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CTRI Number  CTRI/2024/07/069839 [Registered on: 03/07/2024] Trial Registered Prospectively
Last Modified On: 28/09/2024
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   A multi-center study for children with blood cancer (acute lymphoblastic leukemia) for improving their survival. 
Scientific Title of Study   ICiCLe-ALL-24 – The Indian Collaborative Childhood Leukaemia Randomised Trial for Children and Adolescents with Acute Lymphoblastic Leukaemia 2024 
Trial Acronym  NIL 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Venkatraman Radhakrishnan 
Designation  Professor Medical Oncology 
Affiliation  Cancer Institute (W.I.A) 
Address  Canal Bank Road, Adyar, Chennai

Chennai
TAMIL NADU
600020
India 
Phone  9498082771  
Fax    
Email  venkymd@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Venkatraman Radhakrishnan 
Designation  Professor Medical Oncology 
Affiliation  Cancer Institute (W.I.A) 
Address  Canal Bank Road, Adyar, Chennai

Chennai
TAMIL NADU
600020
India 
Phone  9498082771  
Fax    
Email  venkymd@gmail.com  
 
Details of Contact Person
Public Query  
Name  Venkatraman Radhakrishnan 
Designation  Professor Medical Oncology 
Affiliation  Cancer Institute (W.I.A) 
Address  Canal Bank Road, Adyar, Chennai

Chennai
TAMIL NADU
600020
India 
Phone  9498082771  
Fax    
Email  venkymd@gmail.com  
 
Source of Monetary or Material Support  
Indian Council of Medical Research (ICMR) 
 
Primary Sponsor  
Name  Cancer Institute  
Address  Department of Medical Oncology, Cancer Institute (W.I.A), Canal Bank Road, Adyar, Chennai, 600020  
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 = 6  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Deepam Pushpam  AIIMS IRCH  Department of Medical Oncology, All India Institute of Medical Sciences Ansari Nagar New Delhi 110029
South
DELHI 		 9650629370

deepampushpam@gmail.com 
Dr Rachna Seth  AIIMS Pediatrics  Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar New Delhi 110029
South
DELHI 		 9971188687

drrachnaseth1967@gmail.com 
Dr Venkatraman Radhakrishnan  Cancer Institute (W.I.A)  Department of Medical Oncology, Cancer Institute (W.I.A), Canal Bank Road, Adyar, Chennai
Chennai
TAMIL NADU 		 9498082771

venkymd@gmail.com 
Dr Richa Jain  PGIMER Chandigarh  Department of Pediatrics, APC, PGIMER, Sector 12 Chandigarh. 160012
Chandigarh
CHANDIGARH 		 8146738711

docrichajain@gmail.com 
Dr Niharendu Ghara  Tata Medical Center  Department of Pediatric Oncology Tata Medical Center Newtown, Kolkata, West Bengal 700156
Kolkata
WEST BENGAL 		 9831771972

niharendu.ghara@tmckolkata.com 
Dr Nirmalya Roy Moulik  Tata Memorial Hospital  Division of Pediatric Oncology, Tata Memorial Hospital, Dr.E.Borges Road, Mumbai 400012.
Mumbai
MAHARASHTRA 		 7045991385

roymoulik@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 6  
Name of Committee  Approval Status 
AIIMS New Delhi  Approved 
AIIMS New Delhi  Approved 
Cancer Institute (W.I.A)  Approved 
PGIMER CHANDIGARH  Approved 
Tata Medical Center Kolkata  Approved 
Tata Memorial Center  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: C910||Acute lymphoblastic leukemia [ALL],  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Capizzi Methotrexate (R2-A arm)  Interim maintenance: Methotrexate intravenous 100 mg/m2 given as the initial dose, escalate subsequent doses by 50mg/m2 to toxicity and modify dosage in the following days. Day 1, Day 11, Day 21, Day 31, Day 41. For pre-B ALL intermediate risk and CNS 3 negative high risk.  
Intervention  Capizzi methotrexate for BCP-ALL standard risk (SR) and T-ALL. High dose methotrexate (5 gm/m2) for CNS-3 (non-randomised).  B-cell precursor (BCP-ALL) SR and T-ALL/LL will receive Capizzi Methotrexate in Interim Maintenance and CNS3 patients (BCP-ALL and T-ALL) will receive high-dose methotrexate in Interim Maintenance. 
Intervention  High dose methotrexate (R2-B arm)  Methotrexate: 5 g/m2 intravenously on day 1 and 15 of interim maintenance. Repeated on days 1 and 15 after completion of delayed intensification and before starting maintenance. Total 4 doses. Pre-B ALL intermediate risk and CNS 3 negative high risk. 
Intervention  Split dexamethasone in induction (R1-B arm)  Induction phase: Dexamethasone (PO) 6 mg/m2 in 2-divided doses, note that the maximum permitted dose is 12 mg daily. Intermittent dosing: Days 8 – 14 & 22 – 28, No Taper. For all risk groups after one week prednisolone from days 1-7. 
Intervention  Split high-dose methotrexate (non-randomized).  High-dose methotrexate 5 gm/m2 will be split. The first two cycles will be given during the interim maintenance phase and the last 2 cycles will be given after delayed maintenance. 
Comparator Agent  Split Prednisolone in induction (R1-A arm)  Induction phase: Prednisolone 60 mg/m2 in three divided doses, note that the maximum permitted dose is 120 mg daily. Intermittent dosing: Days 8 – 14 & 22 – 28, No Taper. For all risk groups after one week prednisolone from days 1-7. 
Intervention  Vincristine and dexamethasone pulse in maintenance for high-risk patients.(non-randomized)  BCP-ALL high-risk patients will receive vincristine and 5 days of dexamethasone (6 mg/m2) with each intrathecal methotrexate during maintenance (weeks 1-96).  
 
Inclusion Criteria  
Age From  1.00 Year(s)
Age To  18.00 Year(s)
Gender  Both 
Details  Newly diagnosed pediatric acute lymphoblastic leukemia or lymphoblastic lymphoma. 
 
ExclusionCriteria 
Details  1. Age less than 1 year
2. Age more than 18 years
3. Mature B-ALL
4. Down Syndrome
5. Mixed Phenotype Acute Leukaemia
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Event free survival between the R1 and R2 randomisation arms.   3 years and 5 years from inclusion in study.  
 
Secondary Outcome  
Outcome  TimePoints 
Event free survival in comparison to T-ALL cohort in ICiCLe-14 historical cohort.
 		 3 years and 5 years from inclusion in study.  
Overall survival, cummulative incidence of death, cummulative incidence of relapse and toxicity between the randomised arms and non randomised arms with historcial arms.   3 years and 5 years from inclusion in study.  
 
Target Sample Size   Total Sample Size="2567"
Sample Size from India="2567" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   01/10/2024 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary   Rationale/ gaps in existing knowledge: 
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with an estimated 15,000 children diagnosed in India annually. While the outcome for ALL is ~90% in high-income nations, Indian outcomes are suboptimal. The ICiCle ALL-14 (Indian Childhood CollaborativeLeukemia group) trial, carried out between 2016-2022, standardized the treatment of ALL in India and improved the outcomes of childhood ALL. While much improved as compared to historical Indian data, outcomes are lower than international data. Additionally, relapse rates from the trial are higher than the expected. The ICICLE ALL-24 trial will further optimize the treatment of childhood ALL with the end goal of improving the OS and EFS and decreasing the relapse rate.  To this end, improvement in risk stratification of ALL will be done, and treatment strategy will be further refined among the various sub-groups of ALL.
Novelty: -
In the trial, newer genetic risk stratification strategies will be used to refine the pre-existing risk stratification in ALL including cytogenetic markers: IKZF1del, Philadelphia-like; TCF3::HLF1; Hypodiploidy; iAMP21, and MEF2D. More sensitive assessments for MRD will be developed and used during this study. Novel treatment modifications and adaptations will be assessed in this trial, including, 1. non-randomized modification of high-dose methotrexate (HDMTX) into 2 blocks of 2-cycles each, as compared to serial administration of 4-cycles over 8-weeks, 2. randomized comparison between high-dose methotrexate  (HDMTX) versus Capizzi methotrexate (CMTX) in non-standard risk (SR)-ALL, and 3. Randomization between dexamethasone and prednisolone during induction. The end-goal is a reduction in relapse rate while reducing toxicity. 
Objectives: 
1. To improve the outcome of children with ALL in India with enhanced risk-stratification using novel genetic criteria and improved measurable residual disease assessment. 
2. To assess whether the use of dexamethasone instead of prednisolone in induction may lead to better EFS, and decreased intramedullary relapses without an increase in toxicity. 
3. To assess whether in the Indian context, CMTX may be a better option than HDMTX for ALL. 
4. To assess the efficacy of split-administration of HDMTX. 
 
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