CTRI Number	CTRI/2021/04/032727 [Registered on: 12/04/2021] Trial Registered Prospectively
Last Modified On:	31/10/2022
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study Modification(s)	Biological Other (Specify) [Gene Therapy Product]
Study Design	Other
Public Title of Study Modification(s)	It is a study to test a new type of treatment for blood cancer. In this new treatment the blood cells of patients are changed so that they cam kill cancer cell on their own.
Scientific Title of Study	A pilot study of indigenously manufactured HCAR19 (2nd generation Anti-CD19-41BB- CD3ζ chimeric antigen receptor T-cell therapy) in adult patients with relapsed/refractory diffuse large B-cell lymphoma.
Secondary IDs if Any Modification(s)	Secondary ID  Registry  Protocol Number Nil Version 1.1 Dated 17.11.2020  Protocol Number  Stm-CI/26/TMC/2020-BD  DCGI
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)	Name  Dr Hasmukh Jain  Address  Room No 81 Adult Hematolymphoid Unit Main Building, Ground Floor Tata Memorial Hospital Dr E Borges Road Parel, Mumbai Mumbai MAHARASHTRA 400012 India  Phone  02224177018   Fax     Email  dr.hkjain@gmail.com
Details Contact Person Scientific Query Modification(s)	Name  Dr Hasmukh Jain  Address  Room No 81 Adult Hematolymphoid Unit Main Building, Ground Floor Tata Memorial Hospital Dr E Borges Road Parel, Mumbai Mumbai MAHARASHTRA 400012 India  Phone  02224177018   Fax     Email  dr.hkjain@gmail.com
Details Contact Person Public Query Modification(s)	Name  Dr Hasmukh Jain  Address  Room No 81 Adult Hematolymphoid Unit Main Building, Ground Floor Tata Memorial Hospital Dr E Borges Road Parel, Mumbai Mumbai MAHARASHTRA 400012 India  Phone  02224177018   Fax     Email  dr.hkjain@gmail.com
Source of Monetary or Material Support Modification(s)	Extramural Funding- Indian Council of Medical Research V. Ramalingaswami Bhawan, P.O Box No. 4911, Ansari Nagar, New Delhi-110029  Extramural Funding- ImmunoAdoptive Cell Therapy Private Limited, CM-05, SINE Office, 3rd floor, CSRE Building. IIT Bombay, Powai-400076.
Primary Sponsor	Name  Tata Memorial Hospital Research Administrative Council  Address  Tata Memorial Hospital Research Administrative Council Clinical Research Secretariat 3rd Floor, Main Building Tata Memorial Hospital Dr E Borges Road Parel Mumbai-400012  Type of Sponsor  Research institution and hospital
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study	No of Sites = 1   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Hasmukh Jain  Tata Memorial Centre  Dr. E. Borges Road Parel 400012 Mumbai   02224177000 dr.hkjain@gmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 1   Name of Committee  Approval Status  Institutional Ethics Committee, Tata Memorial Centre  Approved
Regulatory Clearance Status from DCGI Modification(s)	Status  Approved/Obtained
Health Condition / Problems Studied	Health Type  Condition  Patients  Unspecified B-cell lymphoma
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  HCAR19 cells   At IIT-Bombay, a novel and indigenous HCAR19 cell product has been designed and developed. The gene therapy product (GTP) has been tested for the ex vivo and in vivo functionality and the results are quite promising. Autologous T-cells will be transduced using a lentiviral vector that will contain a gene coding for a single chain variable fragment (scFv) directed against the surface CD19 antigen. The cells will also express an intracellular signalling domain made of 4-1BB and TCRζ signalling modules. Clinical grade viral vector used for this process will be manufactured at IIT-Bombay. The humanized scFv is designed from FMC63 scFv (murine anti-human CD19 antibody). The signalling domains will be from the native human sequence. Patients will receive the CAR-T cell product as a split-regimen at 10%, 30% and 60% dose on Days 0, 1 and 2 respectively. The minimum dose to be administered is 1x10 raise to power 7 CAR-T cells to a maximum of 5x10 raise to power 9 CAR- T cells. The product will be infused in a single room at Tata Memorial centre, using precautions for immunocompromised patients. The product will be infused at 10-20 ml/min via an 18-G latex free Y- type blood set with a 3-way stopcock.   Comparator Agent  Not Applicable  Not Applicable
Inclusion Criteria	Age From  18.00 Year(s) Age To  80.00 Year(s) Gender  Both  Details  a) Able to give written informed consent. b) Age greater than or equal to 18 years c) Histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. d) Chemotherapy refractory disease, as defined in the SCHOLAR-1 Study-This includes: Patients whose best response to the last chemotherapy regimen was progressive disease or stable disease lasting less than or equal to 6 months. e) Disease progression or recurrence ≤12 months after ASCT. f) Patients must have received an anti-CD20 monoclonal antibody and an anthracycline containing regimen. Patients with transformed follicular lymphoma, must have been treated for follicular lymphoma and have refractory disease after transformation. g) Measurable Disease as per International Working Group Response Criteria) h) Patient who is not willing or not feasible to undergo ASCT. i) Patient life expectancy greater than or equal to 12 weeks. j) Eastern Cooperative Oncology Group performance status of either 0 or 1 at the time of screening. k) Adequate organ function: l) Renal function - a serum creatinine of less than or equal to 1.5 × upper limit of normal (ULN) or an estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m2. m) Liver function- Alanine Aminotransferase ≤2.5 times the ULN for age and gender and bilirubin less than or equal to 2.0 mg/dl unless the patient had Gilbert syndrome, in which case they can be included if their total bilirubin is less than or equal to 5.0 × ULN and direct bilirubin is less than or equal to 1.5 × ULN n) A minimum level of pulmonary reserve, defined as grade less than or equal to 1 dyspnoea and pulse oxygenation greater than 91% on room air. o) Hemodynamically stable and left ventricular ejection fraction greater than or equal to 45% confirmed by echocardiogram or multiple-gated acquisition scan. p) No evidence of pericardial effusion. q) Adequate bone marrow reserve without transfusions, defined as absolute neutrophil count greater than 1000/mm3, platelets greater than or equal to 50,000/mm3, and haemoglobin greater 8.0g/dl r) Sexually active patients (women of childbearing potential) are required to use highly effective methods of contraception for at least 12 months following CAR T cell infusion.
ExclusionCriteria	Details  a) Previous treatment with specific anti-CD19/anti-CD3 therapy or any other anti-CD19 directed therapy. b) Prior CAR-T cell therapy. c) Active central nervous system involvement by malignancy. d) Prior allogeneic HSCT. e) Investigational medicinal product within 30 days before screening. f) Use of following medications to be assessed for subject eligibility: • Steroid should be stopped greater than 72 hours before leukapheresis and CAR T cell infusion (less than 12 mg/m2/day of hydrocortisone or equivalent is allowed) • Immunosuppressive medication has to be stopped greater than or equal to 2 weeks before leukapheresis and cell infusion. • Any anti proliferative therapies other than lymphodepleting chemotherapy within 2 weeks of leukapheresis and 2 weeks before infusion to be stopped • Short-acting drugs used to treat leukaemia or lymphoma (i.e., tyrosine kinase inhibitors, and hydroxyurea), have to be stopped greater than 72 hours before leukapheresis and before cell infusion. • Other cytotoxic drugs, including low-dose daily or weekly maintenance chemotherapy, can be given within 2 weeks before leukapheresis and within 2 weeks before cellular infusion. • Antibodies, including anti-CD20 therapy, not to be used within 4 weeks before infusion or 5 half-lives of the respective antibody, whichever was longer • Central nervous system disease prophylaxis, has to be stopped greater than 1 week before cellular infusion (i.e., intrathecal methotrexate) • Prior radiation therapy within 2 weeks of infusion. g) Active replication of prior infection with hepatitis B or active hepatitis C (HCV RNA positive) h) HIV-positive patients i) Uncontrolled acute life-threatening bacterial, viral, or fungal infection (i.e., blood culture positive less than or equal to 72 hours before infusion) j) Unstable angina and/or myocardial infarction within 6 months before screening k) Previous or concurrent malignancies. Except in the case of adequately treated basal cell or squamous cell carcinoma, in situ carcinoma of the cervix or breast (treated curatively and without evidence of recurrence for greater than or equal to 3 years before study), or primary malignancy which has been completely resected and in complete remission for greater than or equal to 5 years l) Currently pregnant or lactating female subjects. m) A positive serum or urine pregnancy test performed within 24 hours before lymphodepletion n) Intolerance of the excipients of the CAR T cell product o) Cardiac arrhythmia not controlled with medical management P) Prior treatment with any adoptive T-cell therapy p) Active neurological autoimmune or inflammatory disorders.
Method of Generating Random Sequence	Not Applicable
Method of Concealment	Not Applicable
Blinding/Masking	Open Label
Primary Outcome	Outcome  TimePoints  To study the safety of CAR-T cell therapy in DLBCL. Study-related AE includes NCI CTC greater than or equal to Grade 3 signs or symptoms, laboratory toxicities and clinical events that are possible, likely or definitely related to study treatment, in the time-period between CAR-T infusion till week 24.These toxicities include, but are not limited to- Infusional toxicity, cytokine-release syndrome, macrophage activation syndrome, fever, hepatic dysfunction, cytopenias, rash, pulmonary toxicities.  Week 24
Secondary Outcome	Outcome  TimePoints  Objective Response Rate  3 months  Engraftment of CAR-T cells  Day 1, Day 2, Day 3, 1 month, 3 month, 6 month  Late complications  2 year, 5 year, 10 year  Overall Survival and Event fee survival  2 year  Development of host immune response to CART cells  3 months, 6 months  To evaluate the phenotype and functional aspects of CART cells using multi-parametric flow cytometry  3 months, 6 months  Changes in the cytokines and other soluble factors will be measured at different time points  Day 7, Day 10, Day 14, Day 21, Day 28, 3 months  Manufacturing feasibility assessment  minus week 5
Target Sample Size	Total Sample Size="10" Sample Size from India="10"
Phase of Trial Modification(s)	Phase 1
Date of First Enrollment (India) Modification(s)	16/04/2021
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="10" Months="0" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Closed to Recruitment of Participants
Publication Details Modification(s)	None
Brief Summary Modification(s)	Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all the cases of Non-Hodgkin lymphoma (NHL). Two-thirds of patients respond to frontline chemoimmunotherapy. Only 5 per cent of relapsed/refractory DLBCL responds to salvage chemotherapy and could undergo stem cell transplant. There is a large unmet need to be addressed in the relapsed/refractory setting. The CAR-T cell therapy directed against CD19 shown significant clinical benefit. Two CAR-T cell therapy products are granted FDA approval, namely Axicabtagene ciloleucel (Yescarta) and Tisagenlecleucel (Kymriah). The cost of therapy is exorbitant. Therefore, we need to develop an indigenous product with less production costs and make it accessible to our patients.  Our hypothesis is that HCAR19 cell product is safe with manageable toxicities. The primary objective of the study is to assess the safety and tolerability of a clinical-grade HCAR19 cells product in relapsed/refractory DLBCL subjects by recording the frequency and severity of adverse events reporting, including but not limited to, estimating the frequency of cytokine release syndrome ( CRS) and Macrophage activation syndrome (MAS). The secondary objectives of the study is to know the objective response rate, 2-year event-free survival and overall survival, late complications of therapy, to evaluate engraftment of CAR T cells, to study the change in the cytokines, to know phenotype and function of cells, to know manufacturing feasibility. Relapsed/refractory (r/r) patients of age greater than or equal to 18 years with DLBCL, primary mediastinal B-cell lymphoma or transformed high grade B-cell lymphoma (Defined as per the WHO 2016 criteria) and unable to undergo stem-cell transplants will be included in the study. Clinical and laboratory monitoring of patients for complications including Cytokine Release Syndrome (CRS), management of patients and documentation, and management of Serious Adverse Effects (SAEs) over immediate and extended follow up periods till 3 months of therapy will be done. Disease remission status will be monitored by 18-FDG PET-CT scans at Day 90, it will be repeated after every 3 months if patient is not in complete remission. Monitoring will be done monthly basis till the completion of 6 months. After that patient will be monitored 3 monthly till the completion of 2 years. Thereafter patient will be followed up after every 6 months till the completion of 5 years. Finally, there will be an annual follow up till the completion of 10 years. We have taken approval from RCGM and Ethics Committee. DCGI approval has also been obtained.