Clinical Trials /

Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

NCT03589469

Description:

The purpose of this Phase 2 study is to evaluate the clinical efficacy and safety of Loncastuximab Tesirine (ADCT-402) in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
  • Mediastinal Large B-Cell Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
  • Official Title: A Phase 2 Open-Label Single-Arm Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: ADCT-402-201
  • SECONDARY ID: 2017-004288-11
  • NCT ID: NCT03589469

Conditions

  • Diffuse Large B-Cell Lymphoma Refractory
  • Diffuse Large B-cell Lymphoma Recurrent

Interventions

DrugSynonymsArms
Loncastuximab tesirineADCT-402Loncastuximab tesirine

Purpose

The purpose of this Phase 2 study is to evaluate the clinical efficacy and safety of Loncastuximab Tesirine (ADCT-402) in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma.

Detailed Description

      This is a Phase 2, multi-center, open-label, single-arm study of the efficacy and safety of
      loncastuximab tesirine used as monotherapy in patients with relapsed or refractory DLBCL. The
      study will enroll approximately 140 patients

      Loncastuximab Tesirine is an antibody drug conjugate (ADC) composed of a humanized antibody
      directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a
      valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.
      Loncastuximab tesirine has been designed to target and kill CD19-expressing malignant
      B-cells.

      A 2-stage design will be used in this clinical study, with an interim analysis for futility
      on the first 52 patients. If ≥10 patients respond (CR+PR), the study will proceed to complete
      full enrollment. Enrollment will continue during the interim analysis; however, further
      enrollment will be halted if futility is confirmed.

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

      Patients may continue treatment until disease progression, unacceptable toxicity, or other
      discontinuation criteria, whichever occurs first.
    

Trial Arms

NameTypeDescriptionInterventions
Loncastuximab tesirineExperimentalParticipants will receive loncastuximab tesirine as an IV infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg Q3W for 2 cycles, then 75 μg/kg Q3W for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first.
  • Loncastuximab tesirine

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patient aged 18 years or older.

          -  Pathologic diagnosis of DLBCL, as defined by the 2016 WHO classification, to include:
             DLBCL not otherwise specified; primary mediastinal large B-cell lymphoma; and
             high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

          -  Relapsed or refractory disease following two or more multi-agent systemic treatment
             regimens

          -  Patients who have received previous CD19-directed therapy must have a biopsy that
             shows CD19 protein 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 0-2

          -  Adequate organ function

          -  Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior
             to start of study drug (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 16 weeks after
             the last dose of loncastuximab tesirine. 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 16 weeks after
             the patient receives his last dose of loncastuximab tesirine.

        Exclusion Criteria:

          -  Previous treatment with loncastuximab tesirine

          -  Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody

          -  Pathologic diagnosis of Burkitt lymphoma

          -  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

          -  Autologous stem cell transplant (ASCT) within 30 days prior to start of study drug
             (C1D1)

          -  Allogeneic stem cell transplant (AlloSCT) within 60 days prior to start of study drug
             (C1D1)

          -  Active graft-versus-host disease

          -  Post-transplant lymphoproliferative disorders

          -  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

          -  Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 14
             days prior to start of study drug (C1D1), except shorter if approved by the Sponsor

          -  Use of any other experimental medication within 14 days prior to start of study drug
             (C1D1)

          -  Planned live vaccine administration after starting study drug (C1D1)

          -  Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events version
             4.0 [CTCAE v4.0]) 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)

          -  Any other significant medical illness, abnormality, or condition that would, in the
             Investigator's judgment, make the patient inappropriate for study participation or put
             the patient at risk
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description:ORR, as determined by central review according to the 2014 Lugano classification, defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR)

Secondary Outcome Measures

Measure:Duration of Response (DOR)
Time Frame:Up to 3 years
Safety Issue:
Description:DOR defined as the time from the first documentation of tumor response to disease progression or death
Measure:CR rate
Time Frame:Up to 3 years
Safety Issue:
Description:CR rate defined as the percentage of treated patients with a BOR of CR
Measure:Relapse-free survival (RFS)
Time Frame:Up to 3 years
Safety Issue:
Description:RFS defined as the time from the documentation of CR to disease progression or death
Measure:Progression Free Survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:PFS defined as the time between start of treatment and the first documentation of recurrence, progression, or death
Measure:Overall Survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:OS defined as the time between the start of treatment and death from any cause
Measure:Frequency and severity of adverse events (AEs) and serious AEs (SAEs)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Maximum concentration (Cmax) of Loncastuximab Tesirine , pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the maximum concentration (Cmax)
Measure:Time to maximum concentration (Tmax) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the time to maximum concentration (Tmax)
Measure:Area under the curve (AUC0-last) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last)
Measure:Area under the curve (AUC0-τ) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-τ)
Measure:Area under the curve (AUC0-∞) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the area under the concentration-time curve from time zero to infinity (AUC0-∞)
Measure:Accumulation index (AI) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of the accumulation index (AI)
Measure:Clearance (CL) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Noncompartmental analysis of Clearance (CL)
Measure:Measurement of Anti-drug antibodies to Loncastuximab Tesirine
Time Frame:Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks)
Safety Issue:
Description:Measurement of Anti-drug antibodies to ADCT-301 before, during and after treatment with Loncastuximab Tesirine
Measure:Change from baseline in HRQoL as measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)
Time Frame:Day 1 of each cycle until up to 30 days after last dose (each cycle is 3 weeks)
Safety Issue:
Description:EQ-5D-5L is designed as an international, standardized, instrument for describing and evaluating QoL. The EQ-5D-5L consists of two parts: The descriptive system: QoL is classified according to five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises five levels of perceived problems (e.g., none, slight, moderate, severe, extreme). The visual analog scale (VAS): patients are asked to indicate their health state today on a VAS with the endpoints labeled 'the best health you can imagine' (score 100) and 'the worst health you can imagine' (score 0).Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)(EQ-5D-5L)
Measure:Change from baseline in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)
Time Frame:Day 1 of each cycle until up to 30 days after last dose (each cycle is 3 weeks)
Safety Issue:
Description:FACT-Lym is a lymphoma-specific subscale for the Functional Assessment of Cancer Therapy (FACT) questionnaire. It consists of 15 specific items that are used together with the core 27-item questionnaire FACT-G (General). The patient is asked to respond to each item with a score of 0-4, where 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much. A higher score equals a worse level of QoL.
Measure:Changes from baseline of ECOG performance status
Time Frame:Up to 3 years
Safety Issue:
Description:ECOG (Eastern Cooperative Oncology Group) Performance Status is a 5-point scale, from 0 (fully active) to 5 (dead). Characterize the safety profile of loncastuximab tesirine.
Measure:Changes from baseline of 12-lead electrocardiograms (ECGs)
Time Frame:Up to 3 years
Safety Issue:
Description:Characterize the safety profile of loncastuximab tesirine

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:ADC Therapeutics S.A.

Trial Keywords

  • Loncastuximab tesirine

Last Updated

June 15, 2020