Clinical trial NCT03075696: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-Hodgkin's Lymphoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-03-09
Enrollment: 920
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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-into-human (EIH) 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.


Eligibility criteria: 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 least one bi-dimensionally measurable nodal lesion, defined as \> 1.5 cm in its longest dimension, or at least one bi-dimensionally measurable extranodal lesion, defined as \> 1.0 cm in its longest dimension
* Able to provide a tumor tissue pretreatment biopsy at last relapse or during screening 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 stem cell transplantation (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 diffuse large B-cell lymphoma (DLBCL) dexamethasone cohort, participants with a history of hypersensitivity to dexamethasone or systemic corticosteroids will be excluded

Primary outcomes:
measure: Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: From Baseline up to 4 weeks
measure: Part I, II and III: Percentage of Participants With Adverse Events (AEs)
timeFrame: From Baseline up to 90 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years)
measure: Part II: MTD or OBD of Glofitamab
timeFrame: From Baseline up to 4 weeks
measure: Part II: Recommended Phase II Dose (RP2D) of Glofitamab
timeFrame: From Baseline up to 5 years
measure: 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)
timeFrame: From treatment start up to 5 years
measure: Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 to Day 71
measure: Part I, II and III: Maximum Serum Concentration (Cmax) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 to Day 198
measure: Part I, II and III: Minimum Serum Concentration (Cmin) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 up to Day 198
measure: Part I, II and III: Clearance (CL) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 to Day 71
measure: Part I, II and III: Volume of Distribution at Steady-state (Vss) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 to Day 71
measure: Part I, II and III: Half-life (t1/2) of Glofitamab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 to Day 71
Secondary outcomes:
measure: Part I, II and III: Cmax of Obinutuzumab
timeFrame: Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
measure: Part I, II and III: Cmin of Obinutuzumab
timeFrame: Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
measure: Part I, II and III: Anti-drug Antibodies (ADA) to Glofitamab
timeFrame: 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)
measure: Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification
timeFrame: From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
measure: Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate [ORR]) as Determined by the Lugano Classifications
timeFrame: From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
measure: Part I, II and III: Duration of Response (DOR) as Determined by the Lugano Classification
timeFrame: From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 5 years)
measure: Part I, II and III: Duration of Complete Response (DOCR) as Determined by the Lugano Classification
timeFrame: From the first occurrence of a documented, complete response, until the time of relapse or death from any cause (up to 5 years)
measure: Part I, II and III: Progression-Free Survival (PFS) as Determined by the Lugano Classification
timeFrame: From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years)
measure: Overall Survival (OS)
timeFrame: From the time of first study treatment to death from any cause (up to 5 years)
measure: Time to First Overall Response (TFOR)
timeFrame: From time of treatment start to first documented response (up to 5 years)
measure: Time to First Complete Response (TFCR)
timeFrame: From treatment start to first documented complete response (up to 5 years)
measure: Part III: 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)
timeFrame: From baseline through follow-up or until disease progression (up to 5 years)
measure: Part III: HRQoL as Assessed by the Functional Assessment of Cancer Therapy-lymphoma (FACT-lym) Scale
timeFrame: From baseline through follow-up or until disease progression (up to 5 years)
Other outcomes:
Locations:
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: MSKCC
state: New York
city: Pittsburgh
country: United States
facility: Allegheny Health Network (Pittsburg PA)
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Hunstman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Swedish Cancer Inst.
state: Washington
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Praha 2
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Lille
country: France
facility: Hopital Claude Huriez
city: Montpellier
country: France
facility: CHU Saint Eloi
city: Pierre Benite
country: France
facility: Ch Lyon Sud
city: Rennes
country: France
facility: CHU DE RENNES - CHU Pontchaillou
city: Ravenna
country: Italy
facility: AUSL della Romagna
state: Emilia-Romagna
city: Milano
country: Italy
facility: Fond. IRCCS Istituto Nazionale Tumori
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Lombardia
city: Torino
country: Italy
facility: A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette
state: Piemonte
city: Auckland
country: New Zealand
facility: Auckland Cancer Trial Centre
city: Gda?sk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Pozna?
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
city: Wroc?aw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals L'Hospitalet
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan Universtiy Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Frances N, Bacac M, Bray-French K, Christen F, Hinton H, Husar E, Quackenbush E, Schafer M, Schick E, Vyver AV, Richter WF. Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab. J Pharm Sci. 2022 Apr;111(4):1208-1218. doi: 10.1016/j.xphs.2021.12.019. Epub 2021 Dec 22.
citation: Broske AE, Korfi K, Belousov A, Wilson S, Ooi CH, Bolen CR, Canamero M, Alcaide EG, James I, Piccione EC, Carlile DJ, Dimier N, Umana P, Bacac M, Weisser M, Dickinson M. Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. Blood Adv. 2022 Feb 8;6(3):1025-1037. doi: 10.1182/bloodadvances.2021005954.
citation: Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A, Salles G, Martinez-Lopez J, Crump M, Thomas DN, Morcos PN, Ferlini C, Broske AE, Belousov A, Bacac M, Dimier N, Carlile DJ, Lundberg L, Perez-Callejo D, Umana P, Moore T, Weisser M, Dickinson MJ. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021 Jun 20;39(18):1959-1970. doi: 10.1200/JCO.20.03175. Epub 2021 Mar 19.