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A Study of Glofitamab in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Participants With Non-Hodgkin Lymphomas and Participants With DLBCL

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ClinicalTrials.gov Identifier: NCT03467373
Recruitment Status : Recruiting
First Posted : March 16, 2018
Last Update Posted : January 21, 2022
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE March 9, 2018
First Posted Date  ICMJE March 16, 2018
Last Update Posted Date January 21, 2022
Actual Study Start Date  ICMJE March 13, 2018
Estimated Primary Completion Date December 16, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2018)
  • Part I: Percentage of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 29 months ]
  • Part I and II: Percentage of Participants with Adverse Events [ Time Frame: Up to 29 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2020)
  • Parts I and II: Percentage of Participants with a Complete Response (CR) as Assessed by the Investigator using Modified Lugano 2014 Criteria [ Time Frame: Up to 29 months ]
  • Parts I and II: Percentage of Participants with Overall Response (Partial Response [PR] or Complete Response [CR]) [ Time Frame: Up to 29 months ]
  • Parts I and II: Duration of Response (DOR) [ Time Frame: Up to 29 months ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 29 months ]
  • Overall Survival (OS) [ Time Frame: Up to 29 months ]
  • Time to First Complete Response (TFCR) [ Time Frame: Up to 29 months ]
  • Time to First Response (TFOR) [ Time Frame: Up to 29 months ]
  • Parts I and II: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Parts I and II: Time to Maximum Serum Concentration (tmax) of Glofitamab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Parts I and II: Maximum Serum Concentration (Cmax) of Glofitamab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Parts I and II: Minimum Serum Concentration (Cmin) of Glofitamab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Change from Baseline in T-cell Activation Markers [ Time Frame: Up to 29 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 9, 2018)
  • Part II: Percentage of Participants with a Complete Response (CR) as Assessed by the Investigator using Modified Lugano 2014 Criteria [ Time Frame: Up to 29 months ]
  • Part II: Percentage of Participants with Overall Response (Partial Response [PR] or Complete Response [CR]) [ Time Frame: Up to 29 months ]
  • Part II: Percentage of Participants with PR, CR or SD (Disease Control Rate [DCR]) [ Time Frame: Up to 29 months ]
  • Part II: Duration of Response (DOR) [ Time Frame: Up to 29 months ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 29 months ]
  • Overall Survival (OS) [ Time Frame: Up to 29 months ]
  • Part II: Area Under the Serum Concentration Versus Time Curve (AUC) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Part II: Time to Maximum Serum Concentration (tmax) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Par II: Maximum Serum Concentration (Cmax) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Part II: Minimum Serum Concentration (Cmin) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Change from Baseline in T-cell Activation Markers [ Time Frame: Up to 29 months ]
  • Part II: Area Under the Serum Concentration Versus Time Curve (AUC) of Rituxiamb [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Part II: Time to Maximum Serum Concentration (tmax) of Rituximab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Par II: Maximum Serum Concentration (Cmax) of Rituximab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
  • Part II: Minimum Serum Concentration (Cmin) of Rituximab [ Time Frame: Cycle 1 Day 1 up to 29 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Glofitamab in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Participants With Non-Hodgkin Lymphomas and Participants With DLBCL
Official Title  ICMJE A Phase 1B Study Evaluating Glofitamab (RO7082859) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Participants With Relapsed or Refractory Non-Hodgkin Lymphoma (R/R NHL) or in Participants With Untreated Diffuse Large B-Cell Lymphoma (DLBCL)
Brief Summary

This is a phase 1B, multi-center, dose-finding study of glofitamab administered in combination with obinutuzumab (Gazyva; [G]), rituximab (R) and standard doses of CHOP (G/R-CHOP or R-CHOP) in participants with r/r NHL and untreated diffuse large B-cell lymphoma (DLBCL). Evaluating the safety, preliminary activity, pharmacokinetic (PK), and pharmacodynamic effects of this combination will be the main objectives of this study. The study is divided in two parts:

  • Part I: Dose finding in participants with r/r NHL; test use of G vs R in Cycle 1
  • Part II: Dose Expansion. The maximum tolerated dose or optimal biological dose (MTD or OBD) will be further assessed in participants with r/r NHL and those with untreated DLBCL (>60 years of age with an age-adjusted International Prognostic Index (IPI) of 2-3). Particularly, the impact of using glofitamab plus G/R-CHOP (i.e., add-on arm) versus glofitamab plus CHOP (i.e., replacement arm) will be assessed in untreated DLBCL participants.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • B-Cell Lymphoma
  • Non-Hodgkin Lymphoma
Intervention  ICMJE
  • Drug: Glofitamab
    Glofitamab will be administered intravenously (IV) as a step-up dose for Cycle 2 on Days 8 and 15, and as a single dose from Cycle 3 onwards.
    Other Name: RO7082859
  • Drug: Obinutuzumab (G)
    Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only
    Other Name: Gazyva
  • Drug: Rituximab (R)
    Rituximab will be administered as an IV infusion at a dose of 375 mg/m^2 on Day 1 of each 21-day cycle starting from Cycle 1 to Cycle 6 (Part 1) or from Cycles 1-6 (up to 8) (Part 2: DLBCL R-CHOP).
    Other Name: Rituxan
  • Drug: Tocilizumab
    Tocilizumab will be administered as an IV infusion as per the methods described in the Summary of Product Characteristics (SmPC) or other similar local prescribing documents. Tocilizumab will be given as rescue medication.
    Other Name: Actemra
  • Drug: Cyclophosphamide
    Cyclophosphamide 750 mg/m^2 administered IV on Day 1 of each 21-day cycle
  • Drug: Doxorubicin
    Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle
  • Drug: Vincristine
    Vincristine 1.4 mg/m^2 administered by IV push on Day 1 of each 21-day cycle with a recommended cap of 2 mg
    Other Name: Oncovin
  • Drug: Prednisone
    Prednisone 100 mg/day orally on Days 1-5 (prednisone on Day 1 may be administered IV, with the remaining doses on Days 2-5 to be administered orally) of each 21-day cycle
Study Arms  ICMJE
  • Experimental: Part 1: Dose Escalation r/r NHL

    Dose finding in participants with r/r NHL: the study will explore different doses of glofitamab in the induction period, starting at a dose of 70 mcg administered in combination with standard of care doses of G/R CHOP and R-CHOP every 3 weeks (Q3W). Participants with r/r NHL will receive 6 cycles of induction treatment (G/R-CHOP). Glofitamab will be administered using step-up dosing for Cycle 2 on Days 8 and 15, followed by single doses on Day 8 for Cycles 3-6. Participants who achieve a complete response (CR), partial response (PR), or stable disease (SD) at the end of induction (EOInd) may optionally receive post-induction treatment (referred to as maintenance) with glofitamab alone.

    The use of G versus R in Cycle 1 will be compared in parallel dose escalation cohorts.

    Interventions:
    • Drug: Glofitamab
    • Drug: Obinutuzumab (G)
    • Drug: Rituximab (R)
    • Drug: Tocilizumab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Prednisone
  • Experimental: Part 2: Dose Expansion r/r NHL
    Participants with r/r NHL will be assigned to an expansion cohort to further explore glofitamab at the MTD/OBD determined in Part I.
    Interventions:
    • Drug: Glofitamab
    • Drug: Obinutuzumab (G)
    • Drug: Rituximab (R)
    • Drug: Tocilizumab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Prednisone
  • Experimental: Part 2: DLBCL G/R-CHOP
    Participants with untreated DLBCL will receive G-CHOP or R-CHOP in Cycle 1, followed by R-CHOP + glofitamab for subsequent cycles. Glofitamab will be administered using step-up dosing for Cycle 2 on Days 8 and 15, followed by single doses on Day 8 for Cycles 3-6 (up to 8). The starting dose of glofitamab for each arm may be one or more levels below the MTD/OBD determined in Part I.
    Interventions:
    • Drug: Glofitamab
    • Drug: Obinutuzumab (G)
    • Drug: Rituximab (R)
    • Drug: Tocilizumab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Prednisone
  • Experimental: Part 2: DLBCL CHOP
    Participants with untreated DLBCL will receive G-CHOP or R-CHOP in Cycle 1, followed by CHOP + glofitamab for subsequent cycles. Glofitamab will be administered using step-up dosing for Cycle 2 on Days 8 and 15, followed by single doses on Day 8 for Cycles 3-6 (up to 8). The starting dose of glofitamab for each arm may be one or more levels below the MTD/OBD determined in Part I.
    Interventions:
    • Drug: Glofitamab
    • Drug: Rituximab (R)
    • Drug: Tocilizumab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Prednisone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 9, 2018)
172
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 16, 2023
Estimated Primary Completion Date December 16, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age >/=18 years
  • For Part I r/r NHL dose-escalation, and Part II r/r NHL expansion: Histologically-confirmed NHL that is expected to express CD20, and which has relapsed/progressed following at least one prior treatment regimen containing R or G. Participants must be appropriate for treatment with CHOP and typically should not have been exposed to prior anthracyclines or must not exceed the cumulative lifetime dose of anthracyclines
  • For Part II untreated DLBCL expansion: Histologically confirmed previously-untreated DLBCL that is expected to express CD20
  • Able to provide a pretreatment biopsy between the last dose of last prior therapy and initiation of study medication at Cycle 1/Day 1
  • 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.
  • Participants must have at least one measurable target lesion (> or = 1.5 cm) in its largest dimension by computed tomography (CT) scan
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 for participants with r/r NHL; ECOG performance status 0-3 for participants with untreated DLBCL
  • Life expectancy (in the opinion of the Investigator) of 18 weeks
  • Adverse events (AEs) from prior anti-cancer therapy must have resolved to Grade </= 1
  • Adequate liver function
  • Adequate hematological function
  • Adequate 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)

Exclusion Criteria:

  • Inability to comply with protocol mandated hospitalization and restrictions
  • Participants with known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to Epstein Barr virus (EBV), cytomegalovirus (CMV), HBV, HCV, and HIV), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics, this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing
  • Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radioimmuno-conjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies (e.g., anti-CTLA4, anti-PD1, and anti-PDL1) within 4 weeks or five half-lives of the drug, whichever is shorter, before G- or R-CHOP infusion on Cycle 1/Day 1
  • History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents, as follows: Grade >/=3 AEs, with the exception of Grade 3 endocrinopathy managed with replacement therapy; Grade 1-2 AEs that did not resolve to baseline after treatment completion
  • Contraindication to any of the individual components of the chemotherapy
  • Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational anti-cancer agent within 4 weeks prior to study treatment at Cycle 1/Day 1 infusion
  • Prior solid organ transplantation
  • Prior allogeneic stem cell transplantation
  • Autologous stem cell transplantation within 100 days prior to Cycle 1/Day 1
  • Prior treatment with CAR T-cell therapy within 30 days prior to study treatment at Cycle 1 Day 1
  • History of autoimmune disease
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
  • A history of confirmed progressive multifocal leukoencephalopathy
  • Current or past history of central nervous system (CNS) lymphoma
  • Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Participants who received corticosteroid treatment with </=30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks' duration prior to Cycle 1/Day 1. Participants may have received a brief (<7 days) course of systemic steroids (</=100 mg prednisone equivalent per day) prior to initiation of study therapy for control of lymphoma-related symptoms
  • Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
  • 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 (bronchospasm, obstructive pulmonary disease), and known autoimmune diseases
  • Major surgery or significant traumatic injury < 28 days prior to the study treatment infusion at Cycle 1/Day 1 (excluding biopsies) or anticipation of the need for major surgery during study treatment
  • Participants with another invasive malignancy that could affect compliance with the protocol or interpretation of results
  • Significant or extensive cardiovascular disease
  • Left ventricular ejection fraction < 50%
  • Administration of a live, attenuated vaccine within 4 weeks before study treatment infusion on Cycle 1 Day 1 or anticipation that such a live, attenuated vaccine will be required during the study
  • History of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator's judgment
  • Any other diseases, metabolic dysfunction, physical examination finding (including mental status), or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
  • Participants with latent or active tuberculosis
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID: NP40126 https://forpatients.roche.com/ 888-662-6728 (U.S. only) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Australia,   Canada,   Denmark,   France,   Germany,   Italy,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03467373
Other Study ID Numbers  ICMJE NP40126
2017-003648-18 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date January 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP