BiCAR Therapy - A Phase II Trial Evaluating Glofitamab, a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas after CAR T-cells therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lysarc

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

26 Mar 2021 → 21 May 2025

Decision date (initial)

2023-11-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508301-25-00

EudraCT number

2020-001985-12

ClinicalTrials.gov

NCT04703686

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of the study is to assess the anti-lymphoma activity of glofitamab, a bispecific CD3xCD20 monoclonal antibody in patients with relapse/refractory (R/R) DLBCL (cohort 1) disease after anti-CD19 CAR T-cells therapy.

Secondary objectives 3

1. To evaluate safety and tolerability of glofitamab after CAR T-cells therapy fail
2. To assess the efficacy of glofitamab in patients in relapse/refractory after anti- CD19 CAR T-cells therapy with respect to: o Result of PET-CT at each evaluation according to local and central review o Overall Metabolic Response Rate (OMRR) after 2 cycles, after 6 cycles, after cycle 9 and after 11 cycles of glofitamab, or at permanent treatment discontinuation whichever occurs first according to Lugano 2014 response criteria (PET-CT based) assessed by local and central review o Best metabolic response and overall best metabolic response rate will be estimated at the end of treatment (defined as after 11 cycles of glofitamab or at permanent treatment discontinuation whichever occurs first) according to Lugano 2014 response criteria (PET-CT based) assessed by local and central review o Progression Free Survival (PFS) o Duration of Response (DoR), defined from the time of first CMR or PMR (according to Lugano criteria) to the date of first documented disease progression, relapse or death from any cause whichever occurs first
3. To assess 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) and the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale.

Conditions and MedDRA coding

Relapse/Refractory Lymphomas

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. 1. Patients who received CAR T-cells therapy for R/R DLBCL (cohort 1) or R/R PMBL, mantle cell lymphoma, t-iNHL or iNHL (cohort 2), at least 1 month ago
2. 2. Patients who are not at least in partial metabolic response from 1 month after CAR T-cells infusion (i.e no metabolic response or first metabolic progressive disease or first relapse from 1 month after CAR T-cells infusion)
3. 3. First metabolic progression, first relapse or no metabolic response after CAR T-cells infusion must be confirmed by PET-CT central review for enrollment
4. 4. DLBCL with demonstrated lymphoma cells-expressing CD20 at relapse post CAR T-cells as demonstrated by biopsy before enrollment (cohort 1 only)
5. 5. Aged 18 years or more with no upper age limit
6. 6. ECOG performance status 0 or 1
7. 7. Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan, or PET-CT with at least one hypermetabolic lesion
8. 8. No persistant CAR-T neurotoxicity symptoms or previous experience during CAR T-cells therapy of neurotoxicity grade > 3
9. 9. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (hematological toxicities excepted)
10. 10. Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN Note: Patients with documented history of Gilbert’s Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible)
11. 11. Adequate hematological function: Neutrophil count of ≥ 1.0 G/L; Platelet count of ≥ 50 G/L (and platelet transfusion free within 14 days prior to administration of obinutuzumab); Hemoglobin (Hb) ≥ 8.0 g/dL (transfusion free within 21 days prior to administration of obinutuzumab) Note: patients who do not meet the above hematologic criteria, due to extensive tumor involvement in the marrow may be enrolled into the trial after the demonstration of involvement and consultation with the LYSARC. Please consult the LYSARC on the need for transfusion support within 21 days of obinutuzumab.
12. 12. Adequate renal function: creatinine clearance (CrCl) calculated by MDRD/Cockroft-Gault formula of ≥ 30 mL/min 13.
13. 13. Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential.
14. 14. Negative serologic or PCR test results for acute or chronic HBV infection. Note: Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation.
15. 15. Negative test results for HCV and HIV. Note: Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
16. 16. Patients must agree to either remain completely abstinent or to use two effective contraceptive methods until: - If the patient is a male: at least 3 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer Men must refrain from donating sperm during this same period - If patient is a female of childbearing potential: until at least 18 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer
17. 17. Patient must be willing and able to comply with protocol-mandated hospitalization upon administration of the first dose of glofitamab. Patient must also be willing to comply with all study-related procedures.
18. 18. Signed written informed consent
19. 19. Life expectancy ≥ 3 months
20. 20. Patient covered by any social security system
21. 21. Patient who understands and speaks one of the country official languages
22. 22. Patient with a vaccination status in line with French National guidelines/recommendations (COSV, ANRS MIE)
23. 23. Patient must agree to perform a SARS-CoV-2 PCR test within 48 hours prior administration of obinutuzumab, then C2 and each subsequent cycle of glofitamab

Exclusion criteria 29

1. Previously known CD20 negative status, excepted if a new biopsy for cohort 1 or biopsy or cytometry analysis for cohort 2 proving a CD20 positive status is available before enrollment
2. Patients with CLL, Richter and Burkitt lymphoma.
3. Patients relapsing or progressing within 1 month after CAR T-cells therapy
4. History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows: - Grade ≥ 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy - Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation
5. Current or past history of detectable cerebrospinal fluid lymphoma cells, or with a history of CNS lymphoma localization or primary CNS lymphoma.
6. Current or past history of cerebral disorders
7. Any serious psychiatric illness that would prevent the subject from signing the informed consent form
8. Patients with history of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)
9. Patients with known acute infection or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, EBV, cytomegalovirus (CMV), hepatitis B, hepatitis C, 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) in 2 week prior to enrollment.
10. LVEF < 40% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan or significant cardiovascular disease such as New York Heart Association Class III or IV or Objective Class C or D cardiac disease (see appendix 16), myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina
11. Any serious active disease or co-morbid medical condition
12. Clinically significant history of liver disease or cirrhosis
13. Prior history of malignancies other than lymphoma unless the subject has been free of the disease for ≥ 3 years. Exceptions will be allowed for patients with non-melanoma skin tumors (basal cell or squamous cell carcinoma of the skin) or any surgically removed stage 0 (in situ) carcinoma
14. Prior solid organ transplantation.
15. Prior allogeneic SCT
16. Autologous SCT within 100 days prior to obinutuzumab infusion
17. Current uncontrolled autoimmune disease Note: History of autoimmune disease currently controlled and stable is acceptable for such therapy. See detailed description in paragraphe 8.2
18. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
19. Major surgery or significant traumatic injury < 28 days prior to the obinutuzumab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment
20. Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion
21. Treatment between infusion of CAR T-cells and pre-phase (i.e. obinutuzumab infusion on C1/D-3): with standard radiotherapy, systemic immunotherapeutic agents, any chemotherapeutic agent, any systemic immunosuppressive medications or treatment with any other investigational anti-cancer agent (defined as treatment for which there is currently no regulatory authority approved indication). Note: with the exception of corticosteroid treatment < 25 mg/day prednisone or equivalent. Inhaled and topical steroids are permitted
22. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
23. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
24. History of illicit drug or alcohol abuse within 12 months prior to enrollment
25. Person deprived of his/her liberty by a judicial or administrative decision
26. Inability to comply with protocol mandated hospitalization and restrictions.
27. Adult person under legal protection
28. Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness
29. Pregnant or breast-feeding or intending to become pregnant during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Survival (OS).

Secondary endpoints 6

1. tolerability of glofitamab
2. Overall Metabolic Response Rate (OMRR)
3. Best metabolic response and overall best metabolic response rate
4. Progression Free Survival (PFS)
5. Duration of Response (DoR),
6. HRQoL)

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lysarc

Sponsor organisation

LYSARC

Address

2d Lyon Sud Batiment

City

Pierre Benite

Postcode

69495

Country

France

Scientific contact point

Organisation

LYSARC

Contact name

Coordinating Investigator

Public contact point

Organisation

LYSARC

Contact name

Project Management

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 14 files

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

Application history

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