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)
Overview
- Phase
- Phase 1
- Intervention
- Polatuzumab Vedotin
- Conditions
- B-Cell Non-Hodgkin Lymphoma
- Sponsor
- ADC Therapeutics S.A.
- Enrollment
- 200
- Locations
- 83
- Primary Endpoint
- Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female participant aged 18 years or older
- •Pathologic diagnosis of relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) B-NHL (2016 World Health Organization classification) who have failed, or been intolerant to any approved therapy and had received at least two systemic treatment regimens in Part 1; and at least one systemic treatment regimen in Part 2
- •Part 2 Arm E enrollment focused on LBCL only
- •DLBCL, not otherwise specified (NOS)
- •Germinal Center B-cell type
- •Activated B-cell type
- •Transformed FL (note: patients with transformed FL must have received at least one line of systemic therapy post-transformation to be eligible)
- •HGBCL, with MYC and BCL2 and/or BCL6 rearrangements
- •HGBCL, NOS
- •FL Grade 3b
Exclusion Criteria
- •Known history of hypersensitivity resulting in treatment discontinuation to or positive serum human ADA to a CD19 antibody
- •Previous therapy with loncastuximab tesirine
- •Previous treatment with polatuzumab vedotin, glofitamab or mosunetuzumab (applied to relevant arm and/or cohort of the specific drug administered)
- •Participants who received previous treatment of polatuzumab vedotin containing regimen will be excluded from Arm C
- •Participants who received previous treatment of glofitamab containing regimen will be excluded from Arm E
- •Participants who received previous treatment of mosunetuzumab containing regimen will be excluded from Arm F
- •Human immunodeficiency virus (HIV) seropositive
- •Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
- •Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
- •History of confirmed progressive multifocal leukoencephalopathy
Arms & Interventions
Part 2 (Dose Expansion): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants with B-NHL will receive loncastuximab tesirine in combination with polatuzumab vedotin at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received.
Intervention: Polatuzumab Vedotin
Part 1 (Dose Escalation): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive polatuzumab vedotin at a dose of 1.8 mg/kg on D1 of each cycle, infusion will be started one hour after end of loncastuximab tesirine infusion.
Intervention: Loncastuximab Tesirine
Part 1 (Dose Escalation): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive polatuzumab vedotin at a dose of 1.8 mg/kg on D1 of each cycle, infusion will be started one hour after end of loncastuximab tesirine infusion.
Intervention: Polatuzumab Vedotin
Part 1 (Dose Escalation): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on D2 of Cycle (C) 1 and then D1 of all other cycles (where each cycle is 21 days). Participants will also receive glofitamab 2.5 mg on C1 D8, 10 mg on C1 D15 and 30 mg for cycles 2-12 D1. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Loncastuximab Tesirine
Part 1 (Dose Escalation): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on D2 of Cycle (C) 1 and then D1 of all other cycles (where each cycle is 21 days). Participants will also receive glofitamab 2.5 mg on C1 D8, 10 mg on C1 D15 and 30 mg for cycles 2-12 D1. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Glofitamab
Part 1 (Dose Escalation): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on D2 of Cycle (C) 1 and then D1 of all other cycles (where each cycle is 21 days). Participants will also receive glofitamab 2.5 mg on C1 D8, 10 mg on C1 D15 and 30 mg for cycles 2-12 D1. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Obinutuzumab
Part 1 (Dose Escalation): Loncastuximab Tesirine + Mosunetuzumab (Arm F)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive mosunetuzumab 5 mg on C1 D1, 45 mg for C1 D8, C1 D15 and cycles 2-8 D1.
Intervention: Loncastuximab Tesirine
Part 1 (Dose Escalation): Loncastuximab Tesirine + Mosunetuzumab (Arm F)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive mosunetuzumab 5 mg on C1 D1, 45 mg for C1 D8, C1 D15 and cycles 2-8 D1.
Intervention: Mosunetuzumab
Part 2 (Dose Expansion): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants with B-NHL will receive loncastuximab tesirine in combination with polatuzumab vedotin at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received.
Intervention: Loncastuximab Tesirine
Part 2 (Dose Expansion): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants with B-NHL will receive loncastuximab tesirine in combination with glofitamab at the MTD and/or RDE if favorable results of Part 1 are received. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Loncastuximab Tesirine
Part 2 (Dose Expansion): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants with B-NHL will receive loncastuximab tesirine in combination with glofitamab at the MTD and/or RDE if favorable results of Part 1 are received. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Glofitamab
Part 2 (Dose Expansion): Loncastuximab Tesirine + Glofitamab (Arm E)
Participants with B-NHL will receive loncastuximab tesirine in combination with glofitamab at the MTD and/or RDE if favorable results of Part 1 are received. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.
Intervention: Obinutuzumab
Part 2 (Dose Expansion): Loncastuximab Tesirine + Mosunetuzumab (Arm F)
Participants with B-NHL will receive loncastuximab tesirine in combination with mosunetuzumab at the MTD and/or RDE if favorable results of Part 1 are received.
Intervention: Loncastuximab Tesirine
Part 2 (Dose Expansion): Loncastuximab Tesirine + Mosunetuzumab (Arm F)
Participants with B-NHL will receive loncastuximab tesirine in combination with mosunetuzumab at the MTD and/or RDE if favorable results of Part 1 are received.
Intervention: Mosunetuzumab
Outcomes
Primary Outcomes
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)
Time Frame: Up to approximately 2 years for Arm C and 3 years for Arms E and F
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.
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
Time Frame: Baseline up to approximately 1 year
ECOG performance status will be measured on a scale from grades 0-5, where a higher grade indicates a worse outcome.
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 Outcomes
- Complete Response Rate (CRR)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Overall Response Rate (ORR)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Duration of Response (DOR)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Progression-Free Survival (PFS)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Relapse-Free Survival (RFS)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Overall Survival (OS)(Up to approximately 2 years for Arm C and 3 years for Arms E and F)
- Average Concentration of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Maximum Concentration (Cmax) of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine(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(Day 1 to end of treatment (up to approximately 1 year))
- Arm E Only: Number of Participants With ADA Titers to Glofitamab(Day 1 to end of treatment (up to approximately 1 year))
- Arm F Only: Number of Participants With ADA Titers to Mosunetuzumab(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(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(Day 1 to end of treatment (up to approximately 1 year))
- Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Apparent Clearance (CL) of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Accumulation Index (AI) of Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))
- Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine(Day 1 to end of treatment (up to approximately 1 year))