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

Diffuse Large B-cell Lymphoma Recurrent Clinical Trial

— LOTIS-2  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03589469
• Other study ID #: ADCT-402-201
• Secondary ID: 2017-004288-11
• Status: Completed
• Phase: Phase 2
• Start date: August 1, 2018
• Est. completion date: August 9, 2022

Study information

• Verified date: August 2023
• Source: ADC Therapeutics S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: August 9, 2022
• Est. primary completion date: May 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (ß-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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Loncastuximab tesirine
intravenous infusion

Locations

Country	Name	City	State
Italy	A.O. SS Antonio e Biagio e Cesare Arrigo	Alessandria	AL
Italy	Istituto di Ematologia Seragnoli	Bologna	BO
Italy	Dipartimento di Oncomatlolgia - Unita Linfomi	Milano
Italy	Divisione di Oncoematologia	Milano
Italy	U.O. Oncologia ed Ematologia	Rozzano	Milano
Switzerland	Anastasios Stathis	Bellinzona	Canton Ticino
United Kingdom	NHS Greater Glasgow and Clyde	Glasgow	Scotland
United Kingdom	University Hospitals of Leicester NHS Trust.	Leicester	England
United Kingdom	University College London Hospital	London	England
United Kingdom	The Christie NHS Foundation Trust	Manchester	England
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Oxford Cancer Centre, Churchill Hospital	Oxford	England
United Kingdom	Abertawe Bro Morgannwg University Health Board - Singleton Hospital	Swansea	Wales
United States	Northside Hospital	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Hollings Cancer Center	Charleston	South Carolina
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Medical Oncology & Hematology Associates	Des Moines	Iowa
United States	City of Hope (City of Hope National Medical Center, City of Hope Medical Center)	Duarte	California
United States	North Shore Hematology Oncology Associates DBA NY Cancer and Blood Specialists	East Setauket	New York
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Compassionate Care Research Group, Inc., at Compassionate Care Medical Group, Inc.	Fountain Valley	California
United States	GHD Cancer Institute	Greenville	South Carolina
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Northwest Georgia Oncology Centers, PC-Drug Shipment, Lab and Study Supplies Only	Marietta	Georgia
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Hospital and Clinics	Miami	Florida
United States	Froedtert Hospital & the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Vista Oncology Inc. PS	Olympia	Washington
United States	University of Nebraska Medical Center/ Nebraska Medicine	Omaha	Nebraska
United States	Sidney Kimmel Cancer Center at Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California, San Francisco Medical Center	San Francisco	California
United States	Baylor Scott & White Medical Center - Temple	Temple	Texas
United States	The Oncology Institute of Hope and Innovation	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
ADC Therapeutics S.A.

Countries where clinical trial is conducted

United States,  Italy,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Up to 21.5 months
Secondary	Duration of Response (DOR)	DOR defined as the time from the first documentation of tumor response to disease progression or death.	Up to 39 months
Secondary	Complete Response (CR) Rate	CR rate defined as the percentage of treated participants with a best overall response (BOR) of CR.	Up to 39 months
Secondary	Relapse-free Survival (RFS)	RFS was defined as the time from the documentation of CR to disease progression or death.	Up to 39 months
Secondary	Progression-free Survival (PFS)	PFS was defined as the time between start of treatment and the first documentation of recurrence, progression, or death.	Up to 40 months
Secondary	Overall Survival (OS)	OS was defined as the time between the start of treatment and death from any cause.	Up to 43 months
Secondary	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.	Up to 599 days
Secondary	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.	Baseline up to 599 days
Secondary	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.	Baseline up to 599 days
Secondary	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	Baseline and end of treatment (up to 599 days)
Secondary	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.	Baseline up to 599 days
Secondary	Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199		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
Secondary	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		Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-8) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199		Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199		Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199		Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199		Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199	AI is the ratio of AUC0-last for each cycle divided by AUC0-last of the previous cycle.	Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose
Secondary	Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine		Up to 599 days
Secondary	Change From Baseline Score in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS)	EQ-5D-5L is designed as an international, standardized, instrument for describing and evaluating quality of life (QoL). In the EQ-5D-5L VAS participants 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).; A higher score on the VAS indicates better health related QoL. A positive change from baseline indicates an improvement in health related QoL.	Baseline, Day 1 of Cycles 2 to 26 (cycle duration of 3 weeks), and end of treatment (up to 599 days)
Secondary	Change From Baseline Score in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) - Lymphoma Subscale (LymS)	Composed of the Functional Assessment of Cancer Therapy - General (FACT-G) plus the 15-item LymS. The FACT-G questionnaire contains 27 items covering 4 core health related quality of life (QoL) subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The LymS addresses issues including pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. Score range for the LymS was 0 - 60, where a higher score indicates less symptoms. The LymS score is reported. A positive change from baseline indicates an improvement in health related QoL.	Baseline, Day 1 of Cycles 2 to 25 (cycle duration of 3 weeks), and end of treatment (up to 599 days)