A 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Jul 2019 → ongoing

Decision date (initial)

2024-02-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2022-502616-37-00

EudraCT number

2019-000416-28

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Others, Efficacy

Part I/II (Dose-Escalation)
1. 1. To determine the maximum tolerated dose and/ or recommended Phase 2 dose (RP2D) of englumafusp alfa in combination with obinutuzumab and in combination with glofitamab following obinutuzumab pre-treatment (GpT) or double GpT (DGpT) in participants with r/r B-cell NHL (Part I and IIA) and in participants with r/r MCL and Richter’s transformation (Part IIB)
2. To evaluate the safety and tolerability of englumafusp alfa in combination with obinutuzumab and in combination with glofitamab following GpT or DGpT in participants with r/r B-cell NHL (Part I and IIA) and in participants with r/r MCL and Richter’s transformation (Part IIB)
Part III (Dose-Expansion)
3. A1: To compare anti-tumor activity of englumafusp alfa at selected doses (in combination with glofitamab and glofitamab monotherapy) in participants with r/r large B-cell lymphoma (LBCL)
4. A2 and B: To demonstrate anti- tumor activity of englumafusp alfa in combination with glofitamab in r/r follicular lymphoma (FL) and MCL

Secondary objectives 15

1. Part I/II To characterize the pharmacokinetics (PK) of englumafusp alfa in combination with obinutuzumab and glofitamab
2. Part I/II To evaluate the anti-englumafusp alfa immune response after study treatment when administered in combination with obinutuzumab and glofitamab
3. Part I/II To make a preliminary assessment of the anti-tumor activity of englumafusp alfa in combination with obinutuzumab and in combination with glofitamab following GpT or DGpT in participants with r/r NHL and in participants with r/r MCL and Richter’s transformation (Part IIB)
4. Part I/II To assess mode of action and treatment induced pharmacodynamics (PD) effects
5. Part III A1: To compare anti-tumor activity of englumafusp alfa at selected doses in combination with glofitamab and glofitamab monotherapy in participants with r/r LBCL
6. Part III A2 and B: To assess anti-tumor activity of englumafusp alfa in combination with glofitamab in participants with r/r DLBCL and FL and MCL
7. Part III Patient Reported Outcome (PRO): Assessment of disease-related symptoms, function, and health-related quality of life (HRQoL) according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma scale
8. Part III A1: To compare PRO in participants with r/r LBCL treated with englumafusp alfa at selected doses in combination with glofitamab and glofitmab monotherapy
9. Part III A2 and B: To assess PRO in participants with r/r FL and r/r MCL treated with englumafusp alfa in combination with glofitamab
10. Part III A1: To compare the safety and tolerability of englumafusp alfa at selected doses (in combination with glofitamab and glofitamab monotherapy) following GpT in participants with r/r LBCL
11. Part III A2 and B: To evaluate the safety and tolerability of englumafusp alfa in combination with glofitamab following GpT or DGpT in participants with r/r DLBCL, FL and MCL
12. Part III To determine the PK characteristics of englumafusp alfa in combination with glofitamab (A1, A2, B) and of glofitamab administered as monotherapy (A1).
13. Part III To evaluate the anti-englumafusp alfa immune response after study A1: at selected doses in combination with glofitamab and glofitamab monotherapy A2 and B: in combination with obinutuzumab and glofitamab
14. Part III A1: To demonstrate treatment induced PD effects and mode of action of englumafusp alfa at selected doses in combination with glofitamab in comparison to glofitamab monotherapy
15. Part III A2 and B: To assess treatment induced PD effects and mode of action of englumafusp alfa in combination with glofitamab

Conditions and MedDRA coding

Relapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma (r/r B-cell NHL)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Willing and able to comply with protocol-mandated hospitalization per protocol. Participants must also be willing to comply with all study-related procedures
2. A history or status of: - a histologically-confirmed hematological malignancy that is expected to express CD19 and CD20; - certain B-cell malignancies with relapse after or failure to respond to at least one prior treatment regimen for Part I and II - certain B-cell malignancies with relapse after or failure to respond to only one prior systemic treatment regimen for Part 3 - no available treatment options that are expected to prolong survival
3. Must have at least one measureable target lesion (>= 1.5 cm) in its largest dimension by computed tomography scan
4. 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. However, in the absence of fresh biopsy, provide the most recent archival tumor tissue samples that are preferably not older than 6 months and preferably not confounded by major events. For archival biopsies formalin-fixed, paraffin-embedded blocks are preferred, but if not available, unstained slides are acceptable
5. Eastern Cooperative Oncology Group performance status of 0 or 1
6. Life expectancy of >= 12 weeks

Exclusion criteria 6

1. Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count or the presence of abnormal cells in the peripheral blood signifying circulating lymphoma cells
2. 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
3. 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
4. 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
5. History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents and auto-immune disease - Grade >= 3 AEs with the exception of Grade 3 endocrinopathy managed with replacement therapy and Grade 3 CRS which has fully resolved - Grade 1-2 AEs that did not resolve to baseline after treatment discontinuation
6. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part I/II 1. Nature and frequency of dose-limiting toxicities (DLTs)
2. Part I/II 2. Incidence, nature, and severity of adverse events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 and for CRS the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading
3. Part III 3. Investigator assessed CR rate as assessed by FDG-PET/CT scan

Secondary endpoints 27

1. Part I/II 1. Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with obinutuzumab and glofitamab
2. Part I/II 2. Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with obinutuzumab and glofitamab
3. Part I/II 3. Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with obinutuzumab and glofitamab
4. Part I/II 4. Clearance (CL), Volume of distribution of steady state (Vss) and half-life (t½) if data permit
5. Part I/II 5. Analysis of dose-linearity in exposure
6. Part I/II 6. Additional PK parameters may be determined as appropriate
7. Part I/II 7. Incidence and titer of englumafusp alfa anti-drug antibodies (ADAs) during the study relative to prevalence of ADAs at baseline
8. Part I/II 8. Overall response rate (ORR)
9. Part I/II 9. Disease control rate (DCR)
10. Part III 10. Incidence, nature, and severity of AEs graded according to the NCI CTCAE v5.0 and for CRS the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading
11. Part III 11. Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with glofitamab
12. Part III 12. Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with glofitamab
13. Part III 13. Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with glofitamab
14. Part III 14. Clearance (CL), Volume of distribution of steady state (Vss) and half-life (t½) if data permit of englumafusp alfa in combination with glofitamab
15. Part III 15. Analysis of dose-linearity in exposure
16. Part III 16. Additional PK parameters may be determined as appropriate
17. Part III 17. Incidence and titer of englumafusp alfa anti-drug antibodies (ADAs) during the study relative to prevalence of ADAs at baseline
18. Part III 18. Overall response rate (ORR)
19. Part III 19. Duration of complete response (DOCR)
20. Part III 20. Progression-free survival (PFS)
21. Part III 21. Overall survival (OS)
22. Part III 22.Time to first complete response (TFCR)
23. Part III 23. Time to first overall response (TFOR)
24. Part III 24 Change from baseline in physical function, role function, and HRQoL based on EORTC QLQ C30
25. Part III 25. Change from baseline in disease-related symptoms based on the FACT-Lym Lymphoma scale
26. Part III 26. Baseline levels and change from baseline of cellular biomarkers in blood and tumor tissue, using markers of B, and T-cell lineage
27. Part I/II 27. Baseline levels and change from baseline of cellular biomarkers in blood, using markers of B-, T- and NK-cell lineage

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 13

Locations

5 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 86 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications