Clinical trial NCT03589469: 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) (LOTIS-2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-Cell Lymphoma Refractory
Diffuse Large B-cell Lymphoma Recurrent
Keywords: Loncastuximab tesirine
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2018-07-18
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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.

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

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to 21.5 months
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: Up to 39 months
measure: Complete Response (CR) Rate
timeFrame: Up to 39 months
measure: Relapse-free Survival (RFS)
timeFrame: Up to 39 months
measure: Progression-free Survival (PFS)
timeFrame: Up to 40 months
measure: Overall Survival (OS)
timeFrame: Up to 43 months
measure: Number of Participants Who Experience Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to 599 days
measure: Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests
timeFrame: Baseline up to 599 days
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to 599 days
measure: Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment
timeFrame: Baseline and end of treatment (up to 599 days)
measure: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiograms (ECGs)
timeFrame: Baseline up to 599 days
measure: Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: 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
measure: 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
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199
timeFrame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
measure: Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine
timeFrame: Up to 599 days
measure: Change From Baseline Score in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS)
timeFrame: Baseline, Day 1 of Cycles 2 to 26 (cycle duration of 3 weeks), and end of treatment (up to 599 days)
measure: Change From Baseline Score in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) - Lymphoma Subscale (LymS)
timeFrame: Baseline, Day 1 of Cycles 2 to 25 (cycle duration of 3 weeks), and end of treatment (up to 599 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
state: California
city: Fountain Valley
country: United States
facility: Compassionate Care Research Group, Inc., at Compassionate Care Medical Group, Inc.
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Miami
country: United States
facility: University of Miami Hospital and Clinics
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers, PC-Drug Shipment, Lab and Study Supplies Only
state: Georgia
city: Des Moines
country: United States
facility: Medical Oncology & Hematology Associates
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center/ Nebraska Medicine
state: Nebraska
city: East Setauket
country: United States
facility: North Shore Hematology Oncology Associates DBA NY Cancer and Blood Specialists
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center at Thomas Jefferson University
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: GHD Cancer Institute
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center - Temple
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Olympia
country: United States
facility: Vista Oncology Inc. PS
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
city: Alessandria
country: Italy
facility: A.O. SS Antonio e Biagio e Cesare Arrigo
state: AL
city: Bologna
country: Italy
facility: Istituto di Ematologia Seragnoli
state: BO
city: Rozzano
country: Italy
facility: U.O. Oncologia ed Ematologia
state: Milano
city: Milano
country: Italy
facility: Dipartimento di Oncomatlolgia - Unita Linfomi
city: Milano
country: Italy
facility: Divisione di Oncoematologia
city: Bellinzona
country: Switzerland
facility: Anastasios Stathis
state: Canton Ticino
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust.
state: England
city: London
country: United Kingdom
facility: University College London Hospital
state: England
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: England
city: Oxford
country: United Kingdom
facility: Oxford Cancer Centre, Churchill Hospital
state: England
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
state: Scotland
city: Swansea
country: United Kingdom
facility: Abertawe Bro Morgannwg University Health Board - Singleton Hospital
state: Wales
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
References:
citation: Hamadani M, Chen L, Song Y, Xu MK, Liao L, Caimi PF, Carlo-Stella C. Matching-adjusted Indirect Comparison of the Efficacy of Loncastuximab Tesirine Versus Treatment in the Chemoimmunotherapy Era for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):e738-e744. doi: 10.1016/j.clml.2022.04.006. Epub 2022 Apr 8.
citation: Hess B, Townsend W, Ai W, Stathis A, Solh M, Alderuccio JP, Ungar D, Liao S, Liao L, Khouri L, Zhang X, Boni J. Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma. AAPS J. 2021 Dec 10;24(1):11. doi: 10.1208/s12248-021-00660-3.
citation: Spira A, Zhou X, Chen L, Gnanasakthy A, Wang L, Ungar D, Curiel R, Liao L, Radford J, Kahl B. Health-Related Quality of Life, Symptoms, and Tolerability of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2022 Mar;22(3):158-168. doi: 10.1016/j.clml.2021.09.001. Epub 2021 Sep 22.
citation: Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. doi: 10.1016/S1470-2045(21)00139-X. Epub 2021 May 11.