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

Non-Hodgkins Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03533283
• Other study ID #: NP39488
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: May 8, 2018
• Est. completion date: September 30, 2026

Study information

• Verified date: April 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 280
• Est. completion date: September 30, 2026
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• 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.
• 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).
• Obinutuzumab
Obinutuzumab will be administered once, through IV infusion, at a fixed dose 7 days before the first dose of Glofitamab.
• Tocilizumab
Tocilizumab will be administered as necessary to treat cytokine release syndrome (CRS).
• 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).
• 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.

Locations

Country	Name	City	State
Belgium	UZ Gent	Gent
Denmark	Aarhus Universitetshospital Skejby; Blodsygdomme	Aarhus N
Denmark	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø
Denmark	Odense Universitetshospital; Hæmatologisk Afdeling	Odense C
Israel	Hadassah Ein Karem Hospital; Haematology	Jerusalem
Israel	Rabin Medical Center-Beilinson Campus;Hematology-Oncology	Petach Tikva
Israel	Chaim Sheba Medical Center; Department of Hematology	Ramat-Gan
Italy	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia
Italy	Policlinico S.Orsola-Malpighi;Istituto di Ematologia "Seragnoli"	Bologna	Emilia-Romagna
Italy	Fond. IRCCS Istituto Nazionale Tumori; S. C. Ematologia	Milano	Lombardia
Italy	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania
Spain	Hospital Duran i Reynals; Servicio de Hematologia	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
Spain	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
United Kingdom	The HOPE Clinical Trials Unit	Leicester
United Kingdom	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London
United Kingdom	The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne
United States	Novant Health Cancer Institute	Charlotte	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  Denmark,  Israel,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicities (DLTs)		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
Primary	Change in Maximum Standardized Update Value (SUVmax) Based on 89Zr-PET/CT Scans		From baseline to Day 13
Primary	Change in Peak SUV (SUVpeak) Based on 89Zr-PET/CT Scans		From baseline to Day 13
Primary	Change in Mean SUV (SUVmean) Based on 89Zr-PET/CT Scans		From baseline to Day 13
Primary	Change in CD8 Tumor Volume Based on 89Zr-PET/CT		From baseline to Day 13
Secondary	Percentage of Participants with Adverse Events (AEs)		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)
Secondary	Anti-Drug Antibody (ADA) Formation		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)
Secondary	Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan		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)
Secondary	Objective Response Rate (ORR)		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)
Secondary	Disease Control Rate (DCR)		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)
Secondary	Duration of Response (DOR)		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)
Secondary	Duration of Complete Response		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)
Secondary	Time to First Complete Response (TFCR)		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)
Secondary	Time to First Overall Response (TFOR)		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)
Secondary	Progression-Free Survival (PFS)		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)
Secondary	Overall Survival (OS)		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)
Secondary	Elimination Half-Life (T1/2) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Area Under the Concentration-Time Curve (AUC) for Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Time to Maximum Observed Serum Concentration (Tmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Maximum Observed Serum Concentration (Cmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Minimum Serum Concentration (Cmin) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Clearance (CL) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	Volume of Distribution at Steady-State (Vss) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin		At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
Secondary	CD8-Positive T Cell Proliferation		At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)
Secondary	CD20-Positive B-Cell Reduction		At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)
Secondary	SUVmax of 89Zr-Df-IAB22M2C		From baseline to Day 13
Secondary	SUVpeak of 89Zr-Df-IAB22M2C		From baseline to Day 13
Secondary	SUVmean of 89Zr-Df-IAB22M2C		From baseline to Day 13
Secondary	Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake		From baseline to Day 13
Secondary	Quantitation of CD8+ Cells on Biopsy Samples		From baseline to Day 13