FILOCLL015 - GLORIFY - A phase 2 study evaluating the bispecific CD3xCD20 antibody GLOfitamab in combination with rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in patients with RIchter syndrome as Frontline therapY

Overview

Sponsor-declared trial summary

Key facts

Sponsor

French Innovative Leukemia Organization

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

21 Mar 2024 → ongoing

Decision date (initial)

2023-08-28

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

The primary objective is to determine the objective response regarding the RS to 6 cycles of R/G-CHOP + glofitamab in patients with RS.

Secondary objectives 1

1. The secondary objectives are to investigate the safety and toxicity of 6 cycles R/G-CHOP + glofitamab, the response to 6 cycles of R/G-CHOP + glofitamab and the patient outcome. Our study also includes an exploratory objective aiming at deciphering the clonal relationship between CLL and RS and uncovering genetic drivers of transformation.

Conditions and MedDRA coding

Patients with previously untreated Richter’s syndrome (RS), defined as the transformation of chronic lymphocytic leukemia (CLL) into high-grade lymphoma of diffuse large B-cell lymphoma (DLBCL) histology.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma according to the revised iwCLL criterias with biopsy proven transformation to CD20 positive diffuse large B-cell lymphoma, consistent with RS according to the 2016 WHO classification.
2. 2. A fresh or archival tissue biopsy is mandatory
3. 3. Previous therapy for CLL, but not for RS, is allowed
4. 4. Age greater than or equal to 18 years and less or equal to 80 years
5. 5. ECOG performance status 0-2
6. 6. Participants must have at least one measurable target lesion (> 1.5 cm) in its largest dimension by computed tomography (CT) scan. Measurable disease, defined as at least one bi-dimensionally measurable nodal or tumor lesion, defined as >1.5 cm in its longest dimension or PET-CT with at least one hypermetabolic lesion. Patients without measurable disease but with proven bone marrow infiltration by the RS are eligible.
7. 7. Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of either CLL or RS cells confirmed on biopsy: absolute neutrophil count ≥1.5 G/L, hemoglobin >10 g/dL, platelet count ≥75 G/L and independent of transfusion within 7 days of screening 8. Subject must have adequate coagulation tests: Prothrombin Time > 50%, Fibrinogen > 1 g/L 9. Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN
8. 10. Adequate left ventricular ejection function (≥ 50 %) 11. Adequate renal function: creatinine clearance calculated by MDRD/Cockcroft-Gault formula of ≥ 40 mL/min 12. Negative serologic or PCR test results for acute or chronic HBV infection 13. Negative test results for HCV and HIV.
9. 14. Prior vaccination to the SARS-Cov-2 virus and SARS-CoV-2 PCR testing and negative result before study treatment administration at each treatment cycle if clinically indicated (in the event of clinical or biological symptoms that may suggest SAR-Cov-2S infection (e.g. fever, cough, headache, fatigue, increased neutrophil count, CRP, etc.). There is no obligation to perform the test in the absence of clinical and/or biological signs).
10. 15. Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential. 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
11. 16. Ability to understand and the willingness to sign a written informed consent document. 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.
12. 17. Signed written informed consent 18. Patient covered by any social security system

Exclusion criteria 16

1. 1. Patients with the Hodgkin variant of RS
2. 2. Patients with previously treated RS
3. 3. Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)
4. 4. Ineligible to CHOP full dose for any reason
5. 5. Previous treatment with a bispecific antibody
6. 6. Current or past history of DLBCL in the CNS (confirmed by CSF analysis) 7. Steroids treatment (> 1 mg/kg/d for one week) before inclusion 8. History of anaphylactic reactions to human, chimeric, or mouse monoclonal antibodies or to any components of the product. 9. Prior allogeneic HSCT
7. 10. Patients with known acute infection or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, Epstein-Barr virus (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) within 4 weeks prior to the first study treatment.
8. 11. History of other malignancies, except: i) malignancy treated with curative intent and with no recurrence over the last 3 years ii) adequately treated non-melanoma skin cancer without evidence of disease iii) adequately treated carcinoma in situ without evidence of disease 12. Prior solid organ transplantation
9. 13. 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
10. 14. Current uncontrolled autoimmune disease 15. History of human immunodeficiency virus 16. Hepatitis B or C seropositivity (unless clearly due to vaccination) 17. Pregnant or breastfeeding women 18. Unwilling or unable to participate in all required study evaluations and procedures.
11. 19. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information (in accordance with national and local subject privacy regulations)
12. 20. Any serious psychiatric illness that would prevent the subject from signing the informed consent form. 21. Adult under law-control. 22. Fertile male patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study. 23. Patients with history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)
13. 24. LVEF < 50% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan, significant or extensive cardiovascular disease such as New York HeartAssociation Class III or IV cardiac disease or Objective Assessment Class C or D,myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina.
14. 25. Abnormal screening laboratory values as defined as following: a) ALT (SGOT) and/or ALT (SGPT) and/or ALP > or = 3 x upper limit of normal (ULN); b) Total bilirubin > or = 1.5 x ULN, unless due to Gilbert's disease; c) Creatinine > or = 2.0 x ULN or creatinine clearance < 40 mL/min (calculated).
15. 26. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML) 27. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins) 28. 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
16. 29. 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 30. Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion 31. Treatment with another investigational agent or participating in another trial within 30 days prior to entering the study 32. Clinically significant history of liver disease or cirrhosis 33. Pregnant or breast-feeding or intending to become pregnant during the study 34. No affiliation to social security 35. Inability to comply with protocol mandated hospitalization and restrictions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of participants with a complete metabolic response (CMR) as assessed by the investigator using the Cheson IWG 2014 Lugano Classification (i.e. Deauville scale 1-3)50 after 6 cyles of R/G-CHOP or at permanent treatment discontinuation. End of treatment is defined as after 6 cycles of R/G-CHOP + glofitamab. Permanent treatment discontinuation is defined as the discontinuation of all treatments (R/G-CHOP, glofitamab).

Secondary endpoints 6

1. • Toxicity according to the CTCAE v.5 and ASTCT Consensus grading for ICANS and CRS
2. • Overall response rate (ORR) according to Cheson IWG 2014 Lugano Classification (i.e. Deauville scale 1-3) after 4 and 6 cycles
3. • CR rate after 4 and 6 cycles according to Cheson IWG 2014 Lugano Classification (i.e. Deauville scale 1-3)
4. • Progression free survival (PFS)
5. • Time to next treatment (TTNT)
6. • Response duration • Response regarding CLL according to the iwCLL 2018 criteria • Overall survival • Causes of death

Investigational products

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

Test 3

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

French Innovative Leukemia Organization

Sponsor organisation

French Innovative Leukemia Organization

Address

2 Boulevard Tonnelle

City

Tours

Postcode

37000

Country

France

Scientific contact point

Organisation

French Innovative Leukemia Organization

Contact name

Pr GUIEZE

Public contact point

Organisation

French Innovative Leukemia Organization

Contact name

French Innovative Leukemia Organization

Third parties 4

Locations

1 EU/EEA country · 29 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

Documents 13 files

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

Application history

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