Active, not recruiting
Phase 1
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)
Condition(s) studied
B-Cell Non-Hodgkin LymphomaRelapsed B-Cell Non-Hodgkin LymphomaRefractory B-Cell Non-Hodgkin Lymphoma
Investigational drug(s) / intervention(s)
Loncastuximab TesirinePolatuzumab VedotinGlofitamabMosunetuzumabObinutuzumab
Loncastuximab Tesirine: Intravenous (IV) infusion
Polatuzumab Vedotin: IV infusion
Glofitamab: IV infusion
Mosunetuzumab: Subcutaneous (SC) injection
Obinutuzumab: IV infusion
Study 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.
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 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 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 central nervous system (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 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
* Arm E only: Known history of hypersensitivity to obinutuzumab
Primary outcome measure(s)
- 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
Trial sites (40)
| Facility | City | Region | Status |
| University of California San Francisco - Fresno Center for Medical Education and Research |
Clovis |
California |
|
| Scripps Health - Prebys Cancer Center |
San Diego |
California |
|
| Sylvester Comprehensive Cancer Center |
Miami |
Florida |
|
| Miami Cancer Institute |
Miami |
Florida |
|
| Memorial Cancer Institute - Memorial Hospital West |
Pembroke Pines |
Florida |
|
| Winship Cancer Institute of Emory University |
Atlanta |
Georgia |
|
| The Blood and Marrow Transplant Group of Georgia |
Atlanta |
Georgia |
|
| Mission Cancer + Blood - Mission Cancer Foundation |
Des Moines |
Iowa |
|
| Beth Israel Deaconess Medical Center |
Boston |
Massachusetts |
|
| Dana-Farber Cancer Institute |
Boston |
Massachusetts |
|
| University of Minnesota |
Minneapolis |
Minnesota |
|
| Columbia University Irving Medical Center |
New York |
New York |
|
| Cleveland Clinic Main Campus |
Cleveland |
Ohio |
|
| Oregon Health and Science University |
Portland |
Oregon |
|
| Penn Medicine - Perelman Center for Advanced Medicine |
Philadelphia |
Pennsylvania |
|
| Allegheny Health Network - West Penn Hospital |
Pittsburgh |
Pennsylvania |
|
| Brown University Health - Rhode Island Hospital |
Providence |
Rhode Island |
|
| Hollings Cancer Center |
Charleston |
South Carolina |
|
| Greco-Hainsworth Tennessee Oncology Centers for Research (GHCR) |
Nashville |
Tennessee |
|
| Baylor University Medical Center |
Dallas |
Texas |
|
| Huntsman Cancer Institute |
Salt Lake City |
Utah |
|
| Emily Couric Clinical Cancer Center |
Charlottesville |
Virginia |
|
| NEXT Virginia (Virginia Cancer Specialists) |
Fairfax |
Virginia |
|
| Froedtert & Medical College of Wisconsin |
Milwaukee |
Wisconsin |
|
| Universitair Ziekenhuis Gent |
Ghent |
Belgium |
|
| Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne |
Yvoir |
Belgium |
|
| Fakultni nemocnice Ostrava |
Ostrava |
Czechia |
|
| Fakultní Nemocnice Královské Vinohrady |
Prague |
Czechia |
|
| Fakultni nemocnice v Motole |
Prague |
Czechia |
|
| 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 |
Milan |
Italy |
|
| 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 |
Spain |
|
| University College London Hospitals NHS Foundation Trust |
London |
United Kingdom |
|
| Oxford University Hospitals NHS Foundation Trust |
Oxford |
United Kingdom |
|
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