This is an open-label, Phase I/Ib trial with a dose escalation phase, followed by a dose extension phase. The objective of the dose escalation phase is to evaluate the pharmacokinetics (PK) and MTD of P1446A-05 in relapsed/refractory CLL and the objective of the dose extension phase is to evaluate the safety, efficacy and pharmacodynamics of P1446A-05 in 14 patients at the MTD level.
Name: P1446A-05
Description: The study have dose escalation phase, followed by a dose extension phase. Dose escalation phase: five Dose Levels will be evaluated in the 'dose escalation' phase. The Dose Levels selected are 50 mg (Dose Level 1), 75 mg (Dose Level 2), 125 mg (Dose Level 3), 200 mg (Dose Level 4) and 275 mg (Dose Level 5), once daily. If required, a 25 mg once daily dose (Dose Level -1) will also be studied. For Dose Levels 1, 2 and 3 there will be 2- dosing periods: Single Dose and Continuous Dose. At least 3-patients will be enrolled at each Dose Level. Dosing regimens planned for Dose Level 4 and 5 are 200 and 275 mg once daily. In the continuous dose period, patients will receive P1446A-05 on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity. Dose Extension Phase: Up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the dose escalation phase, until the occurrence of disease progression or unacceptable toxicity or death.Type: DrugP1446A-05
Description: To establish maximum tolerated dose (MTD) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). There will be two phase, a dose escalation phase, followed by a dose extension phase. In the 'dose extension phase', up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the 'dose escalation' phase, until the occurrence of disease progression or unacceptable toxicity or death
Measure: Maximum Tolerated Dose Time: Cycle 1 (Day 1 to 28 )Description: To establish dose limiting toxicities (DLTs) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). - There will be two phase, a dose escalation phase, followed by a dose extension phase.
Measure: Dose Limiting Toxicity Time: Cycle 1 (Day 1 to 28 )Description: To determine the efficacy (overall response ) of P1446A 05 in patients with relapsed/refractory CLL. Overall Response will be assessed according to IWCLL 2008 criteria. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Measure: Overall response Time: At the end of every 2 cycles,Until disease progression or unacceptable toxicity (average of 2years)Description: To determine the efficacy (progression-free survival) of P1446A 05 in patients with relapsed/refractory CLL. Kaplan-Meier estimates of progression-free survival i.e. median and inter-quartile range will be presented. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Measure: Progression-free survival Time: At the end of every 2 cycles, until disease progression or unacceptable toxicity (average of 2years)Description: Samples for pharmacokinetic analysis for PK profile (Cmax,Tmax and AUC) will be collected on S-D1at pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post on Day S-D1 of single dose period (for Dose Levels 1, 2 and 3). In the continuous dose period, samples will be collected on Day 28 of Cycle 1 at pre-dose, and at 0.5, 2, 4, 6, 8 and 24 h post-dose. Additional samples will be collected pre dose on Day 15 and 22 of Cycle 1 to monitor the attainment of steady state. Pre-dose samples will also be collected on C2D15, C2D28, C3D15, C3D28 and C5D1. PK parameters will be obtained using standard non-compartmental methods. PK evaluations will not be performed in the dose extension phase. Descriptive statistics will be provided for the PK parameters. The PK analysis will be performed using WinNonlin software
Measure: Pharmacokinetic profile (Cmax,Tmax and AUC) Time: SD1, Cycle1-Cycle 5 (average of 5 month)Description: To assess whether established (IGHV, p53 and Notch mutational status and ZAP70 and CD38 expression,) and exploratory biomarkers (e.g. expression levels of Cyclin D1, p53 etc.) predict response to P1446A-05 in relapsed/refractory CLL
Measure: Biomarker Analysis Time: Cycle1Day1, Cycle1Day28, Until disease progression or unacceptable toxicity (average of 2years)Allocation: Non-Randomized
Single Group Assignment
There is one SNP
A Phase I/Ib Study of P1446A-05 in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).. Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) This is an open-label, Phase I/Ib trial with a dose escalation phase, followed by a dose extension phase. --- P1446A ---
The objective of the dose escalation phase is to evaluate the pharmacokinetics (PK) and MTD of P1446A-05 in relapsed/refractory CLL and the objective of the dose extension phase is to evaluate the safety, efficacy and pharmacodynamics of P1446A-05 in 14 patients at the MTD level. --- P1446A ---
The objective of the dose escalation phase is to evaluate the pharmacokinetics (PK) and MTD of P1446A-05 in relapsed/refractory CLL and the objective of the dose extension phase is to evaluate the safety, efficacy and pharmacodynamics of P1446A-05 in 14 patients at the MTD level. --- P1446A --- --- P1446A ---
To establish maximum tolerated dose (MTD) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). --- P1446A ---
In the 'dose extension phase', up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the 'dose escalation' phase, until the occurrence of disease progression or unacceptable toxicity or death. --- P1446A ---
To establish dose limiting toxicities (DLTs) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). --- P1446A ---
To determine the efficacy (overall response ) of P1446A 05 in patients with relapsed/refractory CLL. --- P1446A ---
To determine the efficacy (progression-free survival) of P1446A 05 in patients with relapsed/refractory CLL. --- P1446A ---
expression levels of Cyclin D1, p53 etc.) predict response to P1446A-05 in relapsed/refractory CLL. --- P1446A ---
P1446A-05 is both highly protein bound and a competitive inhibitor of CYP2C9 at higher concentrations and thus may potentiate the action of warfarin in patients 10. --- P1446A ---