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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03075696




Registration number
NCT03075696
Ethics application status
Date submitted
7/03/2017
Date registered
9/03/2017
Date last updated
3/10/2024

Titles & IDs
Public title
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
Scientific 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
Secondary ID [1] 0 0
2016-001185-28
Secondary ID [2] 0 0
NP30179
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin's Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Glofitamab
Treatment: Drugs - Obinutuzumab
Treatment: Drugs - Tocilizumab

Experimental: Part I: Dose Escalation - Participants (single participant cohorts) will receive obinutuzumab (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 (pre-treatment) followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.

Experimental: Part II: Dose Escalation - In each treatment regimen, participants will receive obinituzumab (Gpt) 1000 milligrams (mg) IV infusion on Day -7 (pre-treatment); or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered.

Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of every 2 or 3 week cycle until either the MTD/OBD is defined.

Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of every 3 week cycle until either the MTD/OBD is defined.

Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on C1D1, followed by a higher dose on C1D8; the total dose in C1 will not exceed the previously determined MTD. Higher doses may be explored from C2 or later cycles.

Experimental: Part III: Dose Expansion - Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7 (pre-treatment), followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered.

Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.


Treatment: Drugs: Glofitamab
Glofitamab will be administered at a dose and as per the schedule specified in the respective arms.

Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
Timepoint [1] 0 0
From Baseline up to 4 weeks
Primary outcome [2] 0 0
Part I, II and III: Percentage of Participants With Adverse Events (AEs)
Timepoint [2] 0 0
From Baseline up to 90 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years)
Primary outcome [3] 0 0
Part II: MTD or OBD of Glofitamab
Timepoint [3] 0 0
From Baseline up to 4 weeks
Primary outcome [4] 0 0
Part II: Recommended Phase II Dose (RP2D) of Glofitamab
Timepoint [4] 0 0
From Baseline up to 5 years
Primary outcome [5] 0 0
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)
Timepoint [5] 0 0
From treatment start up to 5 years
Primary outcome [6] 0 0
Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab
Timepoint [6] 0 0
At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary outcome [7] 0 0
Part I, II and III: Maximum Serum Concentration (Cmax) of Glofitamab
Timepoint [7] 0 0
At pre-defined intervals from Cycle 1 Day 1 to Day 198
Primary outcome [8] 0 0
Part I, II and III: Minimum Serum Concentration (Cmin) of Glofitamab
Timepoint [8] 0 0
At pre-defined intervals from Cycle 1 Day 1 up to Day 198
Primary outcome [9] 0 0
Part I, II and III: Clearance (CL) of Glofitamab
Timepoint [9] 0 0
At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary outcome [10] 0 0
Part I, II and III: Volume of Distribution at Steady-State (Vss) of Glofitamab
Timepoint [10] 0 0
At pre-defined intervals from Cycle 1 Day 1 to Day 71
Primary outcome [11] 0 0
Part I, II and III: Half-Life (t1/2) of Glofitamab
Timepoint [11] 0 0
At pre-defined intervals from Cycle 1 Day 1 to Day 71
Secondary outcome [1] 0 0
Part I, II and III: Cmax of Obinutuzumab
Timepoint [1] 0 0
Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
Secondary outcome [2] 0 0
Part I, II and III: Cmin of Obinutuzumab
Timepoint [2] 0 0
Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1
Secondary outcome [3] 0 0
Part I, II and III: Anti-Drug Antibodies (ADA) to Glofitamab
Timepoint [3] 0 0
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 outcome [4] 0 0
Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification
Timepoint [4] 0 0
From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
Secondary outcome [5] 0 0
Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate) as Determined by the Lugano Classifications
Timepoint [5] 0 0
From Baseline up to end of study or discontinuation due to disease progression (up to 5 years)
Secondary outcome [6] 0 0
Part I, II and III: Duration of Response (DOR) as Determined by the Lugano Classification
Timepoint [6] 0 0
From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 5 years)
Secondary outcome [7] 0 0
Part I, II and III: Duration of Complete Response (DOCR) as Determined by the Lugano Classification
Timepoint [7] 0 0
From the first occurrence of a documented, complete response, until the time of relapse or death from any cause (up to 5 years)
Secondary outcome [8] 0 0
Part I, II and III: Progression-Free Survival (PFS) as Determined by the Lugano Classification
Timepoint [8] 0 0
From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years)
Secondary outcome [9] 0 0
Overall Survival (OS)
Timepoint [9] 0 0
From the time of first study treatment to death from any cause (up to 5 years)
Secondary outcome [10] 0 0
Time to First Overall Response (TFOR)
Timepoint [10] 0 0
From time of treatment start to first documented response (up to 5 years)
Secondary outcome [11] 0 0
Time to First Complete Response (TFCR)
Timepoint [11] 0 0
From treatment start to first documented complete response (up to 5 years)
Secondary outcome [12] 0 0
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)
Timepoint [12] 0 0
From baseline through follow-up or until disease progression (up to 5 years)
Secondary outcome [13] 0 0
HRQoL as Assessed by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale
Timepoint [13] 0 0
From baseline through follow-up or until disease progression (up to 5 years)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/02/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
28/08/2025
Actual
Sample size
Target
860
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Prince of Wales Hospital; Haematology - Randwick
Recruitment hospital [2] 0 0
Peter Maccallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Kansas
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Utah
Country [9] 0 0
United States of America
State/province [9] 0 0
Virginia
Country [10] 0 0
United States of America
State/province [10] 0 0
Washington
Country [11] 0 0
Belgium
State/province [11] 0 0
Bruxelles
Country [12] 0 0
Belgium
State/province [12] 0 0
Gent
Country [13] 0 0
Canada
State/province [13] 0 0
Ontario
Country [14] 0 0
Czechia
State/province [14] 0 0
Praha 2
Country [15] 0 0
Denmark
State/province [15] 0 0
København Ø
Country [16] 0 0
Finland
State/province [16] 0 0
Helsinki
Country [17] 0 0
France
State/province [17] 0 0
Creteil
Country [18] 0 0
France
State/province [18] 0 0
Lille
Country [19] 0 0
France
State/province [19] 0 0
Montpellier
Country [20] 0 0
France
State/province [20] 0 0
Pierre Benite
Country [21] 0 0
France
State/province [21] 0 0
Rennes
Country [22] 0 0
Italy
State/province [22] 0 0
Emilia-Romagna
Country [23] 0 0
Italy
State/province [23] 0 0
Lombardia
Country [24] 0 0
Italy
State/province [24] 0 0
Piemonte
Country [25] 0 0
New Zealand
State/province [25] 0 0
Auckland
Country [26] 0 0
Poland
State/province [26] 0 0
Gda?sk
Country [27] 0 0
Poland
State/province [27] 0 0
Pozna?
Country [28] 0 0
Poland
State/province [28] 0 0
Warszawa
Country [29] 0 0
Poland
State/province [29] 0 0
Wroc?aw
Country [30] 0 0
Spain
State/province [30] 0 0
Barcelona
Country [31] 0 0
Spain
State/province [31] 0 0
Cantabria
Country [32] 0 0
Spain
State/province [32] 0 0
Madrid
Country [33] 0 0
Taiwan
State/province [33] 0 0
Taichung
Country [34] 0 0
Taiwan
State/province [34] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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-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.
Trial website
https://clinicaltrials.gov/study/NCT03075696
Trial related presentations / publications
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: NP30179 https://forpatients.roche.com/
Address 0 0
Country 0 0
Phone 0 0
888-662-6728 (U.S. and Canada)
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03075696