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
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|ClinicalTrials.gov Identifier: NCT02885766|
Recruitment Status : Recruiting
First Posted : August 31, 2016
Last Update Posted : February 15, 2019
|Condition or disease||Intervention/treatment||Phase|
|Chronic Myeloid Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive||Drug: PF-114||Phase 1 Phase 2|
PF-114 is a low molecular inhibitor of a Bcr-Abl kinase activity, which is active with respect to native and mutated forms of this enzyme with mutations in Abl kinase domain. 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.
In contrast to ponatinib, PF-114 is being developed to increase the action selectivity with respect to Bcr-Abl, which potentially should increase safety of drug application in people. The results of performed preclinical studies confirmed improved selectivity of PF-114 action with respect to Bcr-Abl kinases as compared to ponatinib.
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
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||44 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||July 2016|
|Actual Primary Completion Date :||June 2018|
|Estimated Study Completion Date :||April 2019|
PF-114 From 50 mg up to the MTD. Dose escalation for each next cohort is conducted by increasing the dose by 20 % (or the closest lower level, which is a multiple of 25 mg) if there are Grade 3 ADRs according to NCI CTC AE v.4 without reaching а MTD. An increase of the dose by 40 % is applied if there were Grade 2 ADRs. In the absence of Grade 2 or 3 ADRs an increase of 100 % is applied.
When the dose reaches 400 mg/day, the following increase in dose can be made after discussing results of safety findings of PF-114 between the Investigators and the Sponsor.
Orally, once daily
- DLTs during the first cycle of therapy [ Time Frame: 1-st Cycle of Therapy - 28 days ]To study the dose-limiting toxicities (DLTs) of PF-114 mesylate in the target patient population during the 1-st cycle of treatment
- MTD [ Time Frame: 1-st Cycle of Therapy - 28 days ]
To determine the maximum tolerated dose (MTD) of PF-114 in the target patient population.
- The incidence of AEs [ Time Frame: through study completion, an average of 1 year ]To assess the safety and tolerability of PF-114 in the target patient population
- Cmax for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- Tmax for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- AUC0-t for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- AUC0-∞ for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- T1/2 for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- CL/F for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- Vd/F for single and multiple dosing for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- Ctrough for multiple dosing for oral PF-114 in the target patient population [ Time Frame: 31 days ]
- Hematological response to the treatment based on European LeukemiaNet criteria, 2013. [ Time Frame: through study completion, an average of 1 year ]
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
- 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 Frame: through study completion, an average of 1 year ]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.
- 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 Frame: through study completion, an average of 1 year ]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.
- Pharmacodynamic response criterion to PF-114 (change in the level of pCrkL in PBL during therapy compared to baseline level) [ Time Frame: 20 months ]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
- The number of patients who satisfy the pharmacodynamic response criterion depending on the mutation status of BCR-ABL [ Time Frame: 20 months ]
- The number of patients who satisfy the hematologic response depending on the mutation status of BCR-ABL [ Time Frame: 20 months ]
- The number of patients who satisfy the cytogenetic response depending on the mutation status of BCR-ABL [ Time Frame: 20 months ]
- The number of patients who satisfy the molecular response depending on the mutation status of BCR-ABL [ Time Frame: 20 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02885766
|Contact: Veronika Shulgina, PhD||+7 916 815 05 firstname.lastname@example.org|
|Contact: Ghermes Chilov, PhD||+7 916 307 48 email@example.com|
|Federal Haematological Scientific Center||Recruiting|
|Moscow, Russian Federation, 125167|
|Contact: Anna Turkina, Professor 7 495 612 44 72 firstname.lastname@example.org|
|Contact: Oleg Shukhov, PhD +7 985 287 12 69 email@example.com|
|Moscow City Centre of Hematology based on City Hospital named by S.Botkin||Recruiting|
|Moscow, Russian Federation, 125284|
|Contact: Olga Vinogradova, Prof. DMSci +7(495)945-97-61 firstname.lastname@example.org|
|Federal Almazov North-West Medical Research Centre||Recruiting|
|St. Petersburg, Russian Federation|
|Contact: Elza Lomaia, MD, PhD +7 981 936 16 67 email@example.com|
|Principal Investigator:||Anna Turkina, Professor||Federal Haematological Scientific Center|