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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03467373

Collaborator

(none)

172

Enrollment

Locations

Arms

69.1

Anticipated Duration (Months)

6.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
B-Cell Lymphoma Non-Hodgkin Lymphoma	Drug: Glofitamab Drug: Obinutuzumab (G) Drug: Rituximab (R) Drug: Tocilizumab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone Drug: Polatuzumab vedotin	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

172 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Mar 13, 2018

Anticipated Primary Completion Date :

Dec 16, 2023

Anticipated Study Completion Date :

Dec 16, 2023

Arms and Interventions

Arm	Intervention/Treatment
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.	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 Names: RO7082859 Drug: Obinutuzumab (G) Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only Other Names: 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 Names: 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 Names: 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 Names: 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
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.	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 Names: RO7082859 Drug: Obinutuzumab (G) Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only Other Names: 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 Names: 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 Names: 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 Names: 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
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.	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 Names: RO7082859 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 Names: 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 Names: 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: 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

Arm

Intervention/Treatment

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.

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 Names:

RO7082859

Drug: Obinutuzumab (G)

Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only

Other Names:

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 Names:

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 Names:

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 Names:

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

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.

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 Names:

RO7082859

Drug: Obinutuzumab (G)

Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only

Other Names:

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 Names:

Rituxan

Drug: Tocilizumab

Other Names:

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 Names:

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

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.

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 Names:

RO7082859

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 Names:

Rituxan

Drug: Tocilizumab

Other Names:

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: 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

Outcome Measures

Primary Outcome Measures

Part I: Percentage of Participants with Dose Limiting Toxicities (DLTs) [Up to 29 months]
Part I and II: Percentage of Participants with Adverse Events [Up to 29 months]

Secondary Outcome Measures

Parts I and II: Percentage of Participants with a Complete Response (CR) as Assessed by the Investigator using Modified Lugano 2014 Criteria [Up to 29 months]
Parts I and II: Percentage of Participants with Overall Response (Partial Response [PR] or Complete Response [CR]) [Up to 29 months]
Parts I and II: Duration of Response (DOR) [Up to 29 months]
Duration of CR [Up to 29 months]
Progression-Free Survival (PFS) [Up to 29 months]
Overall Survival (OS) [Up to 29 months]
Time to First Complete Response (TFCR) [Up to 29 months]
Time to First Response (TFOR) [Up to 29 months]
Parts I and II: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab [Cycle 1 Day 1 up to 29 months]
Parts I and II: Time to Maximum Serum Concentration (tmax) of Glofitamab [Cycle 1 Day 1 up to 29 months]
Parts I and II: Maximum Serum Concentration (Cmax) of Glofitamab [Cycle 1 Day 1 up to 29 months]
Parts I and II: Minimum Serum Concentration (Cmin) of Glofitamab [Cycle 1 Day 1 up to 29 months]
Change from Baseline in T-cell Activation Markers [Up to 29 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Medical Center	Birmingham	Alabama	United States	35294
2	Florida Hospital Cancer Inst	Orlando	Florida	United States	32804
3	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
4	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
5	Fox Chase-Temple Cancer Center	Philadelphia	Pennsylvania	United States	19111
6	West Virginia University; Health Sciences Center	Morgantown	West Virginia	United States	26506
7	Peter Maccallum Cancer Centre	Melbourne	Victoria	Australia	3000
8	Cross Cancer Institute; Clinical Trials	Edmonton	Alberta	Canada	T6G 1Z2
9	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 1Z5
10	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø		Denmark	2100
11	Hopital Claude Huriez; Hematologie	Lille		France	59037
12	Hopital Hotel Dieu Et Hme; Clinique Hematologie	Nantes		France	44093
13	Centre Henri Becquerel; Hematologie	Rouen		France	76038
14	Universitätsklinikum Erlangen, Translational Research Center (TRC), Medizin 5	Erlangen		Germany	91054
15	Universitätsklinikum Freiburg; Klinik für Innere Medizin I; Hämatologie/Onkologie	Freiburg		Germany	79106
16	Universitätsklinikum Ulm; Medizinische Uni-Klinik III Abt. Innere Medizin III Hämatologie u. Onkolo.	Ulm		Germany	89081
17	Universitätsklinikum Würzburg; Studienzentrale Hämatologie/Onkologie	Würzburg		Germany	97080
18	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania	Italy	80131
19	UO Ematologia, Ospedale S.Maria delle Croci	Ravenna	Emilia-Romagna	Italy	48121
20	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia	Italy	24127
21	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia	Italy	20089
22	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
23	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona		Spain	08036
24	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid		Spain	28040
25	The HOPE Clinical Trials Unit	Leicester		United Kingdom	LE1 5WW
26	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London		United Kingdom	W1T 7HA
27	Nottingham University Hospitals NHS Trust - City Hospital	Nottingham		United Kingdom	NG5 1PB
28	Derriford Hospital; Haematology	Plymouth		United Kingdom	PL6 8DH