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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04703686
Recruitment Status : Recruiting
First Posted : January 11, 2021
Last Update Posted : June 15, 2021
Sponsor:
Information provided by (Responsible Party):
The Lymphoma Academic Research Organisation

Brief Summary:

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


Condition or disease Intervention/treatment Phase
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 Drug: Obinutuzumab Drug: RO7082859 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial Evaluating Glofitamab, a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas After CAR T-cells Therapy
Actual Study Start Date : March 30, 2021
Estimated Primary Completion Date : June 24, 2022
Estimated Study Completion Date : March 1, 2025


Arm Intervention/treatment
Experimental: Obinutuzumab + RO7082859 Drug: Obinutuzumab
1000mg - prephase - one infusion at D-3
Other Name: 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 Name: glofitamab




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: 4 years ]
    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


Secondary Outcome Measures :
  1. Metabolic response rates according to Lugano classification [ Time Frame: At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Response will be assessed by local and central review by PET scan according to Lugano classification

  2. Metabolic response rates according to Lugano classification [ Time Frame: At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Response will be assessed by local and central review by PET scan according to Lugano classification

  3. Metabolic response rates according to Lugano classification [ Time Frame: At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Response will be assessed by local and central review by PET scan according to Lugano classification

  4. Metabolic response rates according to Lugano classification [ Time Frame: At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Response will be assessed by local and central review by PET scan according to Lugano classification

  5. Progression Free Survival (PFS) [ Time Frame: At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  6. Progression Free Survival (PFS) [ Time Frame: At the end of Cycle 4 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  7. Progression Free Survival (PFS) [ Time Frame: At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  8. Progression Free Survival (PFS) [ Time Frame: At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  9. Progression Free Survival (PFS) [ Time Frame: At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  10. Duration of Response (DoR) [ Time Frame: At the end of Cycle 2 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  11. Duration of Response (DoR) [ Time Frame: At the end of Cycle 4 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  12. Duration of Response (DoR) [ Time Frame: At the end of Cycle 6 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  13. Duration of Response (DoR) [ Time Frame: At the end of Cycle 9 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  14. Duration of Response (DoR) [ Time Frame: At the end of Cycle 11 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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

  15. Quality of Life - QLQ-C30 [ Time Frame: at day 1 ]
    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),

  16. Quality of Life - FACT-Lym LymS [ Time Frame: at day 1 ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  17. Quality of Life - QLQ-C30 [ Time Frame: At Cycle 2 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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)

  18. Quality of Life - FACT-Lym LymS [ Time Frame: At Cycle 2 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  19. Quality of Life - EORTC QLQ-C30 [ Time Frame: At Cycle 3 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    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)

  20. Quality of Life _ FACT-Lym LymS [ Time Frame: At Cycle 3 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  21. Quality of Life - QLQ-C30 [ Time Frame: At cycle 5 day 1 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    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)

  22. Quality of Life _ FACT-Lym LymS [ Time Frame: At cycle 5 day 1 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  23. Quality of Life _ QLQ-C30 [ Time Frame: At Cycle 7 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    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)

  24. Quality of Life _ FACT-Lym LymS [ Time Frame: At Cycle 7 Day 1 (1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  25. Quality of Life _ QLQ-C30 [ Time Frame: At Cycle 9 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    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)

  26. Quality of Life _ FACT-Lym LymS [ Time Frame: At Cycle 9 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  27. Quality of Life _ QLQ-C30 [ Time Frame: At Cycle 11 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Lifescale measurements will be the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)

  28. Quality of Life _ FACT-Lym LymS [ Time Frame: At Cycle 11 Day 1(1st cycle of 14 days and subsequent cycles of 21 days) ]
    Quality of Life scale measurements will be the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale

  29. number of Serious Adverse Events [ Time Frame: from the date of first informed consent signature to 30 days after last administration of study drugs ]
  30. Best metabolic response assessed by local review [ Time Frame: after 11 cycles (1st cycle of 14 days and subsequent cycles of 21 days) ]
  31. Best metabolic response assessed by central review [ Time Frame: after 11 cycles (1st cycle of 14 days and subsequent cycles of 21 days) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04703686


Contacts
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Contact: Stéphanie Doyen, PhD +33 (0)427012736 stephanie.doyen@lysarc.org

Locations
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France
CHU de Clermont Ferrand Recruiting
Clermont Ferrand, France, 63000
Contact: Jacques O Bay, MD         
Principal Investigator: Jacques O Bay, MD         
Hopital Henri Mondor Recruiting
Créteil, France, 94010
Contact: Fabien Le Bras, MD         
Principal Investigator: Fabien Le Bras, MD         
CHU de Dijon - Hôpital le Bocage Recruiting
Dijon, France, 21034
Contact: Olivier Casasnovas, MD         
Principal Investigator: Olivier Casasnovas, MD         
CHRU Lille - Hôpital Claude Huriez Recruiting
Lille, France, 59037
Contact: Franck MORSCHHAUSER, MD PhD         
Principal Investigator: Franck MORSCHHAUSER, MD PhD         
CHU Montpellier Recruiting
Montpellier, France, 34295
Contact: Guillaume Cartron, MD PhD         
Principal Investigator: Guillaume Cartron, MD PhD         
CHU Nantes Recruiting
Nantes, France, 44093
Contact: Steven Le Gouill, MD PhD         
Principal Investigator: Steven Le Gouill, MD PhD         
Hôpital Saint Louis Recruiting
Paris, France, 75475
Contact: Catherine THIEBLEMONT, MD PhD         
Principal Investigator: Catherine THIEBLEMONT, MD PhD         
APHP - Hôpital de la Pitiè Salpetrière Recruiting
Paris, France
Contact: Sylvain Choquet, MD         
Principal Investigator: Sylvain Choquet, MD         
APHP - Hôpital Saint Antoine Recruiting
Paris, France
Contact: Mohamad Mohty, MD PhD         
Principal Investigator: Mohamad Mohty, MD PhD         
CHU de Bordeaux - Hôpital Haut Leveque Recruiting
Pessac, France, 33604
Contact: François X Gros, MD         
Principal Investigator: François X Gros, MD         
CHU Lyon Sud Recruiting
Pierre Bénite, France, 69130
Contact: Pierre Sesques, MD         
Principal Investigator: Pierre Sesques, MD         
CHU de Rennes - Hôpital Pontchaillou Recruiting
Rennes, France, 35033
Contact: Roch Houot, MD PhD         
Principal Investigator: Roch Houot, MD PhD         
Centre Henri Becquerel Recruiting
Rouen, France, 76038
Contact: Hervé Tilly, MD PhD         
Principal Investigator: Hervé Tilly, MD PhD         
IUCT Oncopole Recruiting
Toulouse, France, 31059
Contact: Loïc Ysebaert, MD PhD    + 33 (0)5 61 77 20 78    ysebaert.loic@iuct-oncopole.fr   
Principal Investigator: Loïc Ysebaert, MD PhD         
CHU de Brabois Recruiting
Vandoeuvre les Nancy, France
Contact: Pierre Feugier, MD         
Principal Investigator: Pierre Feugier, MD         
Sponsors and Collaborators
The Lymphoma Academic Research Organisation
Investigators
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Study Chair: Guillaume Cartron, MD,PhD Lymphoma Study Association
Study Chair: Pierre Sesques, MD Lymphoma Study Association
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Responsible Party: The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier: NCT04703686    
Other Study ID Numbers: BiCAR
First Posted: January 11, 2021    Key Record Dates
Last Update Posted: June 15, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The Lymphoma Academic Research Organisation:
Post Car T-cells therapy
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Obinutuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents