A Dose Escalation Study of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab, Administered After a Fixed, Single Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma Clinical Trial

Official title:

A Multicenter, Open-Label, Phase I/II Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of Escalating Doses of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab Administered After a Fixed, Single Dose Pre-Treatment of Obinutuzumab (Gazyva®/Gazyvaro™) in Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03075696
• Other study ID #: NP30179
• Secondary ID: 2016-001185-28
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 21, 2017
• Est. completion date: August 28, 2025

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: NP30179 https://forpatients.roche.com
• Phone: 888-662-6728 (U.S. and Canada)
• Email: global-roche-genentech-trials[@]gene.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase I/II, multicenter, open-label, dose-escalation study designed to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of a novel T-Cell bispecific (TCB), glofitamab, administered by intravenous (IV) infusion as a single agent and in combination with obinutuzumab, following pre-treatment with a one-time, fixed dose of obinutuzumab. This entry-to-human study is divided in 3 parts: dose escalation (Parts I and II) and dose expansion (Part III). Single-participant dose-escalation cohorts will be used in Part I, followed by conversion to multiple participant dose-escalation cohorts (Part II), in order to define a tentative maximum tolerated dose (MTD) or optimal biological dose (OBD). The expansion cohorts (Part III) will be initiated when the tentative MTD/OBD is defined, to further evaluate the safety, PK and therapeutic activity of glofitamab.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 860
• Est. completion date: August 28, 2025
• Est. primary completion date: August 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Depending upon study part, a history or status of: 1) a histologically-confirmed hematological malignancy that is expected to express cluster of differentiation (CD)20; 2) relapse after or failure to respond to at least one prior treatment regimen; and 3) no available treatment options that are expected to prolong survival (e.g., standard chemotherapy or autologous stem cell transplant [ASCT])

• Measurable disease, defined as at lease one bi-dimensionally measurable nodal lesion, defined as > 1.5 cm in its longest dimension, or at least one bi-dimensionally measureable extranodal lesion, defined as > 1.0 cm in its longest dimension

• Able to provide a fresh biopsy from a safely accessible site, per investigator determination, providing the patient has more than one measurable target lesion

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Life expectancy of >/=12 weeks

• AEs from prior anti-cancer therapy must have resolved to Grade less than or equal to (</=) 1

• Adequate liver, hematological and renal function

• Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic Hepatitis B virus (HBV) infection

• Negative test results for Hepatitis C virus (HCV) and human immunodeficiency virus (HIV)

• Negative serum pregnancy test within 7 days prior to study treatment in women of childbearing potential. Women who are not of childbearing potential who are considered to be post-menopausal (at least 12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test

Exclusion Criteria:

• Inability to comply with protocol mandated hospitalizations and restrictions

• Participants with chronic lymphocytic leukemia (CLL), Burkitt lymphoma and lymphoplasmacytic lymphoma

• Participants with a known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

• Participants with acute bacterial, viral, or fungal infection at baseline, confirmed by a positive blood culture within 72 hours prior to obinutuzumab infusion or by clinical judgment in the absence of a positive blood culture

• Participants with known active infection, or reactivation of a latent infection, whether bacterial, viral, fungal, mycobacterial, or other pathogens or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of dosing

• Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [anti-CTLA4], anti-programmed death 1 [anti-PD1] and anti-programmed death ligand 1 [anti-PDL1]) within 4 weeks or five half-lives of the drug, whichever is shorter, before obinutuzumab infusion on Cycle 1 Day -7

• History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents

• Documented refractoriness to an obinutuzumab-containing regimen

• Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational anti-cancer agent, including chimeric antigen receptor therapy (CAR-T) within 4 weeks prior to obinutuzumab infusion

• Prior solid organ transplantation

• Prior allogeneic SCT

• Autologous SCT within 100 days prior to obinutuzumab infusion

• Participant with history of confirmed progressive multifocal leukoencephalopathy (PML)

• Current or past history of central nervous system (CNS) lymphoma

• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participants with a past history of stroke that have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits are allowed.

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders and known autoimmune diseases

• Participants with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood for recurrence)

• Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV or Objective Class C or D cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina

• Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion or anticipation that such a live attenuated vaccine will be required during the study

• Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within two weeks prior to obinutuzumab infusion. Treatment with corticosteroid </= 25 mg/day prednisone or equivalent is allowed. Inhaled and topical steroids are permitted.

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug

• History of autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus, erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Participants with a remote history of, or well controlled autoimmune disease, may be eligible to enroll after consultation with the Medical Monitor

• In Part III DLBCL dexamethasone cohort, patients with a history of hypersensitivity to dexamethasone or systemic corticosteroids will be excluded

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Non-Hodgkin's Lymphoma

Intervention

Drug:
• Glofitamab
Glofitamab will be administered at a dose and as per the schedule specified in the respective arms.
• Obinutuzumab
Obinutuzumab 1000 mg single dose IV infusion on Day -7; or 2000 mg single dose administered on Day -7, or split into two 1000 mg doses administered on Days -1 and -7, and per the schedule specified in the respective arms.
• Tocilizumab
Tocilizumab will be administered as an IV infusion, if required, for the management of severe Cytokine Release Syndrome (CRS) occurring during or after any infusion of glofitamab, as per the methods described in the Summary of Product Characteristics (SmPC) or other similar local prescribing documents.

Locations

Country	Name	City	State
Australia	Peter Maccallum Cancer Centre	Melbourne	Victoria
Australia	Prince of Wales Hospital; Haematology	Randwick	New South Wales
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Gent	Gent
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Czechia	Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK	Praha 2
Denmark	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø
Finland	Helsinki University Central Hospital; Dept of Oncology	Helsinki
France	Hopital Henri Mondor; Hematologie Clinique	Creteil
France	Hopital Claude Huriez; Hematologie	Lille
France	CHU Saint Eloi; Service d'Hématologie Clinique	Montpellier
France	Ch Lyon Sud; Hemato Secteur Jules Courmont	Pierre Benite
France	CHU DE RENNES - CHU Pontchaillou; Service d'Hématologie Clinique Adulte	Rennes
Italy	Fond. IRCCS Istituto Nazionale Tumori; S. C. Ematologia	Milano	Lombardia
Italy	AUSL della Romagna; Dipartimento Oncoematologico - U.O.C. Oncologia	Ravenna	Emilia-Romagna
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Italy	A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia	Torino	Piemonte
New Zealand	Auckland Cancer Trial Centre; Ward 64, Auckland City Hospital,	Auckland
Poland	Uniwersyteckie Centrum Kliniczne; Osrodek Badan Wczesnych Faz	Gda?sk
Poland	Uniwersytecki Szpital Kliniczny w Poznaniu; Oddzial Hematologii i Transplantacji Szpiku	Pozna?
Poland	Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie; Oddzial Badan Wczesnych Faz	Warszawa
Poland	Uniwersytecki Szpital Kliniczny; Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku	Wroc?aw
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia	Badalona	Barcelona
Spain	Hospital del Mar; Servicio de Hematologia	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
Spain	Hospital Duran i Reynals L'Hospitalet; Hematology Department	L'Hospitalet de Llobregat	Barcelona
Spain	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Marques de Valdecilla; Servicio de Hematologia	Santander	Cantabria
Taiwan	China Medical University Hospital; Oncology and Hematology	Taichung
Taiwan	National Taiwan Universtiy Hospital; Division of Hematology	Taipei
United States	University of Michigan	Ann Arbor	Michigan
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	University of Kansas Medical Centre	Kansas City	Kansas
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Mount Sinai Medical Center	New York	New York
United States	MSKCC	New York	New York
United States	Allegheny Health Network (Pittsburg PA)	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Washington University; Wash Uni. Sch. Of Med	Saint Louis	Missouri
United States	Hunstman Cancer Institute	Salt Lake City	Utah
United States	Swedish Cancer Inst.	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  Denmark,  Finland,  France,  Italy,  New Zealand,  Poland,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)		From Baseline up to 4 weeks
Primary	Part I, II and III: Percentage of Participants With Adverse Events (AEs)		From Baseline up to 90 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years)
Primary	Part II: MTD or OBD of Glofitamab		From Baseline up to 4 weeks
Primary	Part II: Recommended Phase II Dose (RP2D) of Glofitamab		From Baseline up to 5 years
Primary	Part III: Complete Response (CR) Rate as Assessed by Independent Review Committee (IRC) According to Standard Non-Hodgkin's Lymphoma (NHL) Response Criteria (Lugano Classification)		From treatment start up to 5 years
Primary	Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary	Part I, II and III: Maximum Serum Concentration (Cmax) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 to Day 198
Primary	Part I, II and III: Minimum Serum Concentration (Cmin) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 up to Day 198
Primary	Part I, II and III: Clearance (CL) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary	Part I, II and III: Volume of Distribution at Steady-State (Vss) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary	Part I, II and III: Half-Life (t1/2) of Glofitamab		At pre-defined intervals from Cycle 1 Day 1 to Day 71
Secondary	Part I, II and III: Cmax of Obinutuzumab		Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
Secondary	Part I, II and III: Cmin of Obinutuzumab		Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
Secondary	Part I, II and III: Anti-Drug Antibodies (ADA) to Glofitamab		Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of each cycle from Cycle 2 onwards for a maximum of 8-12 cycles, and at EOT/follow-up visit (up to 5 years)
Secondary	Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification		From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
Secondary	Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate) as Determined by the Lugano Classifications		From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
Secondary	Part I, II and III: Duration of Response (DOR) as Determined by the Lugano Classification		From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 5 years)
Secondary	Part I, II and III: Duration of Complete Response (DOCR) as Determined by the Lugano Classification		From the first occurrence of a documented, complete response, until the time of relapse or death from any cause (up to 5 years)
Secondary	Part I, II and III: Progression-Free Survival (PFS) as Determined by the Lugano Classification		From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years)
Secondary	Overall Survival (OS)		From the time of first study treatment to death from any cause (up to 5 years)
Secondary	Time to First Overall Response (TFOR)		From time of treatment start to first documented response (up to 5 years)
Secondary	Time to First Complete Response (TFCR)		From treatment start to first documented complete response (up to 5 years)
Secondary	Health Related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)		From baseline through follow-up or until disease progression (up to 5 years)
Secondary	HRQoL as Assessed by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale		From baseline through follow-up or until disease progression (up to 5 years)