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

Last updated: February 13, 2020
Sponsor: Fusion Pharma LLC
Overall Status: Active - Not Recruiting

Phase

1/2

Condition

Leukemia

Chronic Myeloid Leukemia

Platelet Disorders

Treatment

N/A

Clinical Study ID

NCT02885766
PF-114-01
  • Ages > 18
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

Inclusion Criteria: Patients must meet all of the following criteria in order to be eligible for participationin 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 EuropeanLeukemiaNet guideline as of 2013;

  4. Available information regarding resistance to the therapy with least one 2-ndgeneration Bcr-Abl inhibitor (dasatinib or nilotinib or bosutinib), or intolerance ofapproved Bcr-Abl inhibitors, or presence of T315I mutation irrespective of treatmenthistory;

  5. In case of previous history of blast crisis phase of CML at least 6 months arerequired 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'ssyndrome;

  • serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 XULN;

  • alkaline phosphatase ≤ 2.5 X ULN;

  • INR ≤ 1.5 X ULN;

  1. Adequate cardiac function defined as LVEF > 40 % by echocardiogram;

  2. QTcF < 470 ms;

  3. Patient has recovered (to Grade 1 or less according to NCI CTCAE V 4.0) fromtoxicities (excluding alopecia) associated with any prior treatments;

  4. Female patients of childbearing potential and male patients who have female partnersof childbearing potential must agree with abstinence from sexual relations or useeffective methods of contraception throughout participation in the study;

  5. Ability to comply with study procedures in the Investigator's opinion.

Exclusion

Exclusion Criteria: Patients must not meet any of the following criteria in order to be eligible forparticipation in the study:

  1. Use of the following previous therapy:

  2. 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 ≤ 42days prior to the first dose of PF-114 mesylate;

  3. approved tyrosine kinase inhibitors or investigational agents ≤ 4 days prior tothe first dose of PF-114;

  4. radiotherapy ≤ 28 days prior to the first dose of PF-114 ;

  5. autologous оr allogeneic stem сеll transplant < 90 days prior to enrollment;

  6. Significant uncontrolled cardiac disease;

  7. Sustained uncontrolled hypertension ≥ Grade 2 (according to NCI CTC AE v4);

  8. Patient is taking medicinal products known to prolong the QT interval on theelectrocardiogram, unless they are absolutely necessary in the opinion of theinvestigator;

  9. Evidence of on-going graft versus host disease (GVHD), or GVHD requiringimmunosuppressive therapy. Patients should be off immunosuppressive therapy forprophylaxis and/or treatment for at least 14 days prior to the first dose of PF-114;

  10. Major surgery within 35 days prior to enrollment;

  11. Uncontrolled intercurrent illness including, but not limited to the following: activesystemic infection, uncontrolled seizure disorder, psychiatric or social circumstancesthat would limit compliance with study requirements or misrepresent results of thestudy;

  12. Patient is unable to swallow study drug or has gastro-intestinal disorders that couldnegatively affect oral absorption of PF-114 ;

  13. Any malignancy other than CML within the past 3 years (except for non-melanoma skincancer or cervical cancer in situ).

  14. Pregnancy or breast feeding.

Study Design

Total Participants: 65
Study Start date:
July 01, 2016
Estimated Completion Date:
May 31, 2020

Study 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

Connect with a study center

  • Federal Haematological Scientific Center

    Moscow, 125167
    Russian Federation

    Site Not Available

  • Moscow City Centre of Hematology based on City Hospital named by S.Botkin

    Moscow, 125284
    Russian Federation

    Site Not Available

  • Federal Almazov North-West Medical Research Centre

    St. Petersburg,
    Russian Federation

    Site Not Available

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