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

• ClinicalTrials.gov Identifier: NCT03467373
• Recruitment Status: Active, not recruiting
• First Posted: March 16, 2018
• Last Update Posted: May 26, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: March 9, 2018
• First Posted Date: March 16, 2018
• Last Update Posted Date: May 26, 2023
• Actual Study Start Date: March 13, 2018
• Estimated Primary Completion Date: December 16, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (submitted: February 28, 2022)

• 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 ]
• Duration of CR [ 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 (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: A Study of Glofitamab in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP), or Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (CHP) in Participants With Non-Hodgkin Lymphomas or With DLBCL
• Official Title: A Phase Ib Study Evaluating Glofitamab (RO7082859) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP), or Polatuzumab Vedotin (POLA) Plus Rituximab (R), Cyclophosphamide, Doxorubicin, and Prednisone (CHP) 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 G/R CHOP or Pola-R-CHP in participants with 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 untreated DLBCL (>18 years of age with an age-adjusted International Prognostic Index (IPI) of 2-5). Glofitamab will be studied in combination with R-CHOP and Pola-R-CHP.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• B-Cell Lymphoma
• Non-Hodgkin Lymphoma

Intervention

• 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
• Drug: Polatuzumab vedotin
  Polatuzumab vedotin 1.8 mg/kg administered IV on Day 1 of each 21-day cycle

Study Arms

• 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: DLBCL G/R-CHOP
  Participants with untreated DLBCL will receive G-CHOP or R-CHOP in Cycle 1, followed by G/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 Pola-R-CHP
  Participants with untreated DLBCL will receive Pola-R-CHP + glofitamab on Day 1 of each 21-day cycle for a maximum of 6 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. 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: Prednisone
  • Drug: Polatuzumab vedotin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 9, 2018): 172
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 16, 2023
• Estimated Primary Completion Date: December 16, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 final 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 or Pola-R-CHP infusion on Cycle 1/Day 1
• Current Grade > 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease (only for participants treated in the polatuzumab vedotin arm)
• 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 immunochemotherapy
• 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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Denmark, France, Germany, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03467373
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2023