Clinical trial NCT04970901: 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)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: B-Cell Non-Hodgkin Lymphoma
Relapsed B-Cell Non-Hodgkin Lymphoma
Refractory B-Cell Non-Hodgkin Lymphoma
Keywords: B-Cell Non-Hodgkin Lymphoma
Relapsed B-Cell Non-Hodgkin Lymphoma
Refractory B-Cell Non-Hodgkin Lymphoma
Loncastuximab Tesirine
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2021-07-21
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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 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.

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 dose-escalation part; and at least one systemic treatment regimen in dose-expansion part

  * Aggressive B Cell Lymphomas:

    * DLBCL (including transformed diseases, but for Arms E and F, including transformed FL only)
    * HGBCL
    * FL Grade 3b
  * Indolent NHL:

    * FL (Grade 1-3a)
    * MZL
  * For Arm C only:

    * 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. For the arm that includes glofitamab, 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. For the arm that includes mosunetuzumab, 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).

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, motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune diseases, 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, 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 CAR-T-cell therapy within 100 days prior to C1D1; primary refractory patients (progressive or persistent disease within 30 days) to CAR-T-cell therapy are not eligible.
* 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 greater than 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

Primary outcomes:
measure: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
timeFrame: Day 1 to Day 21 of Cycle 1, where a cycle is 21 days
measure: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
timeFrame: Up to approximately 2 years
measure: Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay
timeFrame: Up to approximately 1 year
measure: Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption
timeFrame: Up to approximately 1 year
measure: Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction
timeFrame: Up to approximately 1 year
measure: Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements
timeFrame: Baseline up to approximately 1 year
measure: Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs
timeFrame: Baseline up to approximately 1 year
measure: Number of Participants Who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: Baseline up to approximately 1 year
measure: Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Measurements
timeFrame: Baseline up to approximately 1 year
Secondary outcomes:
measure: Complete Response Rate (CRR)
timeFrame: Up to approximately 2 years
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 2 years
measure: Duration of Response (DOR)
timeFrame: Up to approximately 2 years
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 2 years
measure: Relapse-Free Survival (RFS)
timeFrame: Up to approximately 2 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 2 years
measure: Average Concentration of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Maximum Concentration (Cmax) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Area Under the Concentration-Time Curve from Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Area Under the Concentration-Time Curve from Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Apparent Clearance (CL) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Accumulation Index (AI) of Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Arm E Only: Number of Participants With ADA Titers to Glofitamab
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
measure: Arm F Only: Number of Participants With ADA Titers to Mosunetuzumab
timeFrame: Day 1 to end of treatment (up to approximately 1 year)
Other outcomes:
Locations:
city: Clovis
country: United States
facility: University of California San Francisco - Fresno Center for Medical Education and Research
state: California
city: San Diego
country: United States
facility: Scripps Health - Prebys Cancer Center
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Cancer Institute - Memorial Hospital West
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Atlanta
country: United States
facility: The Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Des Moines
country: United States
facility: Mission Cancer + Blood - Mission Cancer Foundation
state: Iowa
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Main Campus
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Penn Medicine - Perelman Center for Advanced Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Health Network - West Penn Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Brown University Health - Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Greco-Hainsworth Tennessee Oncology Centers for Research (GHCR)
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: Emily Couric Clinical Cancer Center
state: Virginia
city: Fairfax
country: United States
facility: NEXT Virginia (Virginia Cancer Specialists)
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert & Medical College of Wisconsin
state: Wisconsin
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Yvoir
country: Belgium
facility: Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno
state: South Moravian
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Prague
country: Czechia
facility: Fakultní Nemocnice Královské Vinohrady
city: Prague
country: Czechia
facility: Fakultni nemocnice v Motole
city: Bergamo
country: Italy
facility: Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Centro di Ricerche Cliniche - IRCCS Azienda Ospedaliero Universitaria di Bologna
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - Hospital Clínico
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
Study officials:
References: