Relapsed /Refractory DLBCL
Conditions
Brief summary
The Double-T trial is a prospective, randomized, single-arm, open-label, multicenter phase II trial investigating a double T-cell therapy strategy, which includes glofitamab with gemcitabine/oxaliplatin (Glofi-Gem/Ox) prior to and glofitamab monotherapy consolidation after standard of care Chimeric Antigen Receptor (CAR)-T cell therapy in high-risk 2nd line relapsed/refractory Large B-Cell Lymphoma (r/r LBCL) patients. Data on safety, efficacy, and quality of life (QoL) will be collected and analyzed.
Interventions
DRUGGlofitamab, Gemcitabine, and Oxaliplatin as Induction Therapy
Induction Therapy before Standard of Care CAR-T Cell therapy
DRUGGlofitamab as Consolidation therapy
Consolidation with Glofitamab after CAR-T Cell Therapy
Sponsors
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Universitätsklinikum Düsseldorf, Germany
Roche Pharma AG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patient\* has given written informed consent. 2. Patient is 18-80 years of age at time of signing the written informed consent 3. Patient has histologically confirmed diagnosis of large B-cell lymphoma by local pathologist at time of relapse. 4. Patient received R-CHOP based first-line therapy containing a CD20-antibody and anthracyclines. 5. Patient has relapsed/refractory disease, defined as follows: * Relapsed: disease that had recurred following partial or complete response (PR/CR) within 12 months of adequate first-line therapy * Refractory: disease that did not respond to, or that progressed \<6 months after, completion of first-line therapy 6. Patient has at least one FDG-PET positive bi-dimensionally measurable (≥1.5 cm) nodal lesion, or one bi dimensionally measurable (\>1 cm extranodal lesion, as measured on computed tomography (CT) scan 7. Patient has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2 8. Patient has an absolute lymphocyte count \> 200/µL 9. Patient is eligible for CAR-T cell therapy as per investigator´s discretion meeting all of the following criteria of adequate organ function: 1. Adequate kidney function, defined as: Serum creatinine estimated glomerular filtration rate (MDRD) ≥ 60 mL/min. 2. Adequate hepatic function, defined as: ALAT and ASAT ≤ 5 ULN. Bilirubin ≤ 2.0 mg/dl (except for Meulengracht disease) 3. Adequate bone marrow function, defined as: Absolute neutrophil count (ANC) ≥ 1000/µL, Platelets ≥ 50.000/µL and Hemoglobin \> 8.0 g/dL. 4. Adequate cardiac function, defined as: Cardiac ejection fraction ≥ 45%. 5. Adequate pulmonary function as per investigators discretion 10. Patient successfully performed MNC-leucapheresis procedure for a commercially available CAR-T-cell product 11. Patient is willing and able to provide baseline biopsy material (archival or fresh tumor sample) for central review 12. Male patients with female partners of childbearing potential are eligible to participate if they agree to contraceptive methods throughout the duration of the trial and at least 18 months after obinutuzumab administration, 12 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last 13. Female participants of childbearing potential must agree to use a highly effective method of contraception (e.g., hormonal contraception, intrauterine device (IUD), or surgical sterilization) throughout the duration of the trial and at least 18 months after obinutuzumab administration, 15 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last. \* There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the trial gender-independently
Exclusion criteria
1. Patient has HIV infection of any stage as determined by presence of anti-HIV antibodies (confirmatory test) and / or presence of RNA confirmed by PCR during screening 2. Patient has previous or concurrent malignancies with the following exceptions: 1. Surgically cured carcinoma in-situ 2. Other kinds of cancer without evidence of disease for at least 3 years 3. Patient has known hypersensitivity to any component of the Glofitamab, Obinutuzumab, Yescarta and/or Breyanzi formulation formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the other trial drugs 4. Patient has severe active infection requiring iv treatment within 14 days prior first dose of study drugs 5. Patient has congenital or acquired immunodeficiency including previous organ or allogeneic stem cell transplantation 6. Patient received prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3 7. Patient received prior treatment with gemcitabine and oxaliplatin in prior lymphoma treatment line 8. Patient had a major surgery within 4 weeks prior to first dose of study drugs 9. Patient has primary or secondary central nervous system (CNS) lymphoma at the time of enrollment or history of CNS lymphoma 10. Patient has current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease 11. Patient has significant or extensive cardiovascular disease such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina 12. Patient has an active autoimmune disease requiring systemic treatment 13. Patient receives ongoing corticosteroid use \>20 mg/day of prednisone or equivalent. Patients on stable low-dose corticosteroids (≤20 mg/day of prednisone or equivalent for at least 7-14 days prior to first IMP administration) or on short courses of higher-dose corticosteroids that are completed before first IMP administration are eligible. 14. Female patients who are pregnant or breast feeding or planning to become pregnant within up to 18 months after start of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of trial treatment. 15. Patient has a relationship of dependence or employer-employee relationship to the sponsor or the investigator 16. Patient lacks accountability and inability to appreciate the nature, meaning and consequences of the trial 17. Patient is non-compliant, for reasons including, but not limited to the following: * Increased alcohol consumption, drug dependency or substance abuse that would interfere with cooperation with requirements of the trial * Refusal of blood products during treatment * Any similar circumstances that appear to make protocol treatment or follow-up impossible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CRR@EOT | at the end of trial treatment, on average after 10 months | Complete response rate (CRR) at end of treatment (CCR@EOT), defined as proportion of patients who achieved complete response (CR) at the end of trial treatment (EOT) as per Lugano classification |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CCR@pIT and CCR@3MpCT | post induction (after 6 weeks) and 3 months post-CAR-T cell infusion (after 4,5 months) | CRR post induction (CCR@pIT) and at 3 months post-CAR-T cell infusion (CCR@3MpCT), defined as proportion of patients who achieved complete response after two cycles induction treatment and 3 months after CAR-T cell infusion as per Lugano classification |
| Overall CRR | from first Investigational Medicinal Product (IMP) administration until end of follow-up, on average 2,5 years | Overall CRR, defined as proportion of patients who achieved CR as best overall response (BOR) |
| ORR post induction, at 3 months post-CAR-T cell infusion, and at EOT | post induction (after 6 weeks), at 3 months post-CAR-T cell infusion (after 4,5 months), and at end of trial treatment (on average after 10 months) | Objective Response rate (ORR) post induction (OOR@pIT), at 3 months post-CAR T cell infusion (ORR@3MpCT) and at end of trial treatment (ORR@EOT), defined as proportion of patients who achieved complete or partial response (CR/PR) after 2 cycles of induction treatment, at 3 months after CAR-T cell infusion and at the end of the treatment |
| Overall ORR | from first IMP administration until end of follow-up, on average 2,5 years | Overall ORR, defined as proportion of patients who achieved CR/PR as BOR |
| Best overall response (BOR) rate | from first IMP administration until end of follow-up, on average 2,5 years | Best overall response (BOR) rate |
| PFS | from first IMP administration until end of follow-up, on average 2,5 years | Progression-free survival (PFS) plus PFS rate at one and two years, defined as time from start of treatment until date of progression or death due to any cause |
| OS | from first IMP administration until end of follow-up, on average 2,5 years | Overall survival (OS) plus OS rate at one and two years, defined as time from start of treatment until death due to any cause |
| CAR-T cell expansion | from CAR-T Cell infusion until End of treatment visit (on average after 10 months) | Quantification of peak CAR-T cell expansion in peripheral blood following glofitamab consolidation (measured by flow cytometry and/or qPCR for CAR transgene) |
| Time to peak CAR-T cell expansion post-infusion | from CAR-T Cell infusion until End of treatment visit (on average after 10 months) | Time to peak CAR-T cell expansion post-infusion |
| CAR-T cell persistence | from CAR-T Cell infusion until End of treatment visit (on average after 10 months) | Duration of CAR-T cell persistence in peripheral blood (up to end of evaluation period or loss of detectability) |
| Correlation between CAR-T cell expansion/persistence and clinical response | End of study, after 3 years | Correlation between CAR-T cell expansion/persistence and clinical response (e.g., CR, PR, PFS) |
| Quality of life (QLQ-C30) | From Screening until End of treatment visit (on average after 10 months) | Quality of life (QoL) over time as determined by EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a widely used, validated, 30-question, self-report questionnaire designed to assess the quality of life of cancer patients. It covers functional scales, symptom scales, and global health status. The questionnaire uses a Likert scale for responses, typically ranging from 1 ("Not at all") to 4 ("Very much"). Global health status/QoL is scaled from 1 ("very poor") to 7 ("Excellent"). The data collected is used to score 10 subscales, providing a multidimensional overview of a patient's quality of life. |
| Adverse events | from first IMP administration until end of follow-up, on average 2,5 years | Assessment of safety of the treatment as determined by the incidence, type, causality, frequency, timing, severity and seriousness of adverse events using NCI CTCAE 6.0 |
| Adverse events of special interest | from first IMP administration until end of follow-up, on average 2,5 years | Incidence of AEs of special Interest (AESIs) as defined in protocol |
| Proportion of patients completing all planned cycles (Tolerability) | from first IMP administration until end of treatment, on average 10 months | Tolerability as determined by proportion of patients completing all planned cycles |
Countries
Germany
Contacts
CONTACTBirte Friedrichs, Dr.
CONTACTJohanna Riedel
PRINCIPAL_INVESTIGATORSascha Dietrich, Prof. Dr.
University Düsseldorf
STUDY_CHAIRSalah-Eddin Al-Batran, Prof. Dr.
Frankfurter Institut für Klinische Krebsforschung IKF GmbH
Outcome results
None listed