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
- Trial ID
- 2022-501554-11-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 2 study is to determine the **objective response** to 6 cycles of R/G-CHOP combined with glofitamab in patients with **Richter's syndrome** (RS). This is clinically relevant as RS represents a transformation of chronic lymphocytic leukemia (CLL) into a more aggressive form of lymphoma, specifically high-grade diffuse large B-cell lymphoma (DLBCL), and effective treatment options are limited.
The secondary objectives include investigating the safety and toxicity of the treatment regimen, assessing the response to the therapy, and evaluating patient outcomes. Additionally, the study aims to explore the clonal relationship between CLL and RS and identify genetic drivers of transformation. These objectives are crucial for understanding the broader implications of the treatment and its potential impact on patient management and prognosis.
Participants
The clinical trial involves **patients with previously untreated Richter’s syndrome**, characterized by the transformation of chronic lymphocytic leukemia into high-grade lymphoma of diffuse large B-cell lymphoma histology. The study population includes both male and female participants, aged between 18 and 80 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma with biopsy-proven transformation to CD20 positive diffuse large B-cell lymphoma. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include the ability to comply with study procedures and the requirement for a fresh or archival tissue biopsy. Participants are expected to have adequate hematologic, liver, and renal function, and must have been vaccinated against the SARS-CoV-2 virus. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **glofitamab**, **rituximab**, or **obinutuzumab** plus **cyclophosphamide**, **doxorubicin**, **vincristine**, and **prednisone** (CHOP) in patients with previously untreated **Richter's syndrome**. This is a phase II, randomized, double-blind, controlled trial. The trial aims to determine the objective response to six cycles of R/G-CHOP plus glofitamab in patients with Richter's syndrome. The trial is expected to last until July 2025, with recruitment starting in July 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and hematologic and organ function. The screening will also include a biopsy to confirm the transformation to CD20 positive diffuse large B-cell lymphoma. Following the screening, participants will receive treatment over six cycles, with each cycle lasting approximately 21 days. Follow-up visits will occur after each cycle to monitor response and assess any adverse events. The end-of-study visit will evaluate the overall response and any long-term effects of the treatment.
The expected length of participant involvement is approximately 8 months, covering the treatment and follow-up period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The primary endpoint is the percentage of participants achieving a complete metabolic response, while secondary endpoints include overall response rate, progression-free survival, and overall survival. The trial will adhere to rigorous safety and efficacy assessments, ensuring that all procedures align with the highest standards of clinical research.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Glofitamab**, a solution for infusion, administered intravenously. The maximum daily dose is 30 mg, with a total maximum dose of 192 mg over a treatment period of 8 weeks. Glofitamab is a protein-based substance provided by F. Hoffmann-La Roche Ltd.
**Rituximab**, marketed as Rixathon, is a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 750 mg/m², with a total maximum dose of 750 mg/m² over a 1-week period. Rituximab is a protein-based substance provided by Sandoz GmbH.
**Obinutuzumab**, marketed as Gazyvaro, is also a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 1000 mg, with a total maximum dose of 1000 mg over a 1-week period. Obinutuzumab is a protein-based substance provided by Roche Registration GmbH.
**Cyclophosphamide**, marketed as Endoxan, is a solution for injection, administered intravenously. The maximum daily dose is 750 mg/m², with a total maximum dose of 750 mg/m² over a 1-week period. Cyclophosphamide is a chemical-based substance provided by Baxter SAS.
**Doxorubicin hydrochloride**, marketed as Doxorubicine Accord, is a solution for infusion, administered intravenously. The maximum daily dose is 50 mg/m², with a total maximum dose of 50 mg/m² over a 1-week period. Doxorubicin hydrochloride is a chemical-based substance provided by Accord Healthcare France SAS.
**Vincristine sulfate**, marketed as Oncovin, is a solution for injection, administered intravenously. The maximum daily dose is 1.4 mg/m², with a total maximum dose of 1.4 mg/m² over a 1-week period. Vincristine sulfate is a chemical-based substance provided by EG Labo Laboratoires Eurogenerics.
**Prednisone**, marketed as Cortancyl, is administered orally in tablet form. The maximum daily dose is 40 mg, with a total maximum dose of 40 mg over a 5-day period. Prednisone is a chemical-based substance provided by Cheplapharm Arzneimittel GmbH.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of these treatments in patients with Richter syndrome, with a focus on the objective response to the combination therapy.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the percentage of participants achieving a complete metabolic response (CMR) as evaluated by the investigator using the Cheson IWG 2014 Lugano Classification, specifically the Deauville scale 1-3, after six cycles of R/G-CHOP or at the point of permanent treatment discontinuation. The end of treatment is defined as the completion of six cycles of R/G-CHOP plus **glofitamab**. Permanent treatment discontinuation is characterized by the cessation of all treatments, including R/G-CHOP and glofitamab.
Secondary endpoints include the assessment of toxicity according to the CTCAE v.5 and ASTCT Consensus grading for ICANS and CRS, overall response rate (ORR) according to the Cheson IWG 2014 Lugano Classification after four and six cycles, and the complete response (CR) rate after four and six cycles. Additional secondary endpoints are progression-free survival (PFS), time to next treatment (TTNT), response duration, response regarding chronic lymphocytic leukemia (CLL) according to the iwCLL 2018 criteria, overall survival, and causes of death.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- A fresh or archival tissue biopsy is mandatory
- Previous therapy for CLL, but not for RS, is allowed
- Age greater than or equal to 18 years and less or equal to 80 years
- ECOG performance status 0-2
- 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.
- 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
- 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.
- 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).
- 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
- 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.
- Signed written informed consent 18. Patient covered by any social security system
Exclusion Criteria
- Patients with the Hodgkin variant of RS
- Patients with previously treated RS
- Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)
- Ineligible to CHOP full dose for any reason
- Previous treatment with a bispecific antibody
- 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
- 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.
- 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
- 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
- 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.
- 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)
- 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)
- 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.
- 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).
- 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
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 03 Jul 2023 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CORTANCYL 20 mg, comprimé sécable | Other | COMPRIMÉ SÉCABLE | ORAL | 40 | 5 | PRD9995018 |
Glofitamab | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 30 | 8 | PRD9870862 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 1 | PRD1753415 |
Rixathon 100 mg concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 750 | 1 | PRD6641103 |
ENDOXAN 1000 mg, poudre pour solution injectable | Other | POUDRE POUR SOLUTION INJECTABLE | INTRAVENOUS USE | 750 | 1 | PRD350186 |
ONCOVIN 1 mg, solution injectable | Other | SOLUTION INJECTABLE | INTRAVENOUS USE | 1.4 | 1 | PRD515684 |
Columvi 10 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 30 | 8 | PRD10561232 |
DOXORUBICINE ACCORD 2 mg/ml, solution pour perfusion | Other | SOLUTION POUR PERFUSION | INTRAVENOUS USE | 50 | 1 | PRD3590500 |