B-Cell Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Relapsed B-Cell Non-Hodgkin Lymphoma
Conditions
Keywords
B-Cell Non-Hodgkin Lymphoma, Relapsed B-Cell Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Loncastuximab Tesirine
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). 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.
Interventions
DRUGLoncastuximab Tesirine
Intravenous (IV) infusion
DRUGPolatuzumab Vedotin
IV infusion
DRUGGlofitamab
IV infusion
DRUGMosunetuzumab
Subcutaneous (SC) injection
DRUGObinutuzumab
IV infusion
Sponsors
ADC Therapeutics S.A.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * LBCL: 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 * Arm F and Part 1 Arm E: * All LBCL histologies listed above * FL (Grade 1-3a) * MZL * For Arm C only: * All histologies listed above * DLBCL (including transformed diseases) * MCL * BL * Life expectancy of at least 24 weeks according to Investigator's judgement * Need of systemic treatment for any of the listed indications as assessed by the investigator, including indolent B-NHLs (e.g. FL and MZL) * Measurable disease as defined by the 2014 Lugano Classification * Availability of formalin-fixed paraffin-embedded tumor tissue block * ECOG performance status 0 to 2 * Adequate organ function * Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent until at least 10 months after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of giving informed consent the first dose until at least 7 months after the last dose of loncastuximab tesirine. Men must refrain from donating sperm during this same period. Arm E: WOCBP must agree to use contraceptive methods that result in a failure of less than 1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for at least 18 months after pretreatment with obinutuzumab. Arm F: WOCBP must agree to use contraceptive methods that result in a failure of less than 1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for at least 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable) * Patients 80 years of age and older at the time of signing the informed consent must be deemed fit by Cumulative Illness Rating Scale - Geriatric (CIRS-G scale), defined as no score of 3-4 in any category AND \< 5 categories with a score of 2 excluding hematologic criteria
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 * History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)/immune effector cell associated HLH-like syndrome (IEC-HS) * Existing pericardial effusion (any grade) or 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 drugs (C1 D1), unless approved by the Sponsor * Live vaccine within 4 weeks prior to C1D1 * Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0) from acute non-hematologic toxicity (excluding alopecia) due to previous therapy prior to screening * 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 Extra
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) | 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) | 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 | Up to approximately 1 year | — |
| Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption | Up to approximately 1 year | — |
| Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction | Up to approximately 1 year | — |
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements | Baseline up to approximately 1 year | — |
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs | 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 | 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 | Baseline up to approximately 1 year | — |
Secondary
| Measure | Time frame |
|---|---|
| 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) |
| 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) |
| 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) |
Countries
Belgium, Czechia, Italy, Spain, United Kingdom, United States
Outcome results
None listed