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CTRI Number  CTRI/2011/07/001858 [Registered on: 01/07/2011] Trial Registered Prospectively
Last Modified On: 23/05/2013
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Single Arm Study 
Public Title of Study   A clinical trial to study the Safety and Tolerability of Daily Oral Administration of P2745 in Patients with blood cancer which is not responding to treatment or apearing again after initial response. 
Scientific Title of Study   A Phase 1, Open Label, Multicenter, Dose Escalating Cohort Study to Evaluate the Safety and Tolerability of Daily Oral Administration of P2745 in Patients with Relapsed/Refractory Hematologic Malignancies 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
P2745/50/10  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Rajnish Nagarkar  
Designation  Consultant 
Affiliation  Curie Manavata Cancer Centre 
Address  Curie Manavata Cancer Centre, Opposite Mahamarg Bus Stand, Mumbai Naka, Nashik

Nashik
MAHARASHTRA
422004
India 
Phone  0253-2592666  
Fax    
Email  drrajnagarkar@yahoo.co.in  
 
Details of Contact Person
Scientific Query  
Name  Dr Shivani Acharya 
Designation  Assistant General Manager- Clinical Research 
Affiliation  Piramal Life sciences limited 
Address  Piramal Life Sciences Limited 1, Nirlon Complex, Off Western Express Highway, Nr NSE Complex, Goregaon (E),Mumbai Maharashtra, India

Mumbai (Suburban)
MAHARASHTRA
400 063
India 
Phone  02230818079  
Fax    
Email  shivani.acharya@piramal.com  
 
Details of Contact Person
Public Query  
Name  Dr Shivani Acharya 
Designation  Assistant General Manager- Clinical Research 
Affiliation  Piramal Life sciences limited 
Address  Piramal Life Sciences Limited 1, Nirlon Complex, Off Western Express Highway, Nr NSE Complex, Goregaon (E),Mumbai Maharashtra, India


MAHARASHTRA
400 063
India 
Phone  02230818079  
Fax    
Email  shivani.acharya@piramal.com  
 
Source of Monetary or Material Support  
Piramal Life Sciences Limited 1, Nirlon Complex, Off Western Express Highway, Nr NSE Complex, Goregaon (E),Mumbai-400 063, Maharashtra, India 
 
Primary Sponsor  
Name  Piramal Life Sciences Limited 
Address  Piramal Life Sciences Limited 1, Nirlon Complex, Off Western Express Highway, Nr NSE Complex, Goregaon (E),Mumbai-400 063, Maharashtra, India 
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
None   
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 7  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Rajnish Nagarkar  Curie Manavata Cancer Centre  Opposite Mahamarg Bus Stand Mumbai Naka Nashik
Nashik
MAHARASHTRA 		 0253-2592666

drrajnagarkar@yahoo.co.in 
Dr Suresh H Advani  Jaslok Hospital and Research Centre  Jaslok Hospital and Research Centre, Peddar Road, 15, Dr. G. Deshmukh Marg, Mumbai -400026, India
Mumbai
MAHARASHTRA 		 02266573254

shadvani2000@yahoo.com 
Dr Vijay Ramanan  Jehangir Clinical Development Centre Private Limited  Jehangir Clinical Development Centre Private Limited, Jehangir Hospital, Premises 32, Sassoon Road, Pune- 411001, India
Pune
MAHARASHTRA 		 919325315471

mvijayr@gmail.com 
Dr Yathish Kumar  NRR Hospital  No. 3 & 3A, Hesarghatta Main Road, Chikkasandra, Near Chikkabanavara Railway Station, Bangalore
Bangalore
KARNATAKA 		 080-283741115

dryathish@hotmail.com 
Dr Anish Maru  SEAROC Cancer Center  SEAROC Cancer Center, S. K. Soni Hospital, Sector 5, Vidhyadhar Nagar, Sikar Road, Jaipur-302013
Jaipur
RAJASTHAN 		 919829060128

anishmaru@yahoo.com 
Dr Cecil Ross  St. Johns Medical College Hospital  St. Johns Medical College Hospital, Department of Medicine, Sarjapur Road, Koramangala, Bangalore - 560034, India
Bangalore
KARNATAKA 		 08025531984

cecilross@bsnl.in 
Dr Hari Menon  Tata Memorial Hospital  Tata Memorial Hospital, Dr. E.Borges Road, Parel, Mumbai- 400012, India
Mumbai
MAHARASHTRA 		 02224177210

vadakepat68@yahoo.co.in 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 7  
Name of Committee  Approval Status 
Institutional Ethics Committee   Approved 
Institutional ethics review board  Approved 
Institutional review board  Approved 
JCDC Institutional review board  Approved 
Manavata Clinical Research Institute, Professional Ethics Committee  Approved 
SEAROC ETHICS COMMITTEE  Approved 
The Institutional ethics committee of jaslok hospital and research centre  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Relapsed/Refractory Hematologic Malignancies,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  P2745  P2745 will be provided n tablets form. 400 mg/day will be administered in Cohort 1. Dose will be increased until the dose level is reached in which 1 patient within a cohort experiences a toxicity during Cycle 1. Or 2 patients within a cohort experience relatively mild toxicity during Cycle 1. The maximum dose to be administered will depend upon the observed tolerability of P2745. Each cycle is equal to 28 days of which 21 days will be daily oral dosing and 7 days rest period. Solid tablet will be available in 2 dosage strengths: 75 and 400 mg. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1. Male or female patients, of any race or ethnic group, of 18 years or more to less than 60 years of age.
2. Patients with a documented (histologically- or cytologically-proven), hematological malignancy that is relapsed or refractory to prior therapeutic regimens, and for whom no available standard therapeutic options that are anticipated to result in a durable remission.
3. Patients enrolled into DOSE ESCALATION COHORTS must have one of the following hematologic malignancies:
Relapsed/refractory leukemias by WHO classification, including ALL, AML, CLL, CML, CMML
Poor-risk myeoldysplastic syndrome (MDS) by WHO classification (i.e. RAEB-1 or RAEB-2)
Myelofibrosis (MF)

4. Patients enrolled into the MTD EXPANSION COHORT must have CML in chronic or accelerated (but not blast) phase, and meet all other eligibility criteria.

5. Patients with an ECOG performance status of less than 2, and an anticipated life expectancy of 3 months and more
6. Patients able to take oral tablets
7. Patients, male and female, who are either not of childbearing potential or who agree to use a medically effective method of contraception during the study and for 1 month after the last dose of study drug
8. Patients with the ability to understand and give written informed consent.
 
 
ExclusionCriteria 
Details  1. Patients with inadequate recovery from toxicity associated with any prior antineoplastic therapy (generally less than Grade 1 will be considered eligible)
2. Patients with CNS (or leptomeningeal) involvement by their disease or symptoms suggesting CNS involvement
3. Women who are pregnant or lactating
4. Patients with any of the following serum chemistry abnormalities:
Total bilirubin higher than 1.5x the ULN unless considered due to Gilbert’s Syndrome
AST or ALT more than 3x the ULN (more than 5x ULN if due to leukemic hepatic involvement).
Serum creatinine more than 1.2x ULN (or a calculated creatinine clearance less than 60 mL/min/1.73 m2)
5. Patients with active, uncontrolled bleeding or with INR ULN for the institution
6. Patients with a significant cardiovascular disease or condition, including:
Uncontrolled congestive heart failure defined as NYHA Class II to IV
History of a clinically significant ventricular arrhythmia such as ventricular tachycardia, ventricular fibrillation, Torsades de pointes, or arrhythmias not controlled by medication,
Diagnosed or suspected congenital or acquired prolonged QT syndrome; history of prolonged QTc interval; prolonged QTc interval (more than 0.45 sec)
Unexplained syncope
Uncontrolled hypertension within 3 months of study entry
Symptomatic coronary heart disease (angina)
Myocardial infarction within 12 months of study entry

7. Patients with significant gastrointestinal (GI) abnormalities, including:
Prior surgical procedures affecting absorption; short bowel syndrome
Malabsorption, GI bleeding within 1 month of study entry
Vomiting or diarrhea of of more than 2 days duration within 2 weeks of study entry

8. Patients with treated or untreated graft versus host disease (GVHD) within 2 months of study entry
9. Patients with a history of allergic reactions attributable to compounds of similar chemical or biologic composition to P2745 (i.e., oxadiazole derivatives)
10. Patients with known seropositivity to HIV, known current acute or chronic Hepatitis B, known Hepatitis C (antigen positive), or hepatic cirrhosis
11. Patients with any other serious/active infection, or any infection requiring parenteral antibiotics
12. Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks of study entry
13. Patients with any other life-threatening illness, significant organ system dysfunction, or clinically significant laboratory abnormality, which would either compromise the patient’s safety or interfere with evaluation of the safety of the study drug
14. Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary studies
15. Patients with the inability to comply with the protocol requirements
 
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
To determine the safety, tolerability, dose-limiting toxicities (DLT), and maximally tolerated dose (MTD) of escalating doses of P2745  MTD at the end of cycle 1 and will be assessed for MTD Throughout the study 
 
Secondary Outcome  
Outcome  TimePoints 
Disease Status Assessment   After every 2 cycles (or prior to start of the next cycle)
End of Study
1 Month Follow-up
As clinically indicated (in patients with hematologic response 
Pharmacokinetics: Plasma Levels of P2745  Cycle 1
Day 1
Pre-dose (within 30 minutes prior to dosing)30 min,1 h,2h,4h,6h,8h,12h,24h
Day 8 and Day 15
Pre-dose (within 30 minutes prior to dosing),
Day 21
Pre-dose,30 min,1h,2h,4h,6h,8h,12h,24h,36h
48h.
Cycle 2
Day 1
Pre-dose

Day 15
Pre-dose

Subsequent Cycles
Day 1
Pre-dose

Day 15
Pre-dose
End of Study
 
Urinary Metabolite(s) of P2745 Metabolite(s) (Optional)  Cycle 1
Day 1
Pre-dose

Day 21
0-4 h (after study drug administration)
4-24 h (ends prior to next day’s dosing)
24-48 hours (if possible)
 
To describe the preliminary antineoplastic activity of P2745   Throughout the study 
 
Target Sample Size   Total Sample Size="100"
Sample Size from India="100" 
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 1 
Date of First Enrollment (India)   15/07/2011 
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="2"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Other (Terminated) 
Publication Details    
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary  

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system that leads to increased numbers of myelocytes, erythrocytes, and thrombocytes in peripheral blood.  The molecular hallmark of CML is the Philadelphia chromosome, first described as shortened chromosome 22 in 1960 and then as a reciprocal t(9;22) translocation in 1973.  This abnormal chromosome is found in cells from the myeloid, erythroid, megakaryocytic, and B lymphoid lineages, indicating the presence of a “cancer stem cell” that is capable of producing several types of differentiated cancer cells.

As in the West, imatinib mesylate (Gleevec®) has supplanted busulphan, hydroxyurea (HU), and interferon-á as first-line treatment.  Its use has resulted in a dramatic decline in the number of hematopoietic stem cell transplantations (HSCT) performed.  Although it is expensive, imatinib induces a complete cytogenetic response in 60–90% of newly diagnosed patients, and up to 10% for those in blastic phase.  In spite of the significant, immediate and sustained effect of imatinib in chronic phase CML, as shown in the IRIS study , at least 30% of patients on imatinib need another modality of treatment within 5 years of initial treatment while others require alternative treatment even earlier.  In India, imatinib-resistant cases usually revert to HU therapy.

Based on the results from in-vitro and in-vivo studies, P2745 has potential activity versus T3151-mutated CML cells as well as wild-type cells, addressing a currently unmet clinical need. 

 

 
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