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

Non-Hodgkin Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03467373
• Other study ID #: NP40126
• Secondary ID: 2017-003648-18
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: March 13, 2018
• Est. completion date: October 30, 2024

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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 172
• Est. completion date: October 30, 2024
• Est. primary completion date: October 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• B-Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

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.
• Obinutuzumab (G)
Obinutuzumab 1000 mg single dose IV infusion on Day 1 of Cycle 1 only
• 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).
• 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.
• Cyclophosphamide
Cyclophosphamide 750 mg/m^2 administered IV on Day 1 of each 21-day cycle
• Doxorubicin
Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle
• 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
• 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
• Polatuzumab vedotin
Polatuzumab vedotin 1.8 mg/kg administered IV on Day 1 of each 21-day cycle

Locations

Country	Name	City	State
Australia	Peter Maccallum Cancer Centre	Melbourne	Victoria
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø
France	Hopital Claude Huriez; Hematologie	Lille
France	Hopital Hotel Dieu Et Hme; Clinique Hematologie	Nantes
France	Centre Henri Becquerel; Hematologie	Rouen
Germany	Universitätsklinikum Erlangen, Translational Research Center (TRC), Medizin 5	Erlangen
Germany	Universitätsklinikum Freiburg; Klinik für Innere Medizin I; Hämatologie/Onkologie	Freiburg
Germany	Universitätsklinikum Ulm; Medizinische Uni-Klinik III Abt. Innere Medizin III Hämatologie u. Onkolo.	Ulm
Germany	Universitätsklinikum Würzburg; Studienzentrale Hämatologie/Onkologie	Würzburg
Italy	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia
Italy	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania
Italy	UO Ematologia, Ospedale S.Maria delle Croci	Ravenna	Emilia-Romagna
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Spain	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
Spain	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid
United Kingdom	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London
United Kingdom	Nottingham University Hospitals NHS Trust - City Hospital	Nottingham
United Kingdom	Derriford Hospital; Haematology	Plymouth
United States	University of Alabama Medical Center	Birmingham	Alabama
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	West Virginia University; Health Sciences Center	Morgantown	West Virginia
United States	Fox Chase-Temple Cancer Center	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part I: Percentage of Participants with Dose Limiting Toxicities (DLTs)		Up to 29 months
Primary	Part I and II: Percentage of Participants with Adverse Events		Up to 29 months
Secondary	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
Secondary	Parts I and II: Percentage of Participants with Overall Response (Partial Response [PR] or Complete Response [CR])		Up to 29 months
Secondary	Parts I and II: Duration of Response (DOR)		Up to 29 months
Secondary	Duration of CR		Up to 29 months
Secondary	Progression-Free Survival (PFS)		Up to 29 months
Secondary	Overall Survival (OS)		Up to 29 months
Secondary	Time to First Complete Response (TFCR)		Up to 29 months
Secondary	Time to First Response (TFOR)		Up to 29 months
Secondary	Parts I and II: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab		Cycle 1 Day 1 up to 29 months
Secondary	Parts I and II: Time to Maximum Serum Concentration (tmax) of Glofitamab		Cycle 1 Day 1 up to 29 months
Secondary	Parts I and II: Maximum Serum Concentration (Cmax) of Glofitamab		Cycle 1 Day 1 up to 29 months
Secondary	Parts I and II: Minimum Serum Concentration (Cmin) of Glofitamab		Cycle 1 Day 1 up to 29 months
Secondary	Change from Baseline in T-cell Activation Markers		Up to 29 months