Clinical Trials /

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

NCT03684694

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: ADCT-402-103
  • SECONDARY ID: 2018-002625-38
  • NCT ID: NCT03684694

Conditions

  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
Loncastuximab TesirineADCT-402Phase 1: Dose-Escalation of ADCT-402
IbrutinibPhase 1: Dose-Escalation of ADCT-402

Purpose

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

      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).
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: Dose-Escalation of ADCT-402ExperimentalA 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.
  • Loncastuximab Tesirine
  • Ibrutinib
Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCLExperimentalParticipants 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.
  • Loncastuximab Tesirine
  • Ibrutinib
Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCLExperimentalParticipants 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.
  • Loncastuximab Tesirine
  • Ibrutinib
Phase 2: MTD or RP2D of ADCT-402 in MCLExperimentalParticipants 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.
  • Loncastuximab Tesirine
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female participant aged 18 years or older

          2. Pathologic diagnosis of DLBCL or MCL

          3. Participants with DLBCL must have relapsed or refractory disease and have failed or
             been intolerant to available standard therapy

          4. Participants with MCL must have relapsed or refractory disease and have received at
             least one prior line of therapy

          5. Participants who have received previous CD19-directed therapy must have a biopsy which
             shows CD19 expression after completion of the CD19-directed therapy

          6. Measurable disease as defined by the 2014 Lugano Classification

          7. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum
             10 freshly cut unstained slides if block is not available)

          8. ECOG performance status 0 to 2

          9. Screening laboratory values within the following parameters:

               1. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72
                  hours)

               2. Platelet count ≥75 × 103/µL without transfusion in the past 7 days

               3. Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed

               4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma
                  glutamyl transferase (GGT) ≤2.5 × the ULN

               5. Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a
                  total bilirubin up to ≤3 × ULN)

               6. Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the
                  Cockcroft and Gault equation

         10. 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

         11. Women of childbearing potential must agree to use a highly effective method of
             contraception from the time of giving informed consent until at least 16 weeks after
             the last dose of study therapy. 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 20 weeks after the participant
             receives his last dose of study therapy

        Exclusion Criteria:

          1. Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA)
             to a CD19 antibody

          2. Known history of hypersensitivity to ibrutinib

          3. Previous therapy with ibrutinib or other BTK inhibitors

          4. Previous therapy with loncastuximab tesirine

          5. Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A
             inhibitor

          6. Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1)

          7. Active graft-versus-host disease

          8. Post-transplantation lymphoproliferative disorder

          9. Active autoimmune disease, including motor neuropathy considered of autoimmune origin
             and other central nervous system (CNS) autoimmune disease

         10. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV)
             virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).

         11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis

         12. Lymphoma with active CNS involvement at the time of screening, including
             leptomeningeal disease

         13. 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)

         14. Breastfeeding or pregnant

         15. 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).

         16. 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

         17. Use of any other experimental medication within 14 days prior to start of study drugs
             (C1D1)

         18. Planned live vaccine administration after starting study drugs (C1D1)

         19. 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

         20. Inherited or acquired bleeding disorders

         21. Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent

         22. 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

         23. Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening
             (unless secondary to pacemaker or bundle branch block)

         24. 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

         25. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Number of Adverse Events (AEs)
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Phase 1: Overall Response Rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Phase 1 and Phase 2: Duration of Response (DOR)
Time Frame:Up to 2 years
Safety Issue:
Description:DOR defined as the time from first tumor response to disease progression or death.
Measure:Phase 1 and Phase 2: Relapse-Free Survival (RFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Time from the documentation of complete response (CR) to disease progression or death.
Measure:Phase 1 and Phase 2: Progression-Free Survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Time between start of treatment and the first documentation of progression, or death.
Measure:Phase 1 and Phase 2: Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Time between the start of treatment and death from any cause.
Measure:Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame: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)
Safety Issue:
Description:
Measure:Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame: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)
Safety Issue:
Description:
Measure: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)
Time Frame: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)
Safety Issue:
Description:
Measure: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)
Time Frame: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)
Safety Issue:
Description:
Measure: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)
Time Frame: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)
Safety Issue:
Description:
Measure:Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame: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)
Safety Issue:
Description:
Measure:Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame: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)
Safety Issue:
Description:
Measure:Phase 1 and Phase 2: Number of Participants with Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine
Time Frame: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)
Safety Issue:
Description:Followed by characterization and evaluation of neutralizing capacity as needed.
Measure:Phase 2: Overall Response Rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Phase 2: Complete Response Rate (CRR) in GCB DLBCL, all DLBCL and MCL Participants
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Phase 2: Complete Response Rate (CRR) in Non-GCB DLBCL Participants
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Adverse Events (AEs)
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Adverse Events (AEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Serious Adverse Events (SAEs)
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Serious Adverse Events (SAEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Laboratory Values
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Vital Signs
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Phase 1: Number of Participants who Experience a Clinically Significant Change in Baseline in Eastern Cooperative Oncology Group (ECOG)
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure:Phase 2: Number of Participants who Experience a Clinically Significant Change in Baseline in Electrocardiogram (ECG) Results
Time Frame:Up to 3.5 years
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years)
Safety Issue:
Description:
Measure:Phase 2: Lymphoma Subscale (LymS) of Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Scores
Time Frame:Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years)
Safety Issue:
Description:
Measure:Phase 2: EuroQoL 5-dimension 5-level (EQ-5D-5L)
Time Frame:Baseline to End of Follow-Up Period (maximum time on follow-up was 2 years)
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ADC Therapeutics S.A.

Trial Keywords

  • Loncastuximab Tesirine in Combination with Ibrutinib

Last Updated

March 24, 2021