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

ADC Therapeutics S.A.145 enrolled

Overview

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.

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 through a cathepsin-cleavable linker to SG3199, 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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

145

Conditions

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

Interventions

Loncastuximab tesirineDRUG

intravenous infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (37)

Outcomes

Primary Outcomes

Overall Response Rate (ORR)

ORR, as determined by central review according to the 2014 Lugano classification, defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR).

Time frame: Up to 21.5 months

Secondary Outcomes

Duration of Response (DOR)

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

Time frame: Up to 39 months

Complete Response (CR) Rate

CR rate defined as the percentage of treated participants with a best overall response (BOR) of CR.

Time frame: Up to 39 months

Relapse-free Survival (RFS)

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

Time frame: Up to 39 months

Progression-free Survival (PFS)

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

Time frame: Up to 40 months

Overall Survival (OS)

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

Time frame: Up to 43 months

Number of Participants Who Experience Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that did not necessarily have to have a causal relationship with treatment. A TEAE was an adverse event with an onset that began or worsened on or after the first dose date and until 30 days after the last dose date, or start of a new anticancer therapy/procedure, whichever came earlier. TEAE assessments also included those per the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Grade ≥3 AEs and serious TEAEs. AEs were graded using CTCAE version 4 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. For events not listed in the CTCAE criteria, the same grading was used.

Data from ClinicalTrials.gov

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City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, United States

Compassionate Care Research Group, Inc., at Compassionate Care Medical Group, Inc.

Fountain Valley, California, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

University of California, San Francisco Medical Center

San Francisco, California, United States

The Oncology Institute of Hope and Innovation

Whittier, California, United States

University of Miami Hospital and Clinics

Miami, Florida, United States

Miami Cancer Institute

Miami, Florida, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Northside Hospital

Atlanta, Georgia, United States

Northwest Georgia Oncology Centers, PC-Drug Shipment, Lab and Study Supplies Only

Marietta, Georgia, United States

...and 27 more locations

Time frame: Up to 599 days

Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests

Clinical laboratory tests included hematology and chemistry. Clinically significant changes were determined by the Investigator.

Time frame: Baseline up to 599 days

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Vital sign measurements included arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.

Time frame: Baseline up to 599 days

Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment

ECOG (Eastern Cooperative Oncology Group) Performance Status is scored on a 6-point scale where higher scores indicate a worse outcome. ECOG scores include the following: * 0 = fully active, able to carry on all pre-disease performance without restriction * 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work * 2 = ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours * 3 = capable of only limited self-care; confined to bed or chair more than 50% of waking hours * 4 = completely disabled; cannot carry on any self-care; totally confined to bed or chair * 5 = dead

Time frame: Baseline and end of treatment (up to 599 days)

Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiograms (ECGs)

Clinically significant changes from baseline for 12-lead ECGs were measured as abnormal QT interval corrected by Fridericia formula (QTcF) and QT interval corrected by Bazett formula (QTcB) values.

Time frame: Baseline up to 599 days

Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

Time frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose and end of infusion

Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199