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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory Indolent Adult Non-Hodgkin Lymphoma; Refractory Mantle Cell Lymphoma; Diffuse Large B-Cell Lymphoma Refractory; Refractory Transformed B-cell Non-Hodgkin Lymphoma; Refractory Primary Mediastinal Large B-Cell Cell Lymphoma
• Intervention / Treatment: Drug: Obinutuzumab; Drug: RO7082859

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Stéphanie Doyen, PhD; Phone Number: +33 (0)427012736; Email: stephanie.doyen@lysarc.org

Study Locations

• France
  • Clermont Ferrand, France, 63000
    • CHU de Clermont Ferrand
  • Créteil, France, 94010
    • Hôpital Henri Mondor
  • Dijon, France, 21034
    • CHU de Dijon - Hopital le Bocage
  • Lille, France, 59037
    • CHRU LILLE - Hôpital Claude Huriez
  • Montpellier, France, 34295
    • CHU Montpellier
  • Nantes, France, 44093
    • CHU Nantes
  • Paris, France, 75475
    • Hopital Saint Louis
  • Paris, France
    • APHP - Hopital de la Pitie Salpetriere
  • Paris, France
    • APHP - Hopital Saint Antoine
  • Pessac, France, 33604
    • CHU de Bordeaux - Hôpital Haut Leveque
  • Pierre Bénite, France, 69130
    • CHU Lyon Sud
  • Rennes, France, 35033
    • CHU de Rennes - Hôpital Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Toulouse, France, 31059
    • IUCT Oncopole
  • Vandoeuvre les Nancy, France
    • CHU de Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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. 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. 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. DLBCL with demonstrated lymphoma cells-expressing CD20 at relapse post CAR T-cells as demonstrated by biopsy before enrollment (cohort 1 only)
5. Aged 18 years or more with no upper age limit
6. ECOG performance status 0 or 1
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. No persistant CAR-T neurotoxicity symptoms or previous experience during CAR T-cells therapy of neurotoxicity grade > 3
9. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (hematological toxicities excepted)
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. 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. Adequate renal function: creatinine clearance (CrCl) calculated by MDRD/cockcroft -Gault formula of ≥ 30 mL/min
13. Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential
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. 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. 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. 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. Signed written informed consent
19. Life expectancy ≥ 3 months
20. Patient covered by any social security system
21. Patient who understands and speaks one of the country official languages

Exclusion Criteria:

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 months (30 days) 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 cardiac disease, 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 below*
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 unable 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Investigators: Study Chair: Guillaume Cartron, MD,PhD, Lymphoma Study Association; Study Chair: Pierre Sesques, MD, Lymphoma Study Association

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2021
• Primary Completion (Actual): January 10, 2023
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: January 4, 2021
• First Submitted That Met QC Criteria: January 8, 2021
• First Posted (Actual): January 11, 2021

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Post Car T-cells therapy
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Antineoplastic Agents; Antineoplastic Agents, Immunological; Obinutuzumab
• Other Study ID Numbers: BiCAR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No