events that did not meet the preceding criteria but based on appropriate medical judgement may have jeopardized the participant or may have required medical or surgical intervention to prevent any of the outcomes listed above.

A DLT was defined as any of the following events which occur during the DLT Period (first 21 days of ibrutinib treatment), except those that are clearly due to underlying disease or extraneous causes: a hematologic DLT (grade ≥3 anaemia, grade 4/febrile neutropenia, grade ≥3 thrombocytopenia), a non-hematologic DLT (including aspartate aminotransferase \[AST\] and/or alanine aminotransferase \[ALT\] \>3× upper limit of normal (ULN) and bilirubin \>2× ULN), any other non-hematologic toxicities ≥ Grade 3, with exceptions.

CRR according to the 2014 Lugano classifications determined by Independent Review Committee (IRC). CRR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR).

ORR according to the 2014 Lugano classification, defined as the percentage of participants with a BOR of CR or partial response (PR).

DOR was defined as the time from the first documentation of tumor response to disease progression or death.

RFS was defined as the time from the documentation of CR to disease progression or death.

PFS was defined as the time between start of treatment and the first documentation of progression, or death.

OS was defined as the time between the start of treatment and death from any cause.

Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199)

Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199).

Detection of ADAs was performed by using a screening assay for identification of antibody positive samples/participants, a confirmation assay, and titer assessment.

ORR according to the 2014 Lugano classification, defined as the percentage of participants with a BOR of CR or PR.

CRR according to the 2014 Lugano classifications determined by the IRC. CRR was defined as the percentage of participants with a BOR of CR in non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL participants.

A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, ECOG performance status, and 12-lead ECGs which occurred after first dose of study drug were recorded as TEAEs.

ADC Therapeutics S.A.

Measured in the safety population, which included all participants who received study drug.

Participants with advanced diffuse large B-Cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) were enrolled to receive 60 µg/kg of loncastuximab tesirine via intravenous (IV) infusion once every 3 weeks (Q3W) for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6.

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Participants with advanced DLBCL or MCL were enrolled to receive 75 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6.

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Participants with advanced DLBCL or MCL were enrolled to receive 90 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6.

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Participants with non-germinal center B-cell (GCB) DLBCL received the recommended phase 2 dose (RP2D) of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of complete response (CR), partial response (PR), and stable disease (SD) received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Phase 2: Loncastuximab Tesirine and Ibrutinib in Non-Germinal Center B-cell (GCB) DLBCL

Participants with GCB DLBCL received the RP2D of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of CR, PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Participants with MCL received the RP2D of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of CR, PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Measured in the safety analysis set, which included all participants who received study drug.

Clinical Trials Information

Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Phase 1: Number of Participants With Serious TEAEs

Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)

Phase 1: Number of Participants With Dose Interruptions

Phase 1: Number of Participants With Dose Reductions

Measured in the efficacy analysis set, which included all participants who received at least 1 dose of study drug, who had valid baseline disease assessment(s), and who had at least one valid post-baseline disease assessment. Participants who did not have a post-baseline assessment due to early clinical progression or death (after receiving study drug) were also included.

Phase 2: Complete Response Rate (CRR)

Phase 1: Overall Response Rate (ORR)

Measured in the efficacy analysis set, which included all participants who received at least 1 dose of study drug, who had valid baseline disease assessment(s), who had at least one valid post-baseline disease assessment who achieved a response. Participants who did not have a post-baseline assessment due to early clinical progression or death (after receiving study drug) were also included.

Phase 1 and Phase 2: Duration of Response (DOR)

Measured in the efficacy analysis set, which included all participants who received at least 1 dose of study drug, who had valid baseline disease assessment(s), and who had at least one valid post-baseline disease assessment who achieved CR. Participants who did not have a post-baseline assessment due to early clinical progression or death (after receiving study drug) were also included.

Phase 1 and Phase 2: Relapse-Free Survival (RFS)

Phase 1 and Phase 2: Progression-Free Survival (PFS)

Phase 1 and Phase 2: Overall Survival (OS)

Cycle 1: PBD-conjugated Antibody

Cycle 1: Total Antibody

Cycle 1: Unconjugated cytotoxin SG3199

Cycle 2: PBD-conjugated Antibody

Cycle 2: Total Antibody

Cycle 2: Unconjugated cytotoxin SG3199

Participants with advanced diffuse large B-Cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) were enrolled to receive 60 µg/kg of loncastuximab tesirine via intravenous (IV) infusion once every 3 weeks (Q3W) for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants in Phase 1 who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6. Participants in Phase 2 who had a response of complete response (CR), partial response (PR), and stable disease (SD) received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Phase 1 and Phase 2: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Measured in the PK population, which included all participants who had at least 1 pre-C1D1 and 1 post-dose valid PK assessment. The "number of participants analzyed" represents the number of participants with collected data. Analysis reported per dose of loncastuximab tesirine as pre-specified.

Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)

ADA-evaluable participants including all participants tested for ADAs in the study.

Phase 1 and Phase 2: Number of Participants With Positive Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine at Any Time

Phase 2: ORR

Participants with all DLBCL types received the RP2D of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of CR, PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Phase 2: Loncastuximab Tesirine and Ibrutinib in All DLBCL Participants

Measured in the efficacy analysis set, which included all participants who received at least 1 dose of study drug, who had valid baseline disease assessment(s), and who had at least one valid post-baseline disease assessment. Participants who did not have a post-baseline assessment due to early clinical progression or death (after receiving study drug) were also included. As pre-specified, data are presented for non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL cohorts.

Phase 2: CRR in Non-GCB DLBCL, GCB DLBCL, All DLBCL and MCL Participants

Phase 2: Number of Participants With TEAEs

Phase 2: Number of Participants With Serious TEAEs

Participants with advanced DLBCL or MCL were enrolled to receive 75 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of PR or SD at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6.

Participants with advanced DLBCL or MCL were enrolled to receive 90 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of PR or SD at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart on Day 1 of Cycles 5 and 6.

Participants with non-germinal center B-cell (GCB) DLBCL received the recommended phase 2 dose (RP2D) of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of complete response (CR), PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Spots Global Cancer Trial Database for loncastuximab tesirine in combination with ibrutinib