A Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Participants With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS-7)

Refractory B-Cell Non-Hodgkin Lymphoma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04970901
• Other study ID #: ADCT-402-105
• Secondary ID: 2021-001071-16
• Status: Recruiting
• Phase: Phase 1
• Start date: June 17, 2022
• Est. completion date: February 10, 2026

Study information

• Verified date: December 2023
• Source: ADC Therapeutics S.A.
• Contact: Contact ADC Therapeutics
• Phone: 954-903-7994
• Email: clinical.trials[@]adctherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 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). 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). 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: February 10, 2026
• Est. primary completion date: February 12, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 dose-escalation part; and at least one systemic treatment regimen in dose-expansion part
• DLBCL (including transformed diseases, but for Arms E and F, including transformed FL only)
• HGBCL
• FL
• MZL
• MCL (for Arm C only)
• BL (for Arm C only)
• 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. For the arm that includes glofitamab, WOCBP must agree to use contraceptive methods that result in a failure of <1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for at least 18 months after pretreatment with obinutuzumab. For the arm that includes mosunetuzumab, WOCBP must agree to use contraceptive methods that result in a failure of <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).

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
• Allogenic or autologous stem cell transplant within 60 days prior to start of study drug (C1 D1)
• 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)
• Lymphoma with active central nervous system (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 drugs (C1 D1), except shorter if 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 (Grade =2 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 Exclusion Criteria for Arms E (includes glofitamab) and F (includes mosunetuzumab) Note: as applicable, the arm-specific exclusion criteria may supersede the general ones, such as stem cell transplant.
• Prior allogeneic stem cell transplant and solid organ transplant
• Autologous stem cell transplant within 100 days prior to C1D1
• History of CNS lymphoma or leptomeningeal infiltration
• Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
• Known active infection, reactivation of a latent infection, whether bacterial, viral, fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within four weeks prior to C1D1
• Active or history of autoimmune disease or immune deficiency, including but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain Barré syndrome, or multiple sclerosis, with certain exceptions
• Prior treatment with anti-cancer/lymphoma targeted therapies (e.g., tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, cluster of differentiation 137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), anti-programmed cell death protein 1 (PD1), and anti-programmed death ligand 1 (PDL1) therapeutic antibodies, radio-immunoconjugates, ADCs, immune/cytokines and monoclonal antibodies) or treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to C1D1, or anticipation of need for systemic immunosuppressive medication during study treatment, with certain exceptions
• Prior treatment with chimeric antigen receptor T-cell therapy within 30 days prior to C1D1
• Toxicities from prior anti-cancer therapy including immunotherapy that did not resolve to = Grade 1 with the exception of alopecia, endocrinopathy managed with replacement therapy and stable vitiligo
• Any history of immune-related Grade =3 AE with the exception of endocrinopathy managed with replacement therapy
• Ongoing corticosteroid use >25 mg/day of prednisone or equivalent within 4 weeks prior and during study treatment
• Administration of a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last dose of study treatment Extra Exclusion Criteria for Arm E (includes glofitamab) only.
• Known history of hypersensitivity to obinutuzumab

Related Conditions & MeSH terms

• B-Cell Non-Hodgkin Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Refractory B-Cell Non-Hodgkin Lymphoma
• Relapsed B-Cell Non-Hodgkin Lymphoma

Intervention

Drug:
• Loncastuximab Tesirine
Intravenous (IV) infusion
• Polatuzumab Vedotin
IV infusion
• Glofitamab
IV infusion
• Mosunetuzumab
Subcutaneous (SC) injection
• Obinutuzumab
IV infusion

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne	Yvoir
Czechia	Fakultni Nemocnice Brno	Brno	South Moravian
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultní Nemocnice Královské Vinohrady	Prague
Czechia	Fakultni nemocnice v Motole	Prague
Italy	Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII	Bergamo
Italy	Centro di Ricerche Cliniche - IRCCS Azienda Ospedaliero Universitaria di Bologna	Bologna
Italy	Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia	Brescia
Italy	Istituto Europeo di Oncologia	Milano
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Complejo Asistencial Universitario de Salamanca - Hospital Clínico	Salamanca
Spain	Hospital Universitari i Politècnic La Fe	Valencia
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford
United States	The Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia
United States	Hollings Cancer Center	Charleston	South Carolina
United States	Emily Couric Clinical Cancer Center	Charlottesville	Virginia
United States	NEXT Virginia (Virginia Cancer Specialists)	Fairfax	Virginia
United States	Miami Cancer Institute	Miami	Florida
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Cancer Institute - Memorial Hospital West	Pembroke Pines	Florida
United States	Oregon Health and Science University	Portland	Oregon
United States	Avera Cancer Institute	Sioux Falls	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
ADC Therapeutics S.A.

Countries where clinical trial is conducted

United States,  Belgium,  Czechia,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Up to approximately 2 years
Primary	Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)		Day 1 to Day 21 of Cycle 1, where a cycle is 21 days
Primary	Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay		Up to approximately 1 year
Primary	Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption		Up to approximately 1 year
Primary	Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction		Up to approximately 1 year
Primary	Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements		Baseline up to approximately 1 year
Primary	Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs		Baseline up to approximately 1 year
Primary	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.	Baseline up to approximately 1 year
Primary	Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Measurements		Baseline up to approximately 1 year
Secondary	Complete Response Rate (CRR)		Up to approximately 2 years
Secondary	Overall Response Rate (ORR)		Up to approximately 2 years
Secondary	Duration of Response (DOR)		Up to approximately 2 years
Secondary	Progression-Free Survival (PFS)		Up to approximately 2 years
Secondary	Relapse-Free Survival (RFS)		Up to approximately 2 years
Secondary	Overall Survival (OS)		Up to approximately 2 years
Secondary	Average Concentration of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Maximum Concentration (Cmax) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Apparent Clearance (CL) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Accumulation Index (AI) of Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Arm E Only: Number of Participants With ADA Titers to Glofitamab		Day 1 to end of treatment (up to approximately 1 year)
Secondary	Arm F Only: Number of Participants With ADA Titers to Mosunetuzumab		Day 1 to end of treatment (up to approximately 1 year)