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.

Phase 1

Conditions: Relapsed/Refractory Hematologic Malignancies

Registration Number: CTRI/2011/07/001858

Lead Sponsor: Piramal Life Sciences Limited

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 1960and 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.xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: Other

Sex: All

Target Recruitment: 100

Inclusion Criteria

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.

Exclusion Criteria

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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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 Measures

Name	Time	Method
Disease Status Assessment	After every 2 cycles (or prior to start of the next cycle)
Pharmacokinetics: Plasma Levels of P2745	Cycle 1
Urinary Metabolite(s) of P2745 Metabolite(s) (Optional)	Cycle 1
To describe the preliminary antineoplastic activity of P2745	Throughout the study

Trial Locations

Locations (7): Curie Manavata Cancer Centre
🇮🇳
Nashik, MAHARASHTRA, India
Jaslok Hospital and Research Centre
🇮🇳
Mumbai, MAHARASHTRA, India
Jehangir Clinical Development Centre Private Limited
🇮🇳
Pune, MAHARASHTRA, India
NRR Hospital
🇮🇳
Bangalore, KARNATAKA, India
SEAROC Cancer Center
🇮🇳
Jaipur, RAJASTHAN, India
St. Johns Medical College Hospital
🇮🇳
Bangalore, KARNATAKA, India
Tata Memorial Hospital
🇮🇳
Mumbai, MAHARASHTRA, India
Curie Manavata Cancer Centre
🇮🇳Nashik, MAHARASHTRA, India
Dr Rajnish Nagarkar
Principal investigator
drrajnagarkar@yahoo.co.in