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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03533283

Collaborator

(none)

280

Enrollment

Locations

Arms

78.8

Anticipated Duration (Months)

12.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkins Lymphoma	Drug: Glofitamab Drug: Atezolizumab Drug: Obinutuzumab Drug: Tocilizumab Drug: Polatuzumab Vedotin Drug: 89Zr-Df-IAB22M2C	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

280 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 8, 2018

Anticipated Primary Completion Date :

Nov 30, 2024

Anticipated Study Completion Date :

Nov 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atezolizumab Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).	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 Names: 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 Names: Actemra
Experimental: Polatuzumab Vedotin Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.	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 Names: RO7082859 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 Names: 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).
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.	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 Names: RO7082859 Drug: Obinutuzumab Obinutuzumab will be administered once, through IV infusion, at a fixed dose 7 days before the first dose of Glofitamab. 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.

Arm

Intervention/Treatment

Experimental: Atezolizumab

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

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 Names:

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 Names:

Actemra

Experimental: Polatuzumab Vedotin

Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.

Drug: Glofitamab

Other Names:

RO7082859

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 Names:

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).

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.

Drug: Glofitamab

Other Names:

RO7082859

Drug: Obinutuzumab

Obinutuzumab will be administered once, through IV infusion, at a fixed dose 7 days before the first dose of Glofitamab.

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.

Outcome Measures

Primary Outcome Measures

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]
Change in Maximum Standardized Update Value (SUVmax) Based on 89Zr-PET/CT Scans [From baseline to Day 13]
Change in Peak SUV (SUVpeak) Based on 89Zr-PET/CT Scans [From baseline to Day 13]
Change in Mean SUV (SUVmean) Based on 89Zr-PET/CT Scans [From baseline to Day 13]
Change in CD8 Tumor Volume Based on 89Zr-PET/CT [From baseline to Day 13]

Secondary Outcome Measures

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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
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)]
CD8-Positive T Cell Proliferation [At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)]
CD20-Positive B-Cell Reduction [At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)]
SUVmax of 89Zr-Df-IAB22M2C [From baseline to Day 13]
SUVpeak of 89Zr-Df-IAB22M2C [From baseline to Day 13]
SUVmean of 89Zr-Df-IAB22M2C [From baseline to Day 13]
Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake [From baseline to Day 13]
Quantitation of CD8+ Cells on Biopsy Samples [From baseline to Day 13]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novant Health Cancer Institute	Charlotte	North Carolina	United States	28204
2	Ohio State University; Clinical Investigations Office	Columbus	Ohio	United States	43210
3	UZ Gent	Gent		Belgium	9000
4	Aarhus Universitetshospital Skejby; Blodsygdomme	Aarhus N		Denmark	8200
5	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø		Denmark	2100
6	Odense Universitetshospital; Hæmatologisk Afdeling	Odense C		Denmark	5000
7	Hadassah Ein Karem Hospital; Haematology	Jerusalem		Israel	9112001
8	Rabin Medical Center-Beilinson Campus;Hematology-Oncology	Petach Tikva		Israel	4941492
9	Chaim Sheba Medical Center; Department of Hematology	Ramat-Gan		Israel	52621
10	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania	Italy	80131
11	Policlinico S.Orsola-Malpighi;Istituto di Ematologia "Seragnoli"	Bologna	Emilia-Romagna	Italy	40138
12	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia	Italy	24127
13	Fond. IRCCS Istituto Nazionale Tumori; S. C. Ematologia	Milano	Lombardia	Italy	20133
14	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
15	Hospital Duran i Reynals; Servicio de Hematologia	Barcelona		Spain	08907
16	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid		Spain	28040
17	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia	Madrid		Spain	28050
18	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga		Spain	29010
19	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
20	The HOPE Clinical Trials Unit	Leicester		United Kingdom	LE1 5WW
21	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London		United Kingdom	W1T 7HA
22	The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne		United Kingdom	NE1 4LP