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

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ClinicalTrials.gov Identifier: NCT03589469
Recruitment Status : Recruiting
First Posted : July 18, 2018
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
ADC Therapeutics S.A.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-cell Lymphoma Recurrent Drug: Loncastuximab tesirine Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : February 22, 2020
Estimated Study Completion Date : February 22, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Loncastuximab tesirine
Participants 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.
Drug: Loncastuximab tesirine
intravenous infusion
Other Name: ADCT-402




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
    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 :
  1. Duration of Response (DOR) [ Time Frame: Up to 3 years ]
    DOR defined as the time from the first documentation of tumor response to disease progression or death

  2. CR rate [ Time Frame: Up to 3 years ]
    CR rate defined as the percentage of treated patients with a BOR of CR

  3. Relapse-free survival (RFS) [ Time Frame: Up to 3 years ]
    RFS defined as the time from the documentation of CR to disease progression or death

  4. Progression Free Survival (PFS) [ Time Frame: Up to 3 years ]
    PFS defined as the time between start of treatment and the first documentation of recurrence, progression, or death

  5. Overall Survival (OS) [ Time Frame: Up to 3 years ]
    OS defined as the time between the start of treatment and death from any cause

  6. Frequency and severity of adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to 3 years ]
  7. 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) ]
    Noncompartmental analysis of the maximum concentration (Cmax)

  8. 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) ]
    Noncompartmental analysis of the time to maximum concentration (Tmax)

  9. 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) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last)

  10. 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) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-τ)

  11. 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) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to infinity (AUC0-∞)

  12. 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) ]
    Noncompartmental analysis of the accumulation index (AI)

  13. 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) ]
    Noncompartmental analysis of Clearance (CL)

  14. 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) ]
    Measurement of Anti-drug antibodies to ADCT-301 before, during and after treatment with Loncastuximab Tesirine

  15. 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) ]

    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)

  16. 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) ]
    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.

  17. Changes from baseline of ECOG performance status [ Time Frame: Up to 3 years ]

    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.


  18. Changes from baseline of 12-lead electrocardiograms (ECGs) [ Time Frame: Up to 3 years ]
    Characterize the safety profile of loncastuximab tesirine



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03589469


Contacts
Contact: ADC Therapeutics 954-903-7994 clinical.trials@adctherapeutics.com

Locations
United States, Georgia
Northside Hospital Recruiting
Atlanta, Georgia, United States, 30342
Contact: Melhem Solh, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Brad Kahl, MD         
United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
United States, South Carolina
GHD Cancer Institute Recruiting
Greenville, South Carolina, United States, 29605
Contact: Elizabeth Cull, MD         
United States, Virginia
Virginia Cancer Specialists, PC Recruiting
Fairfax, Virginia, United States, 22031
Principal Investigator: Alexander I. Spira, MD         
United States, Washington
Vista Oncology Inc. PS Recruiting
Olympia, Washington, United States, 98506
Contact: Joseph Ye, MD         
Italy
Istituto di Ematologia Seragnoli Recruiting
Bologna, BO, Italy, 40138
Contact: Pier L Zinzani, MD         
U.O. Oncologia ed Ematologia Recruiting
Rozzano, Milano, Italy, 20089
Contact: Carmelo Carlo-Stella, MD         
Switzerland
Anastasios Stathis Recruiting
Bellinzona, Canton Ticino, Switzerland, 6500
Contact: Anastasios Stathis, MD         
United Kingdom
The Christie NHS Foundation Trust Recruiting
Manchester, England, United Kingdom, M20 4BX
Contact: John Radford, MD         
Oxford Cancer Centre, Churchill Hospital Recruiting
Oxford, England, United Kingdom, OX3 7 LE
Contact: Graham Collins, MD         
Sponsors and Collaborators
ADC Therapeutics S.A.

Responsible Party: ADC Therapeutics S.A.
ClinicalTrials.gov Identifier: NCT03589469     History of Changes
Other Study ID Numbers: ADCT-402-201
First Posted: July 18, 2018    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ADC Therapeutics S.A.:
Loncastuximab tesirine

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin