A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 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

Lymphoma, Non-Hodgkin Clinical Trial

Official title:

An Open-Label, Phase I Study to Evaluate the Safety, Pharmacokinetics and Preliminary Antitumor Activity of 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04077723
• Other study ID #: BP41072
• Secondary ID: 2019-000416-28
• Status: Recruiting
• Phase: Phase 1
• Start date: August 13, 2019
• Est. completion date: March 31, 2025

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: BP41072 https://forpatients.roche.com
• Phone: 888-662-6728 (U.S. and Canada)
• Email: global-roche-genentech-trials[@]gene.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase I/II, open-label, dose-escalation study designed to evaluate the safety, tolerability, and efficacy of RO7227166 in participants with relapsed/refractory Non-Hodgkin's Lymphoma (r/r NHL). RO7227166 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 seven days prior to the first administration of RO7227166 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 498
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Depending upon study part: a 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 two prior treatment regimens; and no available treatment options that are expected to prolong survival

• Must have at least one measureable 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 performance status of 0 or 1

• Life expectancy of >/= 12 weeks

• Adverse events from prior anti-cancer therapy must have resolved to Grade </= 1

• Adequate liver, haematological, 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 RO7227166, 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 RO7227166, 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 or the presence of abnormal cells in the peripheral blood differential signifying circulating lymphoma cells

• 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 on D-7

• 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 (SCT) and prior chimeric antigen receptor -T-cell therapy

• Autologous SCT 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 steriods are permitted

Related Conditions & MeSH terms

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

Intervention

Drug:
• RO7227166
RO7227166 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).
• Obinutuzumab
A fixed dose of obinutuzumab will be administered seven days prior to first does of RO7227166 and glofitamab and then Q3W in combination with RO7227166 in Part I
• Glofitamab
A fixed dose of glofitamab will be administered Q3W in combination with RO7227166 in Part II and Part III
• Tocilizumab
Participants will receive IV tocilizumab as needed to treat cytokine release syndrome (CRS).

Locations

Country	Name	City	State
Australia	Peter Maccallum Cancer Centre	Melbourne	Victoria
Belgium	UZ Gent	Gent
Denmark	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø
France	CHRU de Lille	Lille
France	CHU Montpellier - Saint ELOI	Montpellier
France	Centre Hospitalier Lyon Sud	Pierre Benite
France	CHU DE RENNES - CHU Pontchaillou; Service d'Hématologie Clinique Adulte	Rennes
Italy	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
United Kingdom	The HOPE Clinical Trials Unit	Leicester
United Kingdom	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London
United States	Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center	Denver	Colorado
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	City of Hope Medical Center; Hematology	Pasadena	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Denmark,  France,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Nature and frequency of dose-limiting toxicities (DLTs)		28 days in Part I and Part II
Primary	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/III: Up to 18 months
Primary	Overall Response Rate (ORR)		Part I: Up to 24 months; Part II/III: Up to 18 months
Primary	Disease Control Rate (DCR)		Part I: Up to 24 months; Part II/III: Up to 18 months
Primary	Duration of Response (DOR)		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Primary	Progression-free Survival (PFS)		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Primary	Overall Survival (OS)		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Primary	Complete Response (CR)		Part III: Up to 18 months
Secondary	Total exposure (area under the concentration time curve [AUC]) of RO7227166 in combination with obinutuzumab and glofitamab		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with obinutuzumab and glofitamab		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with obinutuzumab and glofitamab		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	Clearance (CL) of RO7227166 in combination with obinutuzumab and glofitamab		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with obinutuzumab and glofitamab		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	ORR		Part I: Up to 24 months; Part II/III Up to 18 months
Secondary	DCR		Part I: Up to 24 months; Part II/III Up to 18 months
Secondary	DOR		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Secondary	PFS		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Secondary	OS		After end of Study approximately every 3 months until death, loss to follow-up or study termination
Secondary	Proportion of Participants with Adverse Event (AE)	Incidence, nature, and severity of AEs graded according to the NCI CTCAE v5.0	After end of Study approximately every 3 months until death, loss to follow-up or study termination
Secondary	Total exposure (area under the concentration time curve [AUC]) of RO7227166 in combination with glofitamab		Part III: Up to 18 months
Secondary	Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with glofitamab		Part III: Up to 18 months
Secondary	Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with glofitamab		Part III: Up to 18 months
Secondary	Clearance (CL) of RO7227166 in combination with glofitamab		Part III: Up to 18 months
Secondary	Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with glofitamab Part I/II/III		Part III: Up to 18 months
Secondary	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		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	B-cell reduction in blood and tumor tissue		Part I: Up to 24 months; Part II/III: Up to 18 months
Secondary	Change from Baseline in RO7227166 Anti-Drug Antibody (ADA) Titer		Part 1: Up to 24 months; Part ll/lll: Up to 18 months
Secondary	Time to First Complete Response (TFCR)		Up to 18 months
Secondary	Time to First Overall Response (TFOR)		Up to 18 months
Secondary	Duration of Complete Response (DOCR)		Part III: Up to 18 months
Secondary	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)		Part III: Up to 18 months
Secondary	Change from Baseline in Physical Function, Role Function, and HRQoL According to the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale		Part III: Up to 18 months