A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Englumafusp Alfa in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

NCT04077723 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: BP410722019-000416-282022-502616-37-00
• Study Type: interventional
• Target: 498
• Locations: 12 countries
• Sites: 44

Brief Summary

This is a phase I/II, open-label, dose-escalation study designed to evaluate the safety, tolerability, and efficacy of englumafusp alfa (RO7227166) in participants with relapsed/refractory Non-Hodgkin's Lymphoma (r/r NHL). Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab and in combination with glofitamab. A fixed dose of obinutuzumab (Gpt; pre-treatment) will be administered up to seven days prior to the first administration of englumafusp alfa and seven days prior to the first administration of glofitamab. This entry-into-human study is divided into a dose-escalation stage (Part I and Part II) and a dose expansion stage (Part III).

Conditions

Lymphoma, Non-Hodgkin

Outcome Measures

Primary Outcomes (8)

• Nature and frequency of dose-limiting toxicities (DLTs)

  28 days in Part I and Part II

• Proportion of Participants with Adverse Event (AE)

  Incidence, nature, and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Overall Response Rate (ORR)

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Disease Control Rate (DCR)

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Duration of Response (DOR)

  After end of Study approximately every 3 months until death, loss to follow-up or study termination

• Progression-free Survival (PFS)

  After end of Study approximately every 3 months until death, loss to follow-up or study termination

• Overall Survival (OS)

  After end of Study approximately every 3 months until death, loss to follow-up or study termination

• Complete Response (CR)

  Part III: Up to 9 months or up to 18 months

Secondary Outcomes (24)

• Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with obinutuzumab and glofitamab

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with obinutuzumab and glofitamab

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with obinutuzumab and glofitamab

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Clearance (CL) of englumafusp alfa in combination with obinutuzumab and glofitamab

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

• Volume of distribution of steady state (Vss) and half-life (t1/2) of englumafusp alfa in combination with obinutuzumab and glofitamab

  Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months

Study Arms (3)

Part I

EXPERIMENTAL

Combination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab up to seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab in a three-weekly schedule (Q3W).

Drug: Englumafusp alfa; Drug: Obinutuzumab; Drug: Tocilizumab

Part II

EXPERIMENTAL

Combination Dose-Escalation: Mixed r/r participants and participants with mixed r/r mantle cell lymphoma (MCL) and Richters transformation will receive a fixed dose of obinutuzumab seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).

Drug: Englumafusp alfa; Drug: Obinutuzumab; Drug: Glofitamab; Drug: Tocilizumab

Part III

EXPERIMENTAL

Dose-Expansion Stage: Participants with r/r diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL) will receive englumafusp alfa administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).

Drug: Englumafusp alfa; Drug: Obinutuzumab; Drug: Glofitamab; Drug: Tocilizumab

Interventions

Englumafusp alfa DRUG

Englumafusp alfa will be administered by intravenous (IV) infusion three-weekly (Q3W) in combination with a fixed dose of obinutuzumab (Part I) and in combination with a fixed dose of glofitamab (Part II and Part III).

Also known as: A CD19 Targeted 4-1BB Ligand; RO7227166

Part I; Part II; Part III

Obinutuzumab DRUG

A fixed dose of obinutuzumab will be administered up to 7 days prior to the first dose of englumafusp alfa, then in combination with obinutuzumab Q3W (Part I). A fixed dose of obinutuzumab will be administered up to 7 days prior to the first dose of englumafusp alfa or between Day -3 and -7 (Part II and Part III).

Also known as: Gpt, RO5072759, Gazyva, Gazyvaro

Part I; Part II; Part III

Glofitamab DRUG

A fixed dose of glofitamab will be administered Q3W in combination with englumafusp alfa in Part II and Part III

Also known as: CD20-TCB, RO7082859

Part II; Part III

Tocilizumab DRUG

Participants will receive IV tocilizumab as needed to treat cytokine release syndrome (CRS).

Also known as: Actemra, RoActemra

Part I; Part II; Part III

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• History or status of a histologically-confirmed hematological malignancy that is expected to express CD19 and CD20; relapse after or failure to respond to at least one prior treatment regimen; no available treatment options that are expected to prolong survival (Part I and II); relapsed after or failed to respond to only one prior systemic treatment regimen (Part III)
• Must have at least one measurable target lesion (\>/= 1.5 cm) in its largest dimension by computed tomography scan
• Able and willing to provide a fresh biopsy from a safely accessible site, per Investigator's determination, providing the participant has more than one measurable target lesion
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or \</= 2 for some participants in Part III
• Life expectancy of \>/= 12 weeks
• Adverse events from prior anti-cancer therapy must have resolved to Grade \</= 1
• Adequate liver, hematological, and renal function
• Negative test results for acute or chronic hepatitis B virus infection
• Negative test results for hepatitis C virus and HIV
• The contraception and abstinence requirements are intended to prevent exposure of an embryo to the study treatment. The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure
• Female participants: A female participant is eligible to participate if she is not pregnant and not breastfeeding, and if at least one of the following applies: women of non-childbearing potential (WONCBP); women of child bearing potential (WOCBP) who agree to remain abstinent or use two highly effective contraceptive methods with a failure rate of \<1% per year during the treatment period and for at least 18 months after obinutuzumab or 3.5 months after the last dose of englumafusp alfa, 2 months after last dose of glofitamab, or 3 months after the last dose of tocilizumab, whichever is longer. Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal occlusion/ ligation, male sexual partner who is sterilized, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method; have a negative pregnancy test (blood) within the 7 days prior to the first study treatment administration
• Male participants: During the treatment period and for at least 3 months after obinutuzumab, or 3.5 months after the last dose of englumafusp alfa, 2 months after the last dose of glofitamab, or 2 months after the last dose of tocilizumab whichever is longer, agreement to: Remain abstinent or use contraceptive measures such as a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year, with a partner who is a women of childbearing potential. With pregnant female partner, remain abstinent or use contraceptive measures such as a condom to avoid exposing the embryo; refrain from donating sperm during this same period

You may not qualify if:

• Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count (ALC) or the presence of abnormal cells in the peripheral blood signifying circulating lymphoma cells (for some participants in Part III, ALC only)
• Participants with acute bacterial, viral, or fungal infection at baseline, confirmed by a positive blood culture within 72 hours prior to obinutuzumab infusion or by clinical judgment in the absence of a positive blood culture
• Participants with known active infection, or reactivation of a latent infection, whether bacterial, viral fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics
• Pregnant or breast-feeding or intending to become pregnant during the study
• Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines or monoclonal antibodies within 4 weeks or five half-lives of the drug, whichever is shorter, before obinutuzumab infusion
• History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents and auto-immune disease
• Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational or approved anti-cancer agent within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to obinutuzumab infusion
• Prior solid organ transplantation
• Prior allogeneic stem cell transplant
• Autologous stem cell transplant within 100 days prior to obinutuzumab infusion
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy and confirmed progressive multifocal leukoencephalopathy
• Current or past history of central nervous system (CNS) lymphoma and CNS 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 and known autoimmune diseases
• Major surgery or significant traumatic injury \< 28 days prior to the Gpt infusion or anticipation of the need for major surgery during study treatment
• Participants with another invasive malignancy in the last 2 years

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (44)

City of Hope Medical Center

Pasadena, California, 91105, United States

Location

University of California San Francisco

San Francisco, California, 94158, United States

Location

Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center

Denver, Colorado, 80218, United States

Location

Beth Israel Medical Center

Boston, Massachusetts, 02215, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MSKCC

New York, New York, 10065, United States

Location

OhioHealth Research Institute

Columbus, Ohio, 43221-2417, United States

Location

SCRI Oncology Partners

Nashville, Tennessee, 37203, United States

Location

South Austin Medical Center

Austin, Texas, 78704, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Peter Maccallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

The Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

UZ Gent

Ghent, 9000, Belgium

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Beijing Cancer Hospital

Beijing, 100142, China

Location

Shandong Cancer Hospital

Jinan, 250117, China

Location

Fudan University Shanghai Cancer Center

Shanghai, 201315, China

Location

The First Affiliated Hospital of Xiamen University

Xiamen, 361003, China

Location

Aarhus Universitetshospital Skejby

Aarhus N, 8200, Denmark

Location

Rigshospitalet

København Ø, 2100, Denmark

Location

Odense Universitetshospital

Odense C, 5000, Denmark

Location

CHRU de Lille

Lille, 59037, France

Location

CHU Montpellier - Saint ELOI

Montpellier, 34295, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHU DE RENNES - CHU Pontchaillou

Rennes, 35033, France

Location

Istituto Nazionale Tumori Irccs Fondazione g. Pascale

Naples, Campania, 80131, Italy

Location

Asst Papa Giovanni Xxiii

Bergamo, Lombardy, 24127, Italy

Location

Irccs Istituto Europeo Di Oncologia (IEO)

Milan, Lombardy, 20141, Italy

Location

Istituto Clinico Humanitas

Rozzano, Lombardy, 20089, Italy

Location

Auckland City Hospital, Cancer and Blood Research

Auckland, 1023, New Zealand

Location

Waikato Hospital - Cancer and Blood Research Trials Unit

Hamilton, 3204, New Zealand

Location

Pusan National University Hospital

Busan, 49241, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Hospital Duran i Reynals L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Clinica Universitaria de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Clinica Universidad de Navarra Madrid

Madrid, 28027, Spain

Location

Hospital Univ. 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Clinico Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

The HOPE Clinical Trials Unit

Leicester, LE1 5WW, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, W1T 7HA, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

obinutuzumab; Alanine Transaminase; glofitamab; tocilizumab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Transaminases; Nitrogenous Group Transferases; Transferases; Enzymes; Enzymes and Coenzymes

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2019
• First Posted: September 4, 2019
• Study Start: August 13, 2019
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027
• Last Updated: March 2, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

FR (4); AU (2); CA (2); DK (3); IT (4); KR (4); BE (1); US (10); GB (2); ES (6); NZ (2); CN (4)