Treatment by a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas After CAR T-cells Therapy

Study Overview
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Brief Summary
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This study is a multicenter phase II trial including 2 cohorts of patients in Refractory/Relapse disease at least 1 month after CAR T-cells therapy: cohort 1: DLBCL patients cohort 2: PMBL, mantle cell lymphoma, transformed indolent NHL (t-iNHL) or iNHL CAR T-cells Refractory/Relapse status will be determined by PET-CT central review allowing inclusion in this trial. Patients enrolled will then receive a pre-phase of obinutuzumab followed by experimental treatment:11 cycle of glofitamab. 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 DLBCL (cohort 1) disease after anti-CD19 CAR T-cells therapy

Official Title
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A Phase II Trial Evaluating Glofitamab, a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas After CAR T-cells Therapy

Conditions
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Diffuse Large B-Cell Lymphoma Refractory, Refractory Indolent Adult Non-Hodgkin Lymphoma, Refractory Transformed B-cell Non-Hodgkin Lymphoma, Refractory Primary Mediastinal Large B-Cell Cell Lymphoma, Refractory Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: RO7082859


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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) First metabolic progression, first relapse or no metabolic response after CAR T-cells infusion must be confirmed by PET-CT central review for enrollment DLBCL with demonstrated lymphoma cells-expressing CD20 at relapse post CAR T-cells as demonstrated by biopsy before enrollment (cohort 1 only) Aged 18 years or more with no upper age limit ECOG performance status 0 or 1 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 No persistant CAR-T neurotoxicity symptoms or previous experience during CAR T-cells therapy of neurotoxicity grade > 3 Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (hematological toxicities excepted) 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) 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 Adequate renal function: creatinine clearance (CrCl) calculated by MDRD/cockcroft -Gault formula of ≥ 30 mL/min Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential 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 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 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 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 Life expectancy ≥ 3 months Patient covered by any social security system Patient who understands and speaks one of the country official languages Exclusion Criteria: 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 Patients with CLL, Richter and Burkitt lymphoma Patients relapsing or progressing within 1 months (30 days) after CAR T-cells therapy 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 or past history of detectable cerebrospinal fluid lymphoma cells, or with a history of CNS lymphoma localization or primary CNS lymphoma Current or past history of cerebral disorders Any serious psychiatric illness that would prevent the subject from signing the informed consent form. Patients with history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH) 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 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 cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) Any serious active disease or co-morbid medical condition Clinically significant history of liver disease or cirrhosis 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 Prior solid organ transplantation Prior allogeneic SCT Autologous SCT within 100 days prior to obinutuzumab infusion Current uncontrolled autoimmune disease Note: History of autoimmune disease currently controlled and stable is acceptable for such therapy. See detailed description below* 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 Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion 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 Patient with history of confirmed progressive multifocal leukoencephalopathy (PML) History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins) History of illicit drug or alcohol abuse within 12 months prior to enrollment Person deprived of his/her liberty by a judicial or administrative decision Inability to comply with protocol mandated hospitalization and restrictions Adult person under legal protection Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness Pregnant or breast-feeding or intending to become pregnant during the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab + RO7082859<br> | Drug: Obinutuzumab<br>* 1000mg - prephase - one infusion at D-3<br>* Other names: gazyva;Drug: RO7082859<br>* 2.5 mg D1C1, 10 mg D3C1, then 30 mg D8C1 and D1 every 21 days (C2-C11, D1C2 starts 14 days after D1C1)<br>* Other names: glofitamab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival will be measured from the date of C1D1 of glofitamab to the date of death from any cause. Alive patients will be censored at the date of last contact | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic response rates according to Lugano classification | Response will be assessed by local and central review by PET scan according to Lugano classification | At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Metabolic response rates according to Lugano classification | Response will be assessed by local and central review by PET scan according to Lugano classification | At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Metabolic response rates according to Lugano classification | Response will be assessed by local and central review by PET scan according to Lugano classification | At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Metabolic response rates according to Lugano classification | Response will be assessed by local and central review by PET scan according to Lugano classification | At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Progression Free Survival (PFS) | PFS is defined as the time from enrollment into the study to the first observation of documented disease progression based on central review or death due to any cause | At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Progression Free Survival (PFS) | PFS is defined as the time from enrollment into the study to the first observation of documented disease progression based on central review or death due to any cause | At the end of Cycle 4 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Progression Free Survival (PFS) | PFS is defined as the time from enrollment into the study to the first observation of documented disease progression based on central review or death due to any cause | At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Progression Free Survival (PFS) | PFS is defined as the time from enrollment into the study to the first observation of documented disease progression based on central review or death due to any cause | At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Progression Free Survival (PFS) | PFS is defined as the time from enrollment into the study to the first observation of documented disease progression based on central review or death due to any cause | At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Duration of Response (DoR) | DoR is 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. If a subject has not progressed or died, DoR will be censored at the date of tumor assessment | At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Duration of Response (DoR) | DoR is 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. If a subject has not progressed or died, DoR will be censored at the date of tumor assessment | At the end of Cycle 4 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Duration of Response (DoR) | DoR is 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. If a subject has not progressed or died, DoR will be censored at the date of tumor assessment | At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Duration of Response (DoR) | DoR is 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. If a subject has not progressed or died, DoR will be censored at the date of tumor assessment | At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Duration of Response (DoR) | DoR is 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. If a subject has not progressed or died, DoR will be censored at the date of tumor assessment | At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life - QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), | at day 1 | 
| Quality of Life - FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | at day 1 | 
| Quality of Life - QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At Cycle 2 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life - FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At Cycle 2 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life - EORTC QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At Cycle 3 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At Cycle 3 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life - QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At cycle 5 day 1 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At cycle 5 day 1 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At Cycle 7 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At Cycle 7 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ QLQ-C30 | Quality of Life scale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At Cycle 9 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At Cycle 9 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ QLQ-C30 | Quality of Lifescale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At Cycle 11 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| Quality of Life _ FACT-Lym LymS | Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale | At Cycle 11 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) | 
| number of Serious Adverse Events |  | from the date of first informed consent signature to 30 days after last administration of study drugs | 
| Best metabolic response assessed by local review |  | after 11 cycles (1st cycle of 14 days and subsequent cycles of 21 days) | 
| Best metabolic response assessed by central review |  | after 11 cycles (1st cycle of 14 days and subsequent cycles of 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post Car T-cells therapy