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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

NCT03467373

Description:

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.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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: 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)

Clinical Trial IDs

  • ORG STUDY ID: NP40126
  • SECONDARY ID: 2017-003648-18
  • NCT ID: NCT03467373

Conditions

  • B-Cell Lymphoma
  • Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
GlofitamabRO7082859Part 1: Dose Escalation r/r NHL
Obinutuzumab (G)GazyvaPart 1: Dose Escalation r/r NHL
Rituximab (R)RituxanPart 1: Dose Escalation r/r NHL
TocilizumabActemraPart 1: Dose Escalation r/r NHL
CyclophosphamidePart 1: Dose Escalation r/r NHL
DoxorubicinPart 1: Dose Escalation r/r NHL
VincristineOncovinPart 1: Dose Escalation r/r NHL
PrednisonePart 1: Dose Escalation r/r NHL

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose Escalation r/r NHLExperimentalDose 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.
  • Glofitamab
  • Obinutuzumab (G)
  • Rituximab (R)
  • Tocilizumab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone
Part 2: Dose Expansion r/r NHLExperimentalParticipants with r/r NHL will be assigned to an expansion cohort to further explore glofitamab at the MTD/OBD determined in Part I.
  • Glofitamab
  • Obinutuzumab (G)
  • Rituximab (R)
  • Tocilizumab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone
Part 2: DLBCL G/R-CHOPExperimentalParticipants 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.
  • Glofitamab
  • Obinutuzumab (G)
  • Rituximab (R)
  • Tocilizumab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone
Part 2: DLBCL CHOPExperimentalParticipants 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.
  • Glofitamab
  • Rituximab (R)
  • Tocilizumab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone

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 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 < or =
             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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part I: Percentage of Participants with Dose Limiting Toxicities (DLTs)
Time Frame:Up to 29 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure:Parts I and II: Percentage of Participants with Overall Response (Partial Response [PR] or Complete Response [CR])
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure:Parts I and II: Duration of Response (DOR)
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS)
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure:Time to First Complete Response (TFCR)
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure:Time to First Response (TFOR)
Time Frame:Up to 29 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Parts I and II: Time to Maximum Serum Concentration (tmax) of Glofitamab
Time Frame:Cycle 1 Day 1 up to 29 months
Safety Issue:
Description:
Measure:Parts I and II: Maximum Serum Concentration (Cmax) of Glofitamab
Time Frame:Cycle 1 Day 1 up to 29 months
Safety Issue:
Description:
Measure:Parts I and II: Minimum Serum Concentration (Cmin) of Glofitamab
Time Frame:Cycle 1 Day 1 up to 29 months
Safety Issue:
Description:
Measure:Change from Baseline in T-cell Activation Markers
Time Frame:Up to 29 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

July 9, 2021