Clinical trial NCT02885766: 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
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Chronic Myeloid Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Keywords: CML
Myeloid leukaemia chronic
CML progression
Chronic phase chronic myeloid leukemia
PF-114
Cytogenetic response CCyR
Major molecular response MMR
Complete molecular response CMR
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
2-nd generation Bcr-Abl inhibitors resistant
Lead sponsor: Fusion Pharma LLC
Sponsor class: INDUSTRY
Collaborators: name: OCT LLC
name: Data Matrix Solutions
name: Skolkovo Innovation Center
First posted: 2016-08-31
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

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

Eligibility criteria: 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. In case of previous history of blast crisis phase of CML at least 6 months are required to pass after the end of blast crisis phase before the first dose of PF-114;
6. ECOG performance status ≤ 2 (see Appendix 2);
7. Adequate renal function defined as serum creatinine ≤ 1.5 times upper limit of normal (ULN);
8. Adequate hepatic function defied as:

   * serum bilirubin ≤ 1.5 X ULN unless a patient is diagnosed with Gilbert's syndrome;
   * serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 X ULN;
   * alkaline phosphatase ≤ 2.5 X ULN;
   * INR ≤ 1.5 X ULN;
9. Adequate cardiac function defined as LVEF \> 40 % by echocardiogram;
10. QTcF \< 470 ms;
11. Patient has recovered (to Grade 1 or less according to NCI CTCAE V 4.0) from toxicities (excluding alopecia) associated with any prior treatments;
12. Female patients of childbearing potential and male patients who have female partners of childbearing potential must agree with abstinence from sexual relations or use effective methods of contraception throughout participation in the study;
13. Ability to comply with study procedures in the Investigator's opinion.

Exclusion Criteria:

Patients must not meet any of the following criteria in order to be eligible for participation in the study:

1. Use of the following previous therapy:

   1. chemotherapy ≤ 21 days (except hydroxyurea for which washout is not required) prior to the first dose of PF-114 mesylate; оr nitrosoureas оr mitomycin С ≤ 42 days prior to the first dose of PF-114 mesylate;
   2. approved tyrosine kinase inhibitors or investigational agents ≤ 4 days prior to the first dose of PF-114;
   3. radiotherapy ≤ 28 days prior to the first dose of PF-114 ;
   4. autologous оr allogeneic stem сеll transplant \< 90 days prior to enrollment;
2. Significant uncontrolled cardiac disease;
3. Sustained uncontrolled hypertension ≥ Grade 2 (according to NCI CTC AE v4);
4. Patient is taking medicinal products known to prolong the QT interval on the electrocardiogram, unless they are absolutely necessary in the opinion of the investigator;
5. Evidence of on-going graft versus host disease (GVHD), or GVHD requiring immunosuppressive therapy. Patients should be off immunosuppressive therapy for prophylaxis and/or treatment for at least 14 days prior to the first dose of PF-114;
6. Major surgery within 35 days prior to enrollment;
7. Uncontrolled intercurrent illness including, but not limited to the following: active systemic infection, uncontrolled seizure disorder, psychiatric or social circumstances that would limit compliance with study requirements or misrepresent results of the study;
8. Patient is unable to swallow study drug or has gastro-intestinal disorders that could negatively affect oral absorption of PF-114 ;
9. Any malignancy other than CML within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ).
10. Pregnancy or breast feeding.

Primary outcomes:
measure: DLTs during the first cycle of therapy
timeFrame: 1-st Cycle of Therapy - 28 days
measure: MTD
timeFrame: 1-st Cycle of Therapy - 28 days
Secondary outcomes:
measure: The incidence of AEs
timeFrame: through study completion, an average of 1 year
measure: Cmax for oral PF-114 in the target patient population
timeFrame: 31 days
measure: Tmax for oral PF-114 in the target patient population
timeFrame: 31 days
measure: AUC0-t for oral PF-114 in the target patient population
timeFrame: 31 days
measure: AUC0-∞ for oral PF-114 in the target patient population
timeFrame: 31 days
measure: T1/2 for oral PF-114 in the target patient population
timeFrame: 31 days
measure: CL/F for oral PF-114 in the target patient population
timeFrame: 31 days
measure: Vd/F for single and multiple dosing for oral PF-114 in the target patient population
timeFrame: 31 days
measure: Ctrough for multiple dosing for oral PF-114 in the target patient population
timeFrame: 31 days
measure: Hematological response to the treatment based on European LeukemiaNet criteria, 2013.
timeFrame: through study completion, an average of 1 year
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.
timeFrame: through study completion, an average of 1 year
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).
timeFrame: through study completion, an average of 1 year
Other outcomes:
measure: Pharmacodynamic response criterion to PF-114 (change in the level of pCrkL in PBL during therapy compared to baseline level)
timeFrame: 20 months
measure: The number of patients who satisfy the pharmacodynamic response criterion depending on the mutation status of BCR-ABL
timeFrame: 20 months
measure: The number of patients who satisfy the hematologic response depending on the mutation status of BCR-ABL
timeFrame: 20 months
measure: The number of patients who satisfy the cytogenetic response depending on the mutation status of BCR-ABL
timeFrame: 20 months
measure: The number of patients who satisfy the molecular response depending on the mutation status of BCR-ABL
timeFrame: 20 months
Locations:
city: Moscow
country: Russian Federation
facility: Federal Haematological Scientific Center
city: Moscow
country: Russian Federation
facility: Moscow City Centre of Hematology based on City Hospital named by S.Botkin
city: St. Petersburg
country: Russian Federation
facility: Federal Almazov North-West Medical Research Centre
Study officials:
affiliation: Federal Haematological Scientific Center
name: Anna Turkina, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mian AA, Rafiei A, Haberbosch I, Zeifman A, Titov I, Stroylov V, Metodieva A, Stroganov O, Novikov F, Brill B, Chilov G, Hoelzer D, Ottmann OG, Ruthardt M. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia. 2015 May;29(5):1104-14. doi: 10.1038/leu.2014.326. Epub 2014 Nov 14.