ZAMTOCABTAGENE AUTOLEUCEL for Relapsed/refractory diffuse large B-cell lymphoma

Inclusion criteria

• {"criterion_text":"- 1. Part I: Histologically proven DLBCL and associated subtypes, according to the World Health Organization (WHO) 2016 classification"}
• {"criterion_text":"- 7. Part I: Measurable disease according to Lugano criteria. The lesion must be measurable (nodes > 1.5 cm in the long axis; extranodal lesions > 1 cm in the long axis) and positive on a positron emission tomography scan"}
• {"criterion_text":"- 8. Part I: Estimated life expectancy of > 3 months for other reasons than the primary disease"}
• {"criterion_text":"- 9. Part I: Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive measures"}
• {"criterion_text":"- 1.\tPart II: Histologically proven DLBCL and associated subtypes, according to the WHO 2016 classification."}
• {"criterion_text":"- 2.\tPart II: Relapsed or refractory disease after first-line chemoimmunotherapy."}
• {"criterion_text":"- 3.\tPart II: Participant must have received adequate first-line therapy containing at least the combination of an anthracycline based regimen and rituximab (anti CD20 monoclonal antibody)."}
• {"criterion_text":"- 4.\tPart II: Archival paraffin embedded tumour tissue acquired ≤ 2 years (preferred: ≤ 2 months) prior to screening for the central pathology review to confirm DLBCL diagnosis must be made available for participation in this study."}
• {"criterion_text":"- 5.\tPart II: Measurable disease according to Lugano criteria. The lesion must be measurable (nodes > 1.5 cm in the long axis; extranodal lesions > 1 cm in the long axis) and positive on a positron emission tomography scan."}
• {"criterion_text":"- 6.\tPart II: Approved treatment options not suitable according to investigator’s assessment."}
• {"criterion_text":"- 7.\tPart II: Age ≥ 18 and ≤ 70 years."}
• {"criterion_text":"- 10. Part I: Men with non-pregnant WOCBP partners must agree to use highly effective contraceptive measures"}
• {"criterion_text":"- 8.\tPart II: Estimated life expectancy of > 3 months for other reasons than the primary disease."}
• {"criterion_text":"- 9.\tPart II: ECOG 0-1."}
• {"criterion_text":"- 10.\tPart II: Adequate bone marrow function, defined as: \t• Absolute neutrophil count ≥ 1,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy). \tPlatelet count ≥ 50,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy). •\tAbsolute lymphocyte count ≥ 100/µL."}
• {"criterion_text":"- 11.\tPart II: Adequate organ function, defined as: •\tNew York Heart Association class < 2 or LVEF ≥ 50%. •\tNo severe cardiac arrhythmias or QT prolongation (resting QTcF < 450 msec [male] or < 460 msec [female] at screening). •\tNo clinically relevant pleural effusion or pericardial effusion. •\tResting peripheral oxygen saturation ≥ 92% on room air. •\tTotal bilirubin ≤ 2.0 × ULN, AST and/or ALT ≤ 5 × ULN. •\tSerum creatinine < 1.0 × ULN or eGFR (according to modified MDRD formula) ≥ 60 mL/min."}
• {"criterion_text":"- 12.\tPart II: WOCBP must agree to use highly effective contraceptive measures"}
• {"criterion_text":"- 13.\tMen with non-pregnant WOCBP partners must agree to use highly effective contraceptive measures."}
• {"criterion_text":"- 14.\tPart II: In the opinion of the investigator, the participant must be able to comply with all study related procedures, medication use and evaluations."}
• {"criterion_text":"- 15.\tPart II: Mental capacity and legal ability to consent to participation in the clinical study."}
• {"criterion_text":"- 11. Part I: In the opinion of the investigator, the participant must be able to comply with all study-related procedures, medication use and evaluations"}
• {"criterion_text":"- 12. Part I: Mental capacity and legal ability to consent to participation in the clinical study."}
• {"criterion_text":"- 2. Part I: Relapsed or refractory disease after first-line chemoimmunotherapy"}
• {"criterion_text":"- 3. Part I: Participants must have received adequate first-line therapy containing at least the combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal antibody)."}
• {"criterion_text":"- 4. Part I: Archival paraffin-embedded tumour tissue acquired ≤ 2 years (preferred: ≤ 2 months) prior to screening for the central pathology review to confirm DLBCL diagnosis must be made available for participation in this study. The lesion must be measurable (nodes > 1.5 cm in the long axis; extranodal lesions > 1 cm in the long axis) and positive on a positron emission tomography scan."}
• {"criterion_text":"- 5. Part I: Participants deemed ineligible to receive HDC followed by ASCT based on the treating physician’s assessment"}
• {"criterion_text":"- 6. Part I: Age ≥ 18 years"}

Exclusion criteria

• {"criterion_text":"- 1. Part I: Contraindications for R-GemOx, BR plus polatuzumab vedotin, cyclophosphamide and fludarabine as judged by the treating physician."}
• {"criterion_text":"- 2. Part I: Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy."}
• {"criterion_text":"- 3. Part I: Participants who have received more than one line of treatment for DLBCL or associated subtypes."}
• {"criterion_text":"- 4. Part I: Prior haematopoietic stem cell transplantation (HSCT; as first-line consolidation) < 3 months at the time of leukapheresis."}
• {"criterion_text":"- 5. Part I: ECOG performance status (PS) > 2"}
• {"criterion_text":"- 1. Part II: Contraindications for cyclophosphamide and fludarabine as judged by the treating physician."}
• {"criterion_text":"- 2. Part II: Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy."}
• {"criterion_text":"- 3.\tPart II: Participants who have received more than one line of prior therapy for DLBCL or associated subtypes."}
• {"criterion_text":"- 4.\tPart II: Prior HSCT (as first-line consolidation) < 3 months at the time of leukapheresis."}

Primary endpoints

• {"endpoint_text":"- Part I: Event-free survival (EFS), defined as the time between the date of randomisation and the date of objective disease progression, failure to achieve partial response (PR) or complete response (CR) at or beyond Week 8 after randomisation leading to a new anti-lymphoma therapy or death of any cause, whichever occurs first, based on independent review committee (IRC) assessment.","definition_or_measurement_approach":"Time from randomisation to objective disease progression, failure to achieve PR/CR at or beyond Week 8 leading to new antilymphoma therapy, or death; assessed by Independent Review Committee (IRC)."}
• {"endpoint_text":"- Part II: Best objective response rate (BORR), defined as the proportion of participants with at least one CR or PR between the date of MB-CART2019.1 infusion and the date of objective disease progression, the start of new antilymphoma therapy or the date of death from any cause, whichever occurs first, based on IRC assessment","definition_or_measurement_approach":"Proportion of participants with at least one CR or PR from MB-CART2019.1 infusion until objective progression, start of new antilymphoma therapy, or death; assessed by IRC."}

Secondary endpoints

• {"endpoint_text":"- Part I: Progression-free survival (PFS), defined as the time between the date of randomisation and the date of objective disease progression or death of any cause, whichever occurs first, based on IRC assessment.","definition_or_measurement_approach":"Time from randomisation to objective disease progression or death; IRC-assessed."}
• {"endpoint_text":"- Part I: Best complete response rate (BCRR), defined as the proportion of participants with at least one CR assessment until Week 24 in the MB-CART2019.1 arm and Week 26 in the comparator arm based on IRC assessment.","definition_or_measurement_approach":"Proportion with at least one CR by Week 24 (MB-CART2019.1) or Week 26 (comparator); IRC-assessed."}
• {"endpoint_text":"- Part I: Duration of complete response (DOCR), defined as the time between the date of a first CR and the date of assessment of objective disease progression or the date of death of any cause, whichever occurs first, based on IRC assessment.","definition_or_measurement_approach":"Time from first CR to objective progression or death; IRC-assessed."}
• {"endpoint_text":"- Part I: Overall survival (OS), defined as time between the date of randomisation and the date of death of any cause.","definition_or_measurement_approach":"Time from randomisation to death from any cause."}
• {"endpoint_text":"- Part II: DOR, defined as the time between the date of a first objective response (CR/PR) after MB-CART2019.1 infusion and the date of assessment of objective disease progression or the date of death of any cause, whichever occurs first, based on IRC assessment and based on investigator assessment.","definition_or_measurement_approach":"Time from first objective response after infusion to objective progression or death; assessed by IRC and investigator."}
• {"endpoint_text":"- Part II: PFS, defined as the time between the date of leukapheresis and the date of objective disease progression or death of any cause, whichever occurs first, based on IRC assessment and based on investigator assessment","definition_or_measurement_approach":"Time from leukapheresis to objective progression or death; assessed by IRC and investigator."}
• {"endpoint_text":"- Part II: PFS rates at 6 and at 12 months based on investigator assessment and based on IRC assessment.","definition_or_measurement_approach":"Proportion progression-free at 6 and 12 months; assessed by investigator and IRC."}
• {"endpoint_text":"- Part II: OS, defined as time between the date of leukapheresis and the date of death of any cause.","definition_or_measurement_approach":"Time from leukapheresis to death from any cause."}
• {"endpoint_text":"- Part II: BCRR, defined as the proportion of participants with CR between the date of MB-CART2019.1 infusion and the date of objective disease progression, the start of new anti-lymphoma therapy or the date of death from any cause, whichever occurs first based on IRC assessment and based on investigator assessment","definition_or_measurement_approach":"Proportion with CR between infusion and progression/new therapy/death; assessed by IRC and investigator."}
• {"endpoint_text":"- Part II: DOCR, defined as the time between the date of a first CR and the date of assessment of objective disease progression or the date of death of any cause, whichever occurs first based on IRC assessment and based on investigator assessment","definition_or_measurement_approach":"Time from first CR to progression or death; IRC and investigator assessments."}
• {"endpoint_text":"- Part II: BORR based on investigator assessment.","definition_or_measurement_approach":"Best objective response rate assessed by investigator."}
• {"endpoint_text":"- Part II: Changes in HRQoL","definition_or_measurement_approach":"Health-related quality of life changes measured using specified instruments (e.g., EQ-5D-5L, FACT-Lym) as per protocol."}
• {"endpoint_text":"- Part II: Changes in lymphoma symptoms","definition_or_measurement_approach":"Assessment of lymphoma symptom changes per protocol-defined instruments/assessments."}
• {"endpoint_text":"- Part II: Persistence of MB-CART2019.1 and phenotype of immune cell compositions based on flow cytometry analyses and real time quantitative polymerase chain reaction (qPCR).","definition_or_measurement_approach":"Persistence and phenotype measured by flow cytometry and qPCR analyses."}
• {"endpoint_text":"- Part II: Types and levels of cytokines (sIL-2R, IL-6, IL-10, IL-15, IFN-ʏ and TNFα).","definition_or_measurement_approach":"Cytokine levels measured in blood samples (specified analytes)."}
• {"endpoint_text":"- Part II: Anti-MB-CART2019.1 antibody","definition_or_measurement_approach":"Measurement of anti-drug antibodies against MB-CART2019.1."}
• {"endpoint_text":"- Part II: Type, frequency and severity of AEs, SAEs, and AESIs.","definition_or_measurement_approach":"Standard safety reporting of adverse events, serious AEs, and adverse events of special interest."}
• {"endpoint_text":"- Part II: Hospital days within 7 months after leukapheresis","definition_or_measurement_approach":"Number of days hospitalised in the 7 months post-leukapheresis."}
• {"endpoint_text":"- Part II: ICU admission days within 7 months after leukapheresis.","definition_or_measurement_approach":"Number of ICU admission days in 7 months after leukapheresis."}
• {"endpoint_text":"- Part II: Use of tocilizumab and/or high-dose steroids","definition_or_measurement_approach":"Record of use of tocilizumab and/or high-dose steroids for management of toxicity."}
• {"endpoint_text":"- Part II: Need for transfusions, prophylactic antimicrobial therapy, and gamma globulin substitution within 12 months after leukapheresis.","definition_or_measurement_approach":"Record of transfusion events, prophylactic antimicrobials, and IVIG substitution within 12 months post-leukapheresis."}

Methods

• Website-based recruitment: DALY2 trial website / DALYtrials.com (information pages and website screenshots documented in recruitment materials).
• Info cards and QR codes: Study info cards and QR-code information cards (K2 Info Card / Study_Info Card_QR) used as recruitment material.
• Site-based recruitment: investigators and participating hospital/clinic sites (trial sites listed by country) provide recruitment and referral.

Primary sponsor

Full Name

Miltenyi Biomedicine GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

CTO/CRO responsibilities indicated by sponsor duties codes: 1,10,11,12,14,2,3,5,8 (per CTIS entry); contact CTISApplications-Pharma@iconplc.com

Third parties

• {"country":"Germany","full_name":"Miltenyi Biotec B.V. & Co. KG","duties_or_roles":"Codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Medizinisches Versorgungszentrum fuer Labordiagnostik und Mikrobiologie Rhein-Main GmbH","duties_or_roles":"Codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Liqomics GmbH","duties_or_roles":"Codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Eurofins Central Laboratory B.V.","duties_or_roles":"Codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Miltenyi Biotec B.V. & Co. KG","duties_or_roles":"Codes: 14; 15 (Investigational Medicinal Product Manufacturer, QP release)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Julius-Maximilians-Universitaet Wuerzburg","duties_or_roles":"Codes: 4","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"BioAgilytix Europe GmbH","duties_or_roles":"Codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"SCRATCH Pharmacovigilance GmbH & Co. KG","duties_or_roles":"Codes: 15 (Medical Monitoring)","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Codes: 1,10,11,12,14,2,3,5,8","organisation_type":"Pharmaceutical company (CRO)"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"Codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Codes: 15 (Medical image analysis/ review - X-ray, MRI, ultrasound, etc.)","organisation_type":"Pharmaceutical company"}