An Open-Label Phase lB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

• ClinicalTrials.gov Identifier: NCT03533283
• Recruitment Status: Recruiting
• First Posted: May 23, 2018
• Last Update Posted: March 20, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: May 4, 2018
• First Posted Date: May 23, 2018
• Last Update Posted Date: March 20, 2023
• Actual Study Start Date: May 8, 2018
• Estimated Primary Completion Date: November 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 16, 2021)

• Dose Limiting Toxicities (DLTs) [ Time Frame: Atezolizumab Arm: During DLT period of 21 days (or up to 42 days in the case of cycle delay), starting on Day 1, Cycle 2; Polatuzumab Vedotin Arm: During 5-week DLT period starting Cycle 1, Day 8 ]
• Change in Maximum Standardized Update Value (SUVmax) Based on 89Zr-PET/CT Scans [ Time Frame: From baseline to Day 13 ]
• Change in Peak SUV (SUVpeak) Based on 89Zr-PET/CT Scans [ Time Frame: From baseline to Day 13 ]
• Change in Mean SUV (SUVmean) Based on 89Zr-PET/CT Scans [ Time Frame: From baseline to Day 13 ]
• Change in CD8 Tumor Volume Based on 89Zr-PET/CT [ Time Frame: From baseline to Day 13 ]

• Original Primary Outcome Measures (submitted: May 11, 2018): Dose Limiting Toxicities (DLTs) [ Time Frame: During DLT period of 21 days (or up to 42 days in the case of cycle delay), starting on Day 1 of Cycle 2 ]

Current Secondary Outcome Measures (submitted: March 16, 2021)

• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Anti-Drug Antibody (ADA) Formation [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Objective Response Rate (ORR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Disease Control Rate (DCR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Duration of Response (DOR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Duration of Complete Response [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Time to First Complete Response (TFCR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Time to First Overall Response (TFOR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Progression-Free Survival (PFS) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Overall Survival (OS) [ Time Frame: Baseline through end of survival follow-up phase (survival follow-up is every 3 months until death, lost to follow-up, withdrawal of consent, or study termination) ]
• Elimination Half-Life (T1/2) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Area Under the Concentration-Time Curve (AUC) for Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Time to Maximum Observed Serum Concentration (Tmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Maximum Observed Serum Concentration (Cmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Minimum Serum Concentration (Cmin) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Clearance (CL) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Volume of Distribution at Steady-State (Vss) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• CD8-Positive T Cell Proliferation [ Time Frame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) ]
• CD20-Positive B-Cell Reduction [ Time Frame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) ]
• SUVmax of 89Zr-Df-IAB22M2C [ Time Frame: From baseline to Day 13 ]
• SUVpeak of 89Zr-Df-IAB22M2C [ Time Frame: From baseline to Day 13 ]
• SUVmean of 89Zr-Df-IAB22M2C [ Time Frame: From baseline to Day 13 ]
• Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake [ Time Frame: From baseline to Day 13 ]
• Quantitation of CD8+ Cells on Biopsy Samples [ Time Frame: From baseline to Day 13 ]

Original Secondary Outcome Measures (submitted: May 11, 2018)

• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Anti-Drug Antibody (ADA) Formation [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Objective Response Rate (ORR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Disease Control Rate (DCR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Duration of Response (DOR) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Progression-Free Survival (PFS) [ Time Frame: Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) ]
• Overall Survival (OS) [ Time Frame: Baseline through end of survival follow-up phase (survival follow-up is every 3 months until death, lost to follow-up, withdrawal of consent, or study termination) ]
• Elimination Half-Life (T1/2) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Area Under the Concentration-Time Curve (AUC) for RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Time to Maximum Observed Serum Concentration (Tmax) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Maximum Observed Serum Concentration (Cmax) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Minimum Serum Concentration (Cmin) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Clearance (CL) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• Volume of Distribution at Steady-State (Vss) of RO7082859 Administered in Combination with Atezolizumab [ Time Frame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) ]
• CD8-Positive T Cell Proliferation [ Time Frame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) ]
• CD20-Positive B-Cell Reduction [ Time Frame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Open-Label Phase lB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
• Official Title: An Open-Label, Multi-Center, Phase IB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin (Plus a Single Pre-Treatment Dose of Obinutuzumab) in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

Brief Summary

This is an open-label, single arm, multicenter, dose finding, Phase Ib study in order to assess the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) for this combination treatment and to evaluate the general safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and preliminary anti-tumor activity of this combination treatment in adult patients.

This study includes an additional open-label imaging feasibility sub-study using a tracer in adult participants with relpased/refractory B-cell non-Hodgkin's lymphoma to image CD8+T-cells at baseline and after treatment with glofitamab, including pre-treatment with obinutuzumab.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Hodgkins Lymphoma

Intervention

• Drug: Glofitamab
  Glofitamab will be administered through IV infusion every 3 weeks (Q3W) beginning Cycle 1, Day 1, for up to 17 cycles (Cycle = 21 days). Step-up dosing, in which an initial lower dose will be followed by a higher dose 1 week later, will be considered for the initial treatment phase and for Cycle 9 of the re-treatment phase.
  Other Name: RO7082859
• Drug: Atezolizumab
  Atezolizumab will be administered in combination with Glofitamab through IV infusion Q3W from Cycle 2, Day 1, for up to 16 cycles (Cycle = 21 days).
• Drug: Obinutuzumab
  Obinutuzumab will be administered once, through IV infusion, at a fixed dose 7 days before the first dose of Glofitamab.
• Drug: Tocilizumab
  Tocilizumab will be administered as necessary to treat cytokine release syndrome (CRS).
  Other Name: Actemra
• Drug: Polatuzumab Vedotin
  Polatuzumab vedotin will be administered in combination with Glofitamab (on different days) Q3W from Cycle 1, Day 2, for up to 12 cycles (Cycle = 21 days).
• Drug: 89Zr-Df-IAB22M2C
  Participants will receive 89Zr-Df-IAB22M2C (Cycle 1 only) prior to obinutuzumab pre-treatment and again on Day 10 after dosing with glofitamab, followed by PET/CT.

Study Arms

• Experimental: Atezolizumab
  Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).
  Interventions:

  • Drug: Glofitamab
  • Drug: Atezolizumab
  • Drug: Obinutuzumab
  • Drug: Tocilizumab
• Experimental: Polatuzumab Vedotin
  Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.
  Interventions:

  • Drug: Glofitamab
  • Drug: Obinutuzumab
  • Drug: Tocilizumab
  • Drug: Polatuzumab Vedotin
• Experimental: Imaging Sub-study
  Participants will undergo positive-emission tomography/computed tomography (PET/CT) at screening, followed by an "Imaging Cycle," to replace Cycle 1 of the main study. Eligible participants will have the option roll-over to the atezolizumab arm of the main study from Cycle 2 onwards.
  Interventions:

  • Drug: Glofitamab
  • Drug: Obinutuzumab
  • Drug: 89Zr-Df-IAB22M2C

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 19, 2022): 280
• Original Estimated Enrollment (submitted: May 11, 2018): 140
• Estimated Study Completion Date: November 30, 2024
• Estimated Primary Completion Date: November 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Main Inclusion Criteria

• Histologically-confirmed hematologic malignancy that is expected to express CD20 (Relapsed after or refractory to respond to at least one prior treatment regimen; no available treatment options that are expected to prolong survival or patients refusing chemotherapy or autologous stem cell transplant (SCT). Note: The expansion part is restricted to relapsed/refractory follicular lymphoma (r/r FL) and relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL))
• At least one measurable target lesion
• Fresh pre-treatment biopsy, but if this cannot be taken, a previous archived biopsy from metastatic lesion can be taken as replacement if it is not older than 6 months and not confounded by major events (progression, treatment)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate organ function (liver, hematological, renal)
• Negative test results for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)

Inclusion Criteria Specific to Imaging Substudy

• At least two measurable target lesions
• Able to provide two fresh tumor biopsies (baseline and on-treatment)

Main Exclusion Criteria

• Participants with Chronic Lymphocytic Leukemia (CLL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, Richter's transformation, CD20-positive ALL, Burkitt lymphoma, or lymphoplasmacytic lymphoma
• Current > Grade 1 peripheral neuropathy (only for participants being treated in the polatuzumab vedotin arm)
• Patients with known active infection, or reactivation of a latent infection within 4 weeks prior to Obinutuzumab (Gpt) infusion
• Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)
• History of leptomeningeal disease
• Current or past history of central nervous system (CNS) lymphoma
• Current or past history of CNS disease
• Major surgery or significant traumatic injury </=28 days prior to Gpt infusion
• Significant cardiovascular disease or significant pulmonary disease
• Active or history of autoimmune disease or immune deficiency (with exceptions, e.g. hypothyroidism and Diabetes mellitus Type 1)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Treatment with any other standard anti-cancer radiotherapy / chemotherapy including investigational therapy within 4 weeks prior to Gpt infusion
• Prior solid organ transplantation
• Prior allogenic stem cell transplant (SCT)
• Autologous SCT within 100 days prior to Gpt infusion
• Documented refractoriness to an obinutuzumab-monotherapy regimen
• Prior treatment with anti-cancer/lymphoma therapies and systemic immunotherapeutic/immunostimulating agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to Gpt infusion
• Any history of immune related >/= Grade 3 adverse events (AE) with the exception of endocrinopathy managed with replacement therapy
• Ongoing corticosteroid use >25 milligrams/day of prednisone or equivalent within 4 weeks prior to and during study treatment
• Treatment with systemic immunosuppressive medication
• Administration of a live, attenuated vaccine within 4 weeks prior to Gpt infusion or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last dose of study treatment

Exclusion Criteria Specific to Imaging Substudy

• Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count and/or the presence of abnormal/malignant cells in the peripheral blood differential signifying circulating lymphoma cell
• Participants who have had splenectomy or functional asplenia that could compromise protocol objectives

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: NP39488 https://forpatients.roche.com/; 888-662-6728 (U.S. and Canada); global-roche-genentech-trials@gene.com

• Listed Location Countries: Belgium, Denmark, Israel, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03533283
• Other Study ID Numbers: NP39488
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• 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: March 2023