Clinical trial NCT04077723: 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
Official title: An Open-Label, Phase I/II Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Englumafusp Alfa (RO7227166, A CD19 Targeted 4-1BB Ligand) in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Non-Hodgkin
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-09-04
Enrollment: 498
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* Significant cardiovascular disease
* Administration of a live, attenuated vaccine within 4 weeks before Gpt infusion or anticipation that such a live attenuated vaccine will be required during the study
* Received systemic immunosuppressive medications (including but not limited to cyclohosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within two weeks prior to Gpt, with the exception of corticosteroid treatment \<=25 mg/day of prednisone or equivalent, however there must be documentation that the participant was on a stable dose of at least a 2-week duration prior to Gpt infusion. Inhaled and topical steroids are permitted

Primary outcomes:
measure: Nature and frequency of dose-limiting toxicities (DLTs)
timeFrame: 28 days in Part I and Part II
measure: Proportion of Participants with Adverse Event (AE)
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Overall Response Rate (ORR)
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Disease Control Rate (DCR)
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Duration of Response (DOR)
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: Progression-free Survival (PFS)
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: Overall Survival (OS)
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: Complete Response (CR)
timeFrame: Part III: Up to 9 months or up to 18 months
Secondary outcomes:
measure: Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with obinutuzumab and glofitamab
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with obinutuzumab and glofitamab
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with obinutuzumab and glofitamab
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Clearance (CL) of englumafusp alfa in combination with obinutuzumab and glofitamab
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Volume of distribution of steady state (Vss) and half-life (t1/2) of englumafusp alfa in combination with obinutuzumab and glofitamab
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: ORR
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: DCR
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: DOR
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: PFS
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: OS
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: Proportion of Participants with Adverse Event (AE)
timeFrame: After end of Study approximately every 3 months until death, loss to follow-up or study termination
measure: Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with glofitamab
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with glofitamab
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with glofitamab
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Clearance (CL) of englumafusp alfa in combination with glofitamab
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Volume of distribution of steady state (Vss) and half-life (t1/2) of englumafusp alfa in combination with glofitamab Part I/II/III
timeFrame: Part III: Up to 9 months or up to 18 months
measure: T-cell and Natural killer (NK)-cell status in blood, using markers of T and NK-cell lineage, function and activation including, but not limited to, CD3, CD8, 41BB, and Ki67 expression
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: B-cell reduction in blood and tumor tissue
timeFrame: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
measure: Change from Baseline in englumafusp alfa Anti-Drug Antibody (ADA) Titer
timeFrame: Part 1: Up to 24 months; Part ll/lll: Up to 18 months
measure: Time to First Complete Response (TFCR)
timeFrame: Up to 18 months
measure: Time to First Overall Response (TFOR)
timeFrame: Up to 18 months
measure: Duration of Complete Response (DOCR)
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Change from Baseline in Physical Function, Role Function, and Health-Related Quality of Life (HRQoL) Based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
timeFrame: Part III: Up to 9 months or up to 18 months
measure: Change from Baseline in Physical Function, Role Function, and HRQoL According to the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale
timeFrame: Part III: Up to 9 months or up to 18 months
Other outcomes:
Locations:
city: Pasadena
country: United States
facility: City of Hope Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center
state: Colorado
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Gent
country: Belgium
facility: UZ Gent
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Jinan
country: China
facility: Shandong Cancer Hospital
city: Shanghai City
country: China
facility: Fudan University Shanghai Cancer Center
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital Skejby
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Lille
country: France
facility: CHRU de Lille
city: Montpellier
country: France
facility: CHU Montpellier - Saint ELOI
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rennes
country: France
facility: CHU DE RENNES - CHU Pontchaillou
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione g. Pascale
state: Campania
city: Bergamo
country: Italy
facility: Asst Papa Giovanni Xxiii
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Europeo Di Oncologia (IEO)
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Lombardia
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital, Cancer and Blood Research
city: Hamilton
country: New Zealand
facility: Waikato Hospital - Cancer and Blood Research Trials Unit
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals L'Hospitalet
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre
city: Malaga
country: Spain
facility: Hospital Clinico Universitario Virgen de la Victoria
city: Leicester
country: United Kingdom
facility: The HOPE Clinical Trials Unit
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: