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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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)

Conditions
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Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Loncastuximab Tesirine
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participant aged 18 years or older Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are excluded.) Participants with DLBCL must have relapsed or refractory disease and have failed or been intolerant to available standard therapy Participants with MCL must have relapsed or refractory disease and have received at least one prior line of therapy (For Italy Sites Only: This exclusion criterion is not applicable) Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy Measurable disease as defined by the 2014 Lugano Classification Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available) ECOG performance status 0 to 2 Screening laboratory values within the following parameters: Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours) Platelet count ≥75 × 103/µL without transfusion in the past 7 days Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the ULN Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN) Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft and Gault equation Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drugs on C1D1 for women of childbearing potential Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9 months after the last dose of loncastuximab tesirine or 1 month after last dose of ibrutinib, whichever comes last. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the participant receives his last dose of loncastuximab tesirine or 3 months after last dose of ibrutinib, whichever comes last Exclusion Criteria: Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD19 antibody Known history of hypersensitivity to ibrutinib Previous therapy with ibrutinib or other BTK inhibitors Previous therapy with loncastuximab tesirine Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A inhibitor Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1) Active graft-versus-host disease Post-transplantation lymphoproliferative disorder Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). History of Stevens-Johnson syndrome or toxic epidermal necrolysis Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath) Breastfeeding or pregnant Significant medical comorbidities, including but not limited to, uncontrolled hypertension (blood pressure [BP] ≥160/100 millimeters of mercury (mmHg) repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes mellitus, or severe chronic pulmonary disease, or tuberculosis infection (tuberculosis screening based on local standards). Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor Use of any other experimental medication within 14 days prior to start of study drugs (C1D1) Planned live vaccine administration after starting study drugs (C1D1) Any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel Inherited or acquired bleeding disorders Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) from acute non-hematologic toxicity (Grade ≤2 neuropathy or alopecia) due to previous therapy prior to screening Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block) Active second primary malignancy other than non-melanoma skin cancers, non metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree, and document should not be exclusionary Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the participant inappropriate for study participation or put the participant at risk

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose-Escalation of ADCT-402<br>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 treatment up to 1 year after Cycle 1 Day 1 (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered intravenously (IV), as a frozen liquid. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) infusion.<br>* Other names: ADCT-402;Drug: Ibrutinib<br>* Oral capsule.<br>|
| Experimental: Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCL<br>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 intravenously (IV), as a lyophilized formulation. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) infusion.<br>* Other names: ADCT-402;Drug: Ibrutinib<br>* Oral capsule.<br>|
| Experimental: Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCL<br>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 intravenously (IV), as a lyophilized formulation. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) infusion.<br>* Other names: ADCT-402;Drug: Ibrutinib<br>* Oral capsule.<br>|
| Experimental: Phase 2: MTD or RP2D of ADCT-402 in MCL<br>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 intravenously (IV), as a lyophilized formulation. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) infusion.<br>* Other names: ADCT-402;Drug: Ibrutinib<br>* Oral capsule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. | Up to 3.5 years | 
| Phase 1: Number of Adverse Events (AEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above | Adverse events will be graded according to CTCAE v4.0 (or more recent): Grade 3 - Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ADL). Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to adverse event. For events not included in the CTCAE criteria, the severity of the AE will be graded on a scale of 1 to 5. | Up to 3.5 years | 
| Phase 1: Number of Serious Adverse Events (SAEs) | A SAE is defined as any AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance is not considered an SAE), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or important medical events that do not meet the preceding criteria but based on appropriate medical judgement may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above. | Up to 3.5 years | 
| Phase 1: Number of Serious Adverse Events (SAEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above | Adverse events will be graded according to CTCAE v4.0 (or more recent): Grade 3 - Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to adverse event. For events not included in the CTCAE criteria, the severity of the AE will be graded on a scale of 1 to 5. | Up to 3.5 years | 
| Phase 1: Number of Dose-Limiting Toxicities (DLTs) | Safety and Tolerability (dose escalation only). | Up to 2 years | 
| Phase 1: Number of Dose Interruptions | Safety and Tolerability. | Up to 2 years | 
| Phase 1: Number of Dose Reductions | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 2 years | 
| Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Laboratory Values | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Vital Signs | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Electrocardiogram (ECG) Results | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 2: Complete Response Rate (CRR) | CRR according to the 2014 Lugano classifications determined by Independent Review Committee (IRC). CRR defined as the number of participants with a best overall response (BOR) of complete response (CR) in non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL) participant cohort only (Phase 2). | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Overall Response Rate (ORR) | ORR according to the 2014 Lugano classification, defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). | Up to 2 years | 
| Phase 1 and Phase 2: Duration of Response (DOR) | DOR defined as the time from first tumor response to disease progression or death. | Up to 2 years | 
| Phase 1 and Phase 2: Relapse-Free Survival (RFS) | Time from the documentation of complete response (CR) to disease progression or death. | Up to 2 years | 
| Phase 1 and Phase 2: Progression-Free Survival (PFS) | Time between start of treatment and the first documentation of progression, or death. | Up to 2 years | 
| Phase 1 and Phase 2: Overall survival (OS) | Time between the start of treatment and death from any cause. | Up to 2 years | 
| Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| 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) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| 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) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| 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) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199) |  | Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| Phase 1 and Phase 2: Number of Participants with Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine | Followed by characterization and evaluation of neutralizing capacity as needed. | Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks) | 
| Phase 2: Overall Response Rate (ORR) | ORR according to the 2014 Lugano classification, defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). | Up to 2 years | 
| Phase 2: Complete Response Rate (CRR) in GCB DLBCL, all DLBCL and MCL Participants | CRR according to the 2014 Lugano classifications determined by the investigator and/or independent review committee (IRC). CRR defined as the number of participants with a best overall response (BOR) of complete response (CR) in non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL participants. | Up to 2 years | 
| Phase 2: Complete Response Rate (CRR) in Non-GCB DLBCL Participants | CRR according to the 2014 Lugano classifications determined by the investigator and/or independent review committee (IRC). CRR defined as the number of participants with a best overall response (BOR) of complete response (CR) in non-GCB DLBCL participants. | Up to 2 years | 
| Phase 2: Number of Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. | Up to 3.5 years | 
| Phase 2: Number of Adverse Events (AEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above | AEs will be graded according to CTCAE v4.0 (or more recent). Grade 3 - Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to adverse event. For events not included in the CTCAE criteria, the severity of the AE will be graded on a scale of 1 to 5. | Up to 3.5 years | 
| Phase 2: Number of Serious Adverse Events (SAEs) | A SAE is defined as any AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance is not considered an SAE), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or important medical events that do not meet the preceding criteria but based on appropriate medical judgement may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above. | Up to 3.5 years | 
| Phase 2: Number of Serious Adverse Events (SAEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above | Adverse events will be graded according to CTCAE v4.0 (or more recent): Grade 3 - Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to adverse event. For events not included in the CTCAE criteria, the severity of the AE will be graded on a scale of 1 to 5. | Up to 3.5 years | 
| Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Laboratory Values | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Vital Signs | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 2: Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Eastern Cooperative Oncology Group (ECOG) | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Electrocardiogram (ECG) Results | To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the MTD/recommended dose and schedule for future studies. | Up to 3.5 years | 
| Phase 2: Functional Scales, Symptoms and Global Health State Scores as measured by The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 |  | Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years) | 
| Phase 2: Lymphoma Subscale (LymS) of Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Scores |  | Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years) | 
| Phase 2: EuroQoL 5-dimension 5-level (EQ-5D-5L) | Change from Baseline in Visual Analog Scale scores (VAS) at each scheduled assessment. Individual dimension responses will be summarized at each scheduled assessment with frequency counts and percentage of participants. | Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loncastuximab Tesirine in Combination with Ibrutinib