A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene.
Name: PF-114
Description: To study the dose-limiting toxicities (DLTs) of PF-114 mesylate in the target patient population during the 1-st cycle of treatment
Measure: DLTs during the first cycle of therapy Time: 1-st Cycle of Therapy - 28 daysDescription: Primary Objectives: To determine the maximum tolerated dose (MTD) of PF-114 in the target patient population.
Measure: MTD Time: 1-st Cycle of Therapy - 28 daysDescription: To assess the safety and tolerability of PF-114 in the target patient population
Measure: The incidence of AEs Time: through study completion, an average of 1 yearDescription: Hematological response is evaluated on Day 1 of each therapy cycle Full hematologic response: Leukocytes < 10 х 109 /L Basophils < 5 % Thrombocytes < 450 х 109 /L No myelocytes, promyelocyts, myeloblasts in the differential Absence of splenomegaly - spleen non palpable
Measure: Hematological response to the treatment based on European LeukemiaNet criteria, 2013. Time: through study completion, an average of 1 yearDescription: Molecular response is evaluated on Day 1 of Cycles 2, 4, 7, 10. For cycles > 12, the molecular response will be evaluated once in 3 months, where the procedure is carried out for the first time during Cycle 13.
Measure: Molecular response - the level of BCR-ABL transcripts in the peripheral blood, determined by the method of quantitative polymerase chain reaction (qPCR) using the international scale. Time: through study completion, an average of 1 yearDescription: Cytogenetic response is evaluated on Day 1, Cycles 4, 7, 13. Then if the level of BCR-ABL transcripts exceeds the level of 0.1% using the qPCR method using the international scale, cytogenetic response is evaluated no earlier than in 3 months after the previous cytogenetic analysis. After the complete cytogenetic response has been reached (CCyR), cytogenetic analysis will be carried out every 12 months.
Measure: Cytogenetic response evaluated using the chromosome banding method (in situ (FISH) fluorescence hybridization is allowed only if the chromosome banding method cannot provide enough information). Time: through study completion, an average of 1 yearDescription: To assess pharmacodynamic response to PF-114 mesylate in patients who are not in complete hematologic response upon enrollment into the study by measuring the difference of pCrkL levels in peripheral blood leukocytes (PBL) during therapy compared to baseline
Measure: Pharmacodynamic response criterion to PF-114 (change in the level of pCrkL in PBL during therapy compared to baseline level) Time: 20 monthsAllocation: N/A
Single Group Assignment
There is one SNP
A Multicenter, Open Label Cohort Phase 1 Dose Finding Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 Mesylate for Oral Administration in Adult Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML), Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene. --- T315I ---
Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene. --- T315I ---
Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene. --- T315I --- --- T315I ---
Inclusion Criteria: Patients must meet all of the following criteria in order to be eligible for participation in the study: 1. Able to give written informed consent; 2. Male or female patient ≥ 18 years old; 3. Confirmed diagnosis of CML in chronic or accelerated phase according to European LeukemiaNet guideline as of 2013; 4. Available information regarding resistance to the therapy with least one 2-nd generation Bcr-Abl inhibitor (dasatinib or nilotinib or bosutinib), or intolerance of approved Bcr-Abl inhibitors, or presence of T315I mutation irrespective of treatment history; 5. --- T315I ---
Preclinical in vitro and in vivo studies have demonstrated the ability of PF-114 to inhibit wild Bcr-Abl type and with T315I mutation, as well as other kinds of Bcr-Abl with mutations in kinase domain, including combined mutations. --- T315I ---
Indication: Adult patients with Ph+ CML in chronic phase (CP) or accelerated phase (AP) resistant to previous treatment with at least one 2-nd generation inhibitor of Bcr-Abl (dasatinib, nilotinib, bosutinib) or intolerant of approved Bcr-Abl inhibitors or with T315I mutation in the BCR-ABL gene --- T315I ---