CTRI/2023/03/050689 [Registered on: 14/03/2023] Trial Registered Prospectively
Last Modified On:
11/11/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Other (Specify) [CAR T -Cell Therapy]
Study Design
Other
Public Title of Study
This study is a new type of treatment for B-Acute Lymphoblastic leukemia (a type of Blood Cancer) by using the patients own modified immune cells to target the cancer
Scientific Title of Study
Evaluating Efficacy and Safety of HCAR19 in pediatric, adolescents and young adults
with relapsed/ refractory B- Acute lymphoblastic leukemia (ESHA) - A Phase Ib/II
Clinical Trial.
DCGI Letter CT No. CT-04/2022 File no. stm-CI/08/TMC/2022-BD
DCGI
HCAR19 Clinical Trial Protocol version 3.4 dated 10.05.2024
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Gaurav Narula
Designation
Professor Pediatric Oncology and Health Sciences
Affiliation
Tata Memorial Centre
Address
Homibaba Block, 11th floor, room no. 1111 ,Tata Memorial Centre, Dr. E Borges Marg, Parel, Mumbai, Maharashtra, 400012.
CAR T-cell Therapy Centre, room no. 349A, ACTREC, Tata Memorial Centre, Sector 22, Utsav Chowk- CISF Road, Kharghar, Navi Mumbai, Maharashtra, 410210 Raigarh MAHARASHTRA 400012 India
Phone
02224174135
Fax
Email
ctctc.tmc@gmail.com
Details of Contact Person Scientific Query
Name
Dr Gaurav Narula
Designation
Professor Pediatric Oncology and Health Sciences
Affiliation
Tata Memorial Centre
Address
Homibaba block, 11th floor, room no. 1111, Tata Memorial Centre, Dr. E Borges Marg, Parel, Mumbai, Maharashtra, 400012.
CAR T Cell Therapy Centre, room no. 349A, ACTREC, Tata Memorial Centre, Sector 22, Utsav Chowk- CISF Road, Kharghar, Navi Mumbai, Maharashtra, 410210 Raigarh MAHARASHTRA 400012 India
Phone
02224174135
Fax
Email
ctctc.tmc@gmail.com
Details of Contact Person Public Query
Name
Dr Gaurav Narula
Designation
Professor Pediatric Oncology and Health Sciences
Affiliation
Tata Memorial Centre
Address
Homibhaba Block, 11th floor, room no. 1111, Tata Memorial Centre, Dr. E Borges Marg, Parel, Mumbai, Maharashtra, 400012.
CAR T Cell Therapy Centre, room no. 349A, ACTREC, Tata Memorial Centre, Sector 22, Utsav Chowk- CISF Road, Kharghar, Navi Mumbai, Maharashtra, 410210 Raigarh MAHARASHTRA 400012 India
Phone
02224174135
Fax
Email
ctctc.tmc@gmail.com
Source of Monetary or Material Support
DBT BIRAC National Biopharma Mission vide Grant BIRAC/BT/NBM0339/NBM/06/19 dt 21 Jan 2021
Primary Sponsor
Name
Tata Memorial Hospital Research Administrative Council
Address
Tata Memorial Hospital Research Administrative Council, Tata Memorial Centre, Dr. E Borges Marg, Parel (E), Mumbai, Maharashtra, 400012.
ImmunoACT, 1st Floor, Plot no R-977, TTC
Industrial Area, MIDC Rabale Navi Mumbai
400701, Maharashtra, India
Countries of Recruitment
India
Sites of Study
No of Sites = 1
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Gaurav Narula
Tata Memorial Centre
Homibaba Block, 11th floor, Room no. 11, Tata Memorial Centre, Dr. E Borges Marg, Parel, Mumbai, Maharashtra, 400012
CAR T Cell Therapy Centre, Room no. 349A, Tata Memorial Centre, ACTREC, Sector 22, Utsav Chowk- CISF Road, Kharghar, Navi Mumbai, Maharashtra, Raigarh.410210. Indi Mumbai MAHARASHTRA
HCAR19 will be infused to relapsed refractory B NHL patients on compassionate arm at Tata Memorial Centre at dose of 3 to 5 million per kg body weight and 10 to 15 million per kg body weight after appropriate lymphodepletion conditioning regimen with all precautions for immune suppressed patients. There is only one time Intervention involved followed by Observation.
Intervention
HCAR19 for relapsed refractory B ALL
A humanized Second generation anti CD19 CAR construct HCAR 19 with 4 1BB co stimulatory domain has been designed and developed at IIT Bombay. Both the anti CD19 CAR T Cell product and processes are covered in the IPA no. 2018 2100 5457 and 2018 2100 5458 also covered under PCT IN20190 50111. CAR T Cell product will be manufactured at respective manufacturing sites for Product Manufacturing IIT B vide Licence no. BDC T 11.60.2020 and CTCTC at ACTREC, TMH vide Licence no. in process. The vector will be manufactured IIT B vide CDSCO License no. BDC T 11.06.2020 dated 26 Mar 2021.
HCAR19 will be infused to relapsed refractory B-ALL patients at Tata Memorial Centre at dose of 3 to 5 million per kg body weight and 10 to 15 million per kg body weight after appropriate lymphodepletion conditioning regimen with all precautions for immune suppressed patients.
Comparator Agent
Not Applicable
There is no comparator for both intervention and compassionate arms.
a. Disease Criteria: i. Relapsed or refractory pediatric, adolescent or young adult (3-25 years at screening) with B-cell ALL.
ii. Relapse for the purpose of this study is defined as 1. Presence of > 5% blasts at screening, and confirmation by FCM, AND
2. Second or subsequent bone marrow (BM) relapse, OR
3. Any BM relapse after allogeneic SCT
4. First Relapse will be considered if:
1. First Relapse has occurred very early, within 18 months of initial diagnosis
2. Is not in remission after re-induction chemotherapy as defined by FSM MRD
3. First Relapse in High-risk groups such as Ph+ and Ph-like ALL, and other known poor-prognostic cytogenetics/molecular profiles
iii. Refractory B-ALL is defined as:
1. Not achieving an initial CR after 2 cycles of a standard chemotherapy regimen (primary refractory). AND
2. Such patients have received 1 or more lines of second line or salvage chemotherapy and are still not in FCM based MRD defined remission.
iv. CD19 expression criteria:
1. CD19 tumor expression in bone marrow (BM) or peripheral blood (PB) within 3 months of study entry.
2. B-lineage of blast and expression of CD19 should be established.
3. There should be no other detectable clone that does not express CD19.
4. Absence of CD19 negative subclone of any type at time of study entry.
b. Host Criteria: i. Age criteria: Age 3 years to less than 25 completed years at screening for enrolment on the study.
ii. Fitness criteria: a. Adequate organ function. Clinically assessed, with further investigation if clinically indicated. This will include but not limited to those with severe systemic compromise of any major organ system as assessed by ejection fraction of < 50% for age as assessed by DTPA scan, anatomical and functional loss of respiratory function as assessed by radiology or respiratory rate at rest in excess of 20% above normal for age, or performance status of less than 80% (KPS & Pediatric scores), will be considered ineligible.
iii. For males or females of reproductive potential, has agreed to use effective contraception method during the study for minimum 6 months after study treatment.
ExclusionCriteria
Details
a. Failure to meet any of the inclusion criteria
b. Patients who test positive on urine pregnancy testing and are pregnant or are lactating
c. Isolated extra-medullary relapse
d. Concomitant genetic syndromes associated with bone marrow failure states such as Fanconi anemia, Kostmann syndrome, Schwachmann syndrome or any other BM failure syndromes with the exception of Downs syndrome.
e. Any syndrome with genetic predisposition to cancer eg. Li Fraumeni syndrome
f. Any prior malignancy
g. Active or latent hepatitis B or active hepatitis C detected at screening. Any test in the preceding 8 weeks will be considered valid
h. Any uncontrolled infection at time of screening.
i. Positive HIV test at screening.
j. Grade II to IV graft-versus-host-disease (GVHD) for post Allo-SCT patients.
k. Receiving an investigational medicinal product within 30 days of screening.
l. Medications or treatments that will be excluded:
• Corticosteroids within 72 hours of HCAR19 T-cell infusion, with the exception of physiologic replacement.
• Allogeneic cellular therapy, such as donor lymphocyte in fusion within 6 weeks prior to infusion
• Any ongoing GVHD therapies
• Chemotherapy stopped prior to lymphodepletion based on clearance
• CNS prophylaxis treatment
m. Active CNS disease, whether established clinically, radiologically, or by CSF studies. Exception would be CNS 2 disease i.e. CSF containing blasts, but < 5 WBCs/microliter. Such patients, with no other evidence of CNS involvement would be eligible).
Method of Generating Random Sequence
Not Applicable
Method of Concealment
Not Applicable
Blinding/Masking
Not Applicable
Primary Outcome
Outcome
TimePoints
i. To find the Phase 2 Dose P2D of HCAR19 in patients with relapsed refractory B ALL aged to 25 years.
ii. To demonstrate efficacy of HCAR19 T cells in patients to 3 to 25 years of age with relapsed refractory B Cell ALL by Day 30 Bone Marrow Flow Cytometry Response
iii. To establish safety and efficacy of HCAR19 when used as above.
i. Day 30 Bone Marrow Response by Morphology and Flow Cytometry
ii. Best Bone Marrow Flow Cytometry Response by Day 90
iii. Early Toxicities till Day 30
iv. Late Toxicities Beyond Day 30 till on follow up
Secondary Outcome
Outcome
TimePoints
i. To study the persistence, expansion and phenotype of HCAR19 T-cells in the target tissues (blood, bone-marrow, cerebrospinal fluid (CSF), and other extramedullary sites if involved.
ii. To study cytokine level and other biomarkers of toxicity and efficacy of infused HCAR19 T cells. To correlate toxicities, efficacy and biomarkers profile with steps and protocols of manufacturing HCAR19T cells.
i. Early Dynamics till Day-30
ii. Subsequent Dynamics beyond Day- 30 till on follow-up
Target Sample Size
Total Sample Size="70" Sample Size from India="70" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
For years, cancer treatment was dominated by chemotherapy, radiation therapy, and stem cell transplantation. New insights into genetic characteristics of leukemic cells have initiated the development of the chimeric antigen receptor (CAR) T-cell therapy. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukemia. In August 2018, the first CAR T-cell products – tisagenlecleucel (Kymriah®, Novartis) and axicabtageneciloleucel (Yescarta®, Gilead) – were approved -for hematological neoplasms. As CAR T-cells are a living drug, its benefits can persist. The administration of CAR T-cells is a complex and costly endeavour involving cell manufacture, shipping of apheresis products, and management of novel and severe adverse reactions. However, as experience with these therapies have increased, strategies to diminish the occurrence and severity of these complications have also evolved, as have effective treatments for them once they develop.
In India, however, the gaps in the field of CART-cell Therapy and research & development are still very huge. In the past six years, as a part of a collaborative project between IITB & TMC, on CAR T-cells, we have focused on harnessing this personalized therapy based on CAR T-cells and bring it to the clinics in India. With the help of various intramural and extramural grants from both IIT-B & TMC, we have completed the pre–clinical & developmental work for CD 19 CART Cell therapy. At IIT-B, we have constructed the CAR vector that encodes an anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) that recognizes the CD19 antigen. All protocols related to viral vector production, leucocyte transfection, T-cell expansion and release criteria & product testing assays, have been optimized on the designed vector. Additionally, in vitro and in vivo efficacy studies have also been performed, which have demonstrated successfully, that the designed CAR T-cells are functional in killing of CD19 tumor cells. Additionally, a GMP unit has also been developed to ensure quality production of vector and CAR T-cell product and processes that match regulatory norms. Both Institutes have now developed cGMP (Good Manufacturing Practices) facilities capable of producing CD19-directed CAR T-cells. an all the mandatory cGMP compliant Standard Operating Procedures (SOPs) for clinical manufacturing of CAR T-cells, have been optimized. Our combined efforts resulted in approval by the Drug Controller General of India and related regulatory/ oversight bodies in March 2021 for a first-in-India human Pilot Phase I clinical trial of our indigenously produced CAR T-cell product- HCAR19 in relapsed/ refractory B-ALL in patients aged 3-25 years of age. We also got simultaneous approval for the same IND for a Phase I trial for patients above 18 years of age with relapsed/ refractory Diffuse Large B-Cell Lymphoma (DLBCL), who had failed two lines of therapy. Both clinical trials are currently underway, and no trial related issues have been noted so far in either.
The aim of our Pilot Phase I trials was to conduct a first in human pilot trial on r/r BALL pediatric patients, as a “Proof of Principle” trial in patients who have otherwise exhausted all available options of cure. The trial tested the feasibility of further development of this therapy for Phase I/II trials. As the Pilot Phase I trial has completed enrollment meeting objectives, we will continue with the current trial in which we will find the ideal Phase II dose (P2D), and then roll on to a Phase II study that will establish efficacy. CAR T-manufacturing will occur from both sites (IIT-B & TMC), while IITB will remain the site for clinical-grade vector production. The Trial is funded by a grant from the Department of Biotechnology- BIRAC National Biopharma Mission.
Modification Date: 03.10.2024
The Investigational New Drug HCAR19 (Now Referred as Talycabtagene autoleucel also known as NexCAR19.
Phase Ib trial is concluded and the dose range i.e Phase 2 Dose (P2D) 5-10 x 10^6 CAR T- cells/kg cells capped at 12 x 10^8 is finalized. Phase II trial will use P2D to establish efficacy.
Phase II trial will only enrol B-ALL patient in accordance with 21st SEC recommendation dated 09 May 2024.
ImmunoACT is added as Co-sponsor and also the manufacturing site.
Four more sites have been added as Phase II trial will be multicentric trial.