A Phase 1b Open-Label Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS-7)
Summary
The primary objective of this study is to characterize the safety and tolerability of loncastuximab tesirine in combination with polatuzumab vedotin, glofitamab, or mosunetuzumab, and to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) for the combinations.
Detailed description
This is a Phase 1b, multi-center, open-label, multi-arm study to evaluate the safety and anti-cancer activity of loncastuximab tesirine in combination with polatuzumab vedotin, glofitamab, or mosunetuzumab in participants with relapsed or refractory B-cell Non-Hodgkin Lymphoma (R/R B-NHL). The study will enroll approximately 200 participants. Loncastuximab tesirine (ADCT-402; Zynlonta) is an antibody drug conjugate (ADC), composed of a humanized monoclonal antibody directed against human cluster of differentiation 19 (CD19) conjugated through a cathepsin-cleavable linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Loncastuximab tesirine has been granted by Food and Drug Administration (FDA) as accelerated approval for adult participants with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma (HGBCL). In the European Union (EU), the European Commission (EC) granted conditional approval for the treatment of adult patients with relapsed or refractory DLBCL and HGBCL, after two or more lines of systemic therapy. The study includes multiple arms in two parts, Dose Escalation part (Part 1) and Dose Expansion part (Part 2). In Part 1, for the arm of loncastuximab tesirine in combination with polatuzumab vedotin includes DLBCL, HGBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Burkitt lymphoma (BL); for the arms of loncastuximab tesirine in combination with glofitamab or mosunetuzumab include DLBCL, HGBCL, FL, and MZL. In Part 2, participants will be treated at the dose level(s) determined from Part 1. The Sponsor will conduct the safety monitoring and the overall supervision of the study in consultation with the Dose-Escalation Steering Committee (DESC)/Data Safety Monitoring Committee (DSMC). For each participant, the study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 21 days), and a Follow-up Period (approximately every 12 week visits for up to two years for Arm C and three years for Arms E and F). Participants may continue treatment for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. Treatment with gemcitabine (Arm A), lenalidomide (Arm B), and umbralisib (Arm D) were removed.
Arms & interventions
- DrugLoncastuximab Tesirine
Intravenous (IV) infusion
- DrugPolatuzumab Vedotin
IV infusion
- DrugGlofitamab
IV infusion
- DrugMosunetuzumab
Subcutaneous (SC) injection
- DrugObinutuzumab
IV infusion
Outcome measures
Primary
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
Time frame: Day 1 to Day 21 of Cycle 1, where a cycle is 21 days
Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
Frequency and severity of TEAEs and treatment-emergent serious adverse events (TESAEs). TEAEs and TESAEs will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay
Time frame: Up to approximately 1 year
Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption
Time frame: Up to approximately 1 year
Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction
Time frame: Up to approximately 1 year
Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements
Time frame: Baseline up to approximately 1 year
Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs
Time frame: Baseline up to approximately 1 year
Number of Participants Who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status will be measured on a scale from grades 0-5, where a higher grade indicates a worse outcome.
Time frame: Baseline up to approximately 1 year
Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Measurements
Time frame: Baseline up to approximately 1 year
Secondary
Complete Response Rate (CRR)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Overall Response Rate (ORR)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Duration of Response (DOR)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Progression-Free Survival (PFS)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Relapse-Free Survival (RFS)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Overall Survival (OS)
Time frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
Average Concentration of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Maximum Concentration (Cmax) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Area Under the Concentration-Time Curve from Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Area Under the Concentration-Time Curve from Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Apparent Clearance (CL) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Accumulation Index (AI) of Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Arm E Only: Number of Participants With ADA Titers to Glofitamab
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Arm F Only: Number of Participants With ADA Titers to Mosunetuzumab
Time frame: Day 1 to end of treatment (up to approximately 1 year)
Eligibility criteria
Study locations (25)
University of California San Francisco - Fresno Center for Medical Education and Research
Clovis, California, 93611
Scripps Health - Prebys Cancer Center
San Diego, California, 92103
Sylvester Comprehensive Cancer Center
Miami, Florida, 33136
Miami Cancer Institute
Miami, Florida, 33176
Memorial Cancer Institute - Memorial Hospital West
Pembroke Pines, Florida, 33028
Winship Cancer Institute of Emory University
Atlanta, Georgia, 30322
The Blood and Marrow Transplant Group of Georgia
Atlanta, Georgia, 30342
Mission Cancer + Blood - Mission Cancer Foundation
Des Moines, Iowa, 50309
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
University of Minnesota
Minneapolis, Minnesota, 55455
Columbia University Irving Medical Center
New York, New York, 10027
Cleveland Clinic Main Campus
Cleveland, Ohio, 44195
Oregon Health and Science University
Portland, Oregon, 97239
Penn Medicine - Perelman Center for Advanced Medicine
Philadelphia, Pennsylvania, 19104
Allegheny Health Network - West Penn Hospital
Pittsburgh, Pennsylvania, 15224
Brown University Health - Rhode Island Hospital
Providence, Rhode Island, 02903
Hollings Cancer Center
Charleston, South Carolina, 29425
Avera Cancer Institute
Sioux Falls, South Dakota, 57105
Greco-Hainsworth Tennessee Oncology Centers for Research (GHCR)
Nashville, Tennessee, 37203
Baylor University Medical Center
Dallas, Texas, 75246
Huntsman Cancer Institute
Salt Lake City, Utah, 84112
Emily Couric Clinical Cancer Center
Charlottesville, Virginia, 22903
NEXT Virginia (Virginia Cancer Specialists)
Fairfax, Virginia, 22031
Froedtert & Medical College of Wisconsin
Milwaukee, Wisconsin, 53226