AXICABTAGENE CILOLEUCEL for Diffuse large B-cell lymphoma

Inclusion criteria

• {"criterion_text":"- Signed written Informed Consent Form\n- Age > 18 years\n- Patient who understands and speaks one of the country official language\n- Histologically proven relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) and follicular lymphoma Grade 3B per WHO 2016 classification. Indolent B-NHL who transformed into aggressive B-NHL and were previously treated with R-CHOP-like after transformation are eligible. Primary mediastinal B-cell lymphoma are not eligible\n- Positron-emission tomography (PET)-positive disease\n- Patients must have received adequate first-line therapy including at a minimum: An anti-CD20 monoclonal antibody (rituximab or obinutuzumab), and CHOP or CHOP-like chemotherapy. Note: CHOP-like chemotherapy corresponds to ACVBP, EPOCH, or COPADEM. Dose-reduced CHOP (i.e., miniCHOP) is excluded except for dose-reductions of vincristine due to peripheral neuropathy. Patients who have received additional drugs in combination with CHOP or CHOP-like regimen are eligible.\n- Relapsed disease after first line chemo immunotherapy (full dose of R-CHOP or R-CHOP-like regimen), documented by PET-scan and biopsy: Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease relapse after 12 months and up to 5 years from end of first-line therapy.\n- Patients must meet CAR-T-eligible criteria as defined by: Patient deemed eligible for CAR T-cells therapy by the CAR-T physician and all the following criteria: ECOG performance status of 0, 1 or 2; Adequate vascular access for leukapheresis procedure (either peripheral or central venous line); Absolute neutrophil count (ANC) ≥ 1 x 10^9/L; Platelets ≥ 75 x 10^9/L; Absolute lymphocyte count ≥ 0.1 x 10^9/L; Creatinine clearance (CrCl) as estimated by Cockcroft Gault or MDRD ≥ 40 mL/min; Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5xULN; Total bilirubin <1.5 mg/dL, except in patients with Gilbert’s syndrome; Cardiac ejection fraction ≥ 45%; Baseline oxygen saturation ≥ 92% on room air\n- Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 12 months are not considered to be of childbearing potential)"}

Exclusion criteria

• {"criterion_text":"- Patients who received more than one prior line of systemic therapy\n- Patients with detectable Central Nervous System (CNS) lymphoma. Patients with a history of CNS lymphoma but no active CNS disease (after systematic MRI and lumbar puncture) at the time of enrolment will be eligible\n- Presence of CNS disorder such as dementia, autoimmune disease with CNS involvement, cerebral edema with confirmed structural defects by appropriate imaging, or seizure disorders requiring active anticonvulsive medication. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrolment\n- Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs and dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted\n- History of acute or chronic active hepatitis B or C infection (seropositivity). If there is a positive history of treated hepatitis B or hepatitis C (negative HBsAg and positive Anti-HBc/ positive anti-HCV), the viral load HBV DNA/ HCV RNA) must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing\n- Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/uL.\n- Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antimicrobials or other treatment at the time of leukapheresis or axicabtagene ciloleucel administration\n- History of any one of the following cardiovascular conditions within the past 12 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease\n- Presence of primary immunodeficiency\n- History of any medical condition including but not limited to autoimmune disease (e.g., Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression and/or systemic disease modifying agents within the last year. Endocrine conditions that require maintenance with physiologic dose steroids are allowed.\n- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.\n- Early relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease relapse before 12 months from end of first-line therapy\n- History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study\n- History of severe, immediate hypersensitivity reaction attributed to aminoglycosides, cyclophosphamide or fludarabine\n- Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study\n- Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of lymphodepletion chemotherapy on the fetus or infant\n- Patients of either sex who are not willing to practice birth control from the time of consent during treatment and for at least 12 months after conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, whichever is later\n- In the investigator’s judgment, the patient is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation\n- Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness\n- Refractory disease defined as: Progressive disease during first-line therapy; Stable disease as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP); Partial response as best response after at least 6 cycles, and biopsy-proven residual disease\n- Patients who received first line of R-CHOP or obinutuzumab-CHOP for an indolent B-NHL who relapse as transformed aggressive B-NHL after a year from the end of first-line therapy are NOT eligible.\n- Prior CD19 targeted therapy\n- Patients with cardiac atrial or cardiac ventricular lymphoma involvement\n- Requirement for urgent therapy due to tumor mass effects, such as bowel obstruction or blood vessel compression\n- Patient with clinically significant pleural effusion\n- History of another primary malignancy that has not been in remission for at least 3 years (except for nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast)). A maintenance treatment is not allowed."}

Primary endpoints

• {"endpoint_text":"- Complete Metabolic Response, defined as negative findings on a PET/CT scan at Month 3, after receiving axicabtagene ciloleucel infusion at day 0. The negativity of PET/CT findings will be assessed according to Lugano Classification and Deauville criteria","definition_or_measurement_approach":"Complete Metabolic Response: negative findings on a PET/CT scan at Month 3 after axicabtagene ciloleucel infusion at day 0; PET/CT negativity assessed according to Lugano Classification and Deauville criteria"}

Secondary endpoints

• {"endpoint_text":"- Complete metabolic response, defined as negative findings on a PET/CT scan at Month 3 after receiving axicabtagene ciloleucel infusion at day 0, as assessed by central imaging review of PET/CT\n- The Overall Response Rate, defined as the percentage of patients who achieved partial metabolic response or complete metabolic response according to the Lugano Classification criteria at Month 3 determined by both central and investigator assessments\n- Best objective response rate defined as the percentage of complete metabolic response + partial metabolic response determined by the investigator assessment among all patients between month 1 and month 12 from axicabtagene ciloleucel infusion\n- Best complete response rate defined as the percentage of complete metabolic response determined by the investigator assessment among all patients between month 1 and month 12 from axicabtagene ciloleucel infusion\n- Overall survival, defined as the time from inclusion to date of death from any cause. Alive patients will be censored at their last follow-up date\n- Progression free survival, defined as the time from axicabtagene ciloleucel infusion to the first observation of documented disease progression/relapse (based on investigator disease assessment or death due to any cause. If a patient has not progressed or died, progression free survival will be censored at the time of last visit with adequate assessment\n- Event-free survival, defined as the time from leukapheresis to any event preventing axicabtagene ciloleucel infusion if axicabtagene ciloleucel is never infused, or death, disease progression, or instauration of a new lymphoma therapy for lymphoma progression after axicabtagene ciloleucel infusion.\n- Duration of Response, defined as the time from attainment of partial metabolic response or complete metabolic response to the date of first documented disease progression/relapse (based on investigator disease assessment) or death from any cause.\n- Duration of complete response, defined as the time from achievement complete metabolic response to the date of first documented disease progression/relapse (based on investigator disease assessment) or death from any cause\n- Type, frequency and severity of adverse events and serious adverse events occurring after leukapheresis procedure to 28 days after the infusion of the study treatment\n- Type, frequency and severity of adverse events of special interest: Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, hypogammaglobulinemia, prolonged cytopenias and infections and emergent secondary malignancies occurring after leukapheresis procedure to the end of follow-up (5 years)\n- The patient quality of life assessed by the administration of the EORTC QLQ-C30, EQ-5D-5L, and QLQ-NHL-HG29 patient reported outcomes at screening and after 4 weeks of infusion and after 3 months of infusion\n- Correlation between total metabolic tumor volume pre-axicabtagene ciloleucel infusion and efficacy/toxicity\n- Biological exploratory endpoints described in relation to efficacy and toxicity based on correlation with biological parameters such as: Histologic, phenotypic, genomic, transcriptomic, and molecular characteristics of malignant cells and tumor microenvironment pre and post-treatment; Immune response markers in tumor and blood (cytokine levels, immune cells, and TCR repertoire); Minimal residual disease; Immune-escape mechanisms","definition_or_measurement_approach":"Definitions are provided in the endpoint text for each listed secondary endpoint (e.g., OS defined as time from inclusion to date of death; PFS defined as time from infusion to progression or death; response endpoints defined per Lugano Classification and PET/CT assessments; adverse events captured from leukapheresis to 28 days and AEs of special interest to end of follow-up (5 years); QoL measured by EORTC QLQ-C30, EQ-5D-5L and QLQ-NHL-HG29)."}

Other endpoints

• {"endpoint_text":"- Biological exploratory endpoints described in relation to efficacy and toxicity based on correlation with biological parameters such as: Histologic, phenotypic, genomic, transcriptomic, and molecular characteristics of malignant cells and tumor microenvironment pre and post-treatment; Immune response markers in tumor and blood (cytokine levels, immune cells, and TCR repertoire); Minimal residual disease; Immune-escape mechanisms","definition_or_measurement_approach":"Exploratory biological endpoints will be correlated with efficacy and toxicity using histologic, phenotypic, genomic, transcriptomic and molecular analyses of tumor and microenvironment pre-/post-treatment; blood immune markers (cytokines, immune cell profiling, TCR repertoire); MRD assessment; evaluation of immune-escape mechanisms."}

Spain

Earliest CTIS Part Ii Submission Date

05-09-2024

Latest Decision Or Authorization Date

27-09-2024

Processing Time Days

22

Number Of Sites

15

Number Of Participants

45

Primary sponsor

Full Name

Fundacion Geltamo

Organisation Type

Patient organisation/association

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Evidenze Health Espana S.L.","duties_or_roles":"codes: 1,10,11,12,14,5,6,7,8","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Hospital Clinic De Barcelona","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Kite Pharma EU B.V.","duties_or_roles":"codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Hospital General Universitario Gregorio Maranon","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Spain","full_name":"Azierta Life Sciences & Health Consulting Firm S.L.","duties_or_roles":"codes: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Kite Pharma Inc.","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Kite Pharma Inc.","duties_or_roles":"codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Hospital Universitario De Salamanca","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}