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CTRI Number  CTRI/2020/05/025367 [Registered on: 27/05/2020] Trial Registered Prospectively
Last Modified On: 08/05/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   To Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone in Older Patients (≥50 years) suffering from Acute Myeloid Leukemia. 
Scientific Title of Study   Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML). 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
AML003, Version 5.0 dated 28 Oct 2019  Protocol Number 
NCT03504410  ClinicalTrials.gov 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Shashikant Apte 
Designation  Consultant Hematologist  
Affiliation  Sahyadri Superspeciality Hospital 
Address  Department of Haematology , Sahyadri Superspeciality Hospital, 30-C Erandawane, Pune- 411004, Maharashtra, India.

Pune
MAHARASHTRA
411004
India 
Phone  09822404983  
Fax    
Email  shashikant.apte@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Diptendu Santra 
Designation  Medical Monitor 
Affiliation  JSS Medical Research India Private Limited 
Address  Plot 12/2,6th Floor, Vatika Mindscapes (Tower-B), Sector 27 D, Faridabad, Haryana-121003, India

Faridabad
HARYANA
121003
India 
Phone  08698065660   
Fax  01296613520   
Email  diptendu.santra@jssresearch.com  
 
Details of Contact Person
Public Query  
Name  Dr Shariq Anwar 
Designation  Head – Operations 
Affiliation  JSS Medical Research India Private Limited 
Address  Plot 12/2,6th Floor, Vatika Mindscapes (Tower-B), Sector 27 D, Faridabad, Haryana-121003, India

Faridabad
HARYANA
121003
India 
Phone  09810979215  
Fax  01296613520   
Email  shariq.anwar@jssresearch.com  
 
Source of Monetary or Material Support  
Rafael Pharmaceuticals Inc., 1 Duncan Drive Cranbury, NJ 08512-3629  
 
Primary Sponsor  
Name  Rafael Pharmaceuticals Inc 
Address  1 Duncan Drive Cranbury, NJ 08512-3629  
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     Republic of Korea
Australia
Austria
Belgium
Canada
France
Germany
India
Italy
Spain
United States of America
Poland  
Sites of Study  
No of Sites = 6  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Tulika Seth  AIIMS Hospital  All India Institute of Medical Sciences Room No.10, Porta Cabin, 5th Floor, Teaching Block, Ansari Nagar, New Delhi – 110029, India
New Delhi
DELHI 		 09811262092

drtulikaseth@gmail.com 
Dr Vikram Mathews  Christian Medical College  Christian Medical College, Vellore Room no: 4, First floor, Department of Hematology, IDA Scudder Rd, Vellore – 632004, TAMIL NADU, India
Vellore
TAMIL NADU 		 04162282352

vikram@cmcvellore.ac.in 
Dr Anupam Datta  Netaji Subhash Chandra Bose Hospital  Netaji Subhash Chandra Bose Cancer Research Institute Department of Radiation Oncology, 3081, Nayabad Ave, New Garia, Pancha Sayar, Kolkata- 700094, West Bengal, India
Kolkata
WEST BENGAL 		 09836479790

dranupamdatta@gmail.com 
Dr Shashikant Apte  Sahyadri Super Speciality Hospital  Sahyadri Super Specialty Hospital, Department of Haematology, 30-C, Erandawane, Karve road, Pune- 411004, Maharashtra, India.
Pune
MAHARASHTRA 		 09822404983

shashikant.apte@gmail.com 
Dr Vivek Radhakrishnan  TATA Medical Center  Tata Medical Center, Kolkata Department of Clinical Hematology 14, Major Arterial (EW), New Town Rajarhat, Kolkata 700160, West Bengal, India
Kolkata
WEST BENGAL 		 03366057620

vivek.radhakrishnan@tmckolkata.com 
Dr Maju Sengar  TATA Memorial Hospital  Tata Memorial Hospital, Mumbai Hematology Department, Room No 20, Ground floor, Main Building, Dr. E. Borges Marg, Parel, Mumbai - 400012, Maharashtra, India.
Mumbai
MAHARASHTRA 		 02224177211

manju.sengar@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 6  
Name of Committee  Approval Status 
Ethics Committee N S C B C Research Institute  Submittted/Under Review 
Ethics Committee, All India Medical Sciences  Submittted/Under Review 
Institutional Review Board Christian Medical College  Submittted/Under Review 
Institutional Review Board, Tata Medical Center  Submittted/Under Review 
Sahyadri Hospitals Ltd. Ethics Committee Sahyadri Clinical Research & Development Center  Approved 
TMH, Institutional Ethics Committee  Submittted/Under Review 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: C92||Myeloid leukemia,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  CPI-613® (Devimistat)  Induction and Consolidation: CPI-613® (devimistat): 2,000 mg/m2 over 2 hours as a central line IV infusion): 5 doses, once a day (QD) Days 1 to 5 High Dose Cytarabine: 1 g/m2 over 3 hours as a central line IV infusion: 5 doses, every 12 hours starting on day 3 through day 5. Mitoxantrone: 6 mg/m2 over 15 minutes as a central line IV infusion: 3 doses, QD following the 1st, 3rd and 5th doses of Cytarabine starting on Day 3 through Day 5 Cycle duration: 14 days Maintenance: CPI-613® (devimistat): 2,500 mg/m2 over 2 hours as a central line IV infusion): 5 doses, once a day (QD) Days 1 to 5 Cycle duration: 28 days  
Comparator Agent  Mitoxantrone and Cytarabine   High Dose Cytarabine: 1 g/m2 over 3 hours as a central line IV infusion: 5 doses, every 12 hours starting on day 1 through day 3. Mitoxantrone: 6 mg/m2 over 15 minutes as a central line IV infusion: 3 doses, QD following the 1st, 3rd and 5th doses of Cytarabine starting on Day 1 through Day 3 Cycle duration: 14 days  
 
Inclusion Criteria  
Age From  50.00 Year(s)
Age To  85.00 Year(s)
Gender  Both 
Details  1. Patient has provided an informed consent prior to initiation of any study specific activities/procedures.
2. Males and females age ≥ 50 years must have histologically documented AML that is relapsed from, or refractory to, prior standard therapies.
3. Refractory is defined as failure to achieve CR or CRi following
a. Two standard dose Cytarabine based induction cycles or one HiDAC based cycle or,
b. Persistent disease after one cycle of standard dose cytarabine (defined as no decrease in marrow blast percentage from diagnosis on Day 14 marrow) or,
c. Persistent disease after at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax.
4. Relapse is defined as development of recurrent AML (as described by Döhner et al, 2017) after CR or CRi has been achieved with a prior chemotherapy or after disease progression on a hypomethylating agent with or without venetoclax.
5. ECOG PS 0-2
6. Expected survival greater than 3 months.
7. Women of child-bearing potential (i.e. women who are pre-menopausal or < 2 years post-menopausal or not surgically sterile) must practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods.
Examples are use of oral, injected or implanted hormonal methods of contraception, placement of an intra uterine device or intra uterine system, male partner sterilization, true abstinence during and for 6 months after the last administered dose of CHAM or HAM therapy and must have a negative serum pregnancy test within 1 week prior to treartment initiation and at first day of each cycle and at the end of systemic exposure.
(Note: Pregnant patients are excluded because the effects of CPI-613® (devimistat) on a fetus are unknown.
8. Fertile men who are sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during the study period and up to 6 months after completion of the study screening, unless documentation of infertility exists
9. Good state of mental health, ability to understand and willingness to sign the informed consent form (ICF).
10. No radiotherapy, treatment with cytotoxic chemotherapy, treatment with biologic agents or any anti-cancer therapy within the 1 week prior to treatment with CPI-613® (devimistat). Hydroxyurea and oral tyrosine kinase (FLT3) or Isocitrate Dehydrogenase 1 and 2 (IDH1/2) inhibitors being used with Grade ≤ 2 toxicity can be taken until the day prior to starting study therapy. Previous exposure to a hypomethylating agent either alone or in combination with Venetoclax is allowed. Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities with the exception of alopecia (returned to baseline status as noted before most recent treatment). Patients with persisting, non-hematologic, non-infectious toxicities from prior treatment Grade ≤ 2 are eligible but must be documented as such
11. Laboratory values ≤ 2 weeks before dosing must be:
a. Adequate hepatic function (aspartate aminotransferase/serum glutamic-oxaloacetic transaminase [AST/SGOT] ≤ 5 x upper limit of normal [ULN], alanine aminotransferase/serum glutamic oxaloacetic transaminase [ALT/SGPT] ≤ 5 × ULN, bilirubin ≤ 1.5 × ULN).
b. Adequate renal function (serum creatinine clearance ≥ 60 mL/min per CockCroft-Gault formula).
c. Adequate coagulation (International Normalized Ratio [INR] must be < 1.7 unless on vitamin k antagonist anticoagulation).
12. Left Ventricular Ejection Fraction (LVEF) by Transthoracic Echocardiogram (TTE) or Multigated Acquisition Scan (MUGA) or cardiac Magnetic Resonance Imaging (MRI), sufficient to safely administer mitoxantrone. Subjects must have an LVEF ≥ 45%.
13. No marked baseline prolongation of QT/QTc interval (repeated exhibition of a QTc interval >450 ms for male and > 470 ms for female patients).
14. No history of additional risk factors for torsade de pointes (e.g. clinically significant heart failure, hypokalemia, immediate family history of Long QT Syndrome).
15. Allow only patients who experienced relapse after 1 year from previous HiDAC treatment or who didn’t receive HiDAC previously (Note: This inclusion applies only to South Korea).


 
 
ExclusionCriteria 
Details  1. Patients who have received cytotoxic chemotherapy treatment for their current relapsed or refractory AML. (Treatment with hypomethylating agents (decitabine or azacytidine) either alone or in combination with venetoclax is allowed. Targeted therapies including FLT3 or IDH1/2 inhibitors or Hydrea or venetoclax are allowed. Targeted therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy) .
2. Vulnerable adult and patient whose health conditions does not allow them to give their consent.
3. History or evidence of any other clinically significant disorder, condition or disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, symptomatic myocardial infection, uncontrolled cardiac arrhythmia, pericardial disease or heart failure New York Heart Association Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ risk for toxicity and in the opinion of the Investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion.
4. Patients with active Central Nervous System (CNS) involvement (leukemic infiltration, blast in the spinal fluid).
5. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g active peptic ulcer disease)
bleeding diathesis (e.g. active peptic ulcer disease).
6. Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of CHAM or HAM therapy (the teratogenic potential of CPI-613® (devimistat) is unknown). Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at Screening.
7. Women of childbearing potential (i.e. women who are pre-menopausal or < 2 years postmenopausal or not surgically sterile) unwilling to practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods during treatment and for 6 months after completion of CHAM or HAM therapy for AML.
8. Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of CHAM or HAM therapy.
9. Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of CHAM or HAM therapy with potential highest teratogenic risk.
10. Known hypersensitivity to study treatment drugs or any of the excipient(s) contained in the drug formulation.
11. Life expectancy less than 3 months.
12. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients.
13. Unwilling or unable to follow protocol requirements.
14. Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly).
15. Patients with any amount of clinically significant pericardial effusion that requires drainage.
16. Evidence of ongoing, uncontrolled bacterial, viral or fungal infection.
17. Patients with known human immunodeficiency virus infection.
18. History of other malignancy within the past 5 years, with the following exception(s):
a. Malignancy treated with curative intent and with no known active disease present for ≥ 5 years before enrolment and felt to be at low risk for recurrence by the treating physician
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of recurrent or residual disease
c. Adequately treated cervical carcinoma in situ without evidence of disease
d. Prostate cancer Stage 1
19. Patients receiving any other standard or investigational treatment for AML, or any other investigational agent for any indication within the past 1 week prior to initiation of CPI-613® (devimistat) treatment (the use of Hydrea and/or venetoclax, oral tyrosine kinase inhibitors FLT3 or IDH 1/2 inhibitors is allowed until the day prior to starting CHAM or HAM therapy. Previous exposure to a hypomethylating agent either alone or in combination with venetoclax is allowed).
20. Patients who have received immunotherapy of any type within the past 1 week prior to initiation of CPI-613® (devimistat) treatment.
21. Requirement for immediate palliative treatment of any kind including minor surgery.
22. Patients who have received a chemotherapy regimen with autologous stem cell support (bone marrow transplantation) within 6 months.
23. Patients who have had allogenic bone marrow transplantation within the last 6 months. Patients who have had an allogenic transplant more than 6 months ago are eligible provided they have no graft vs host disease.
24. Cytarabine contraindications
a. Hypersensitivity to the cytarabine or to any of the excipients of cytarabine injection.
b. Anemia, leucopenia and thrombocytopenia of non-malignant aetiology (e.g bone marrow aplasia); unless the clinician feels that such management offers the most hopeful alternative for the patient.
c. Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation.
25. Mitoxantrone contraindications
a. Mitoxantrone Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride, other anthracyclines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances.
b. Mitoxantrone Sterile Concentrate should not be used during pregnancy or lactation
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
CR  a. 1st Interim Analysis: 14 months after first randomization
b. 2nd Interim Analysis: 25 months after first randomization
c. 3rd Interim Analysis: 36 Months after first randomization
 
 
Secondary Outcome  
Outcome  TimePoints 
OS (Overall survival)
CR and CRh (Complete remission and Complete remission with partial hematologic recovery)
Safety  		 From date of randomization to date of death
36 months after first randomization 
 
Target Sample Size   Total Sample Size="530"
Sample Size from India="30" 
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)   15/06/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  23/11/2018 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="4"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Open to Recruitment 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary   This is Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML). Both Male and Female can be enrolled in the study. 
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