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

NCT02885766 | Unknown Phase 1 DMC

• 1 other identifier: PF-114-01
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 3

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.

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

Outcome Measures

Primary Outcomes (2)

• DLTs during the first cycle of therapy

  To study the dose-limiting toxicities (DLTs) of PF-114 mesylate in the target patient population during the 1-st cycle of treatment

  1-st Cycle of Therapy - 28 days

• MTD

  Primary Objectives: To determine the maximum tolerated dose (MTD) of PF-114 in the target patient population.

  1-st Cycle of Therapy - 28 days

Secondary Outcomes (12)

• The incidence of AEs

  through study completion, an average of 1 year

• Cmax for oral PF-114 in the target patient population

  31 days

• Tmax for oral PF-114 in the target patient population

  31 days

• AUC0-t for oral PF-114 in the target patient population

  31 days

• AUC0-∞ for oral PF-114 in the target patient population

  31 days

Other Outcomes (5)

• Pharmacodynamic response criterion to PF-114 (change in the level of pCrkL in PBL during therapy compared to baseline level)

  20 months

• The number of patients who satisfy the pharmacodynamic response criterion depending on the mutation status of BCR-ABL

  20 months

• The number of patients who satisfy the hematologic response depending on the mutation status of BCR-ABL

  20 months

Study Arms (1)

PF-114

EXPERIMENTAL

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

Drug: PF-114

Interventions

PF-114 DRUG

PF-114

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet all of the following criteria in order to be eligible for participation in the study:
• Able to give written informed consent;
• Male or female patient ≥ 18 years old;
• Confirmed diagnosis of CML in chronic or accelerated phase according to European LeukemiaNet guideline as of 2013;
• 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;
• 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;
• ECOG performance status ≤ 2 (see Appendix 2);
• Adequate renal function defined as serum creatinine ≤ 1.5 times upper limit of normal (ULN);
• 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;
• Adequate cardiac function defined as LVEF \> 40 % by echocardiogram;
• QTcF \< 470 ms;

You may not qualify if:

• Patients must not meet any of the following criteria in order to be eligible for participation in the study:
• Use of the following previous therapy:
• 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;
• approved tyrosine kinase inhibitors or investigational agents ≤ 4 days prior to the first dose of PF-114;
• radiotherapy ≤ 28 days prior to the first dose of PF-114 ;
• autologous оr allogeneic stem сеll transplant \< 90 days prior to enrollment;
• Significant uncontrolled cardiac disease;
• Sustained uncontrolled hypertension ≥ Grade 2 (according to NCI CTC AE v4);
• 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;
• 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;
• Major surgery within 35 days prior to enrollment;
• 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;
• Patient is unable to swallow study drug or has gastro-intestinal disorders that could negatively affect oral absorption of PF-114 ;
• Any malignancy other than CML within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ).
• Pregnancy or breast feeding.

Sponsors & Collaborators

• Fusion Pharma LLC: lead
• OCT LLC: collaborator
• Data Matrix Solutions: collaborator
• Skolkovo Innovation Center: collaborator

Study Sites (3)

Federal Haematological Scientific Center

Moscow, 125167, Russia

Location

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

Moscow, 125284, Russia

Location

Federal Almazov North-West Medical Research Centre

Saint Petersburg, Russia

Location

Related Publications (2)

• 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.

  PMID: 25394714 RESULT

• Turkina A, Vinogradova O, Lomaia E, Shatokhina E, Shukhov O, Chelysheva E, Shikhbabaeva D, Nemchenko I, Petrova A, Bykova A, Siordiya N, Shuvaev V, Mikhailov I, Novikov F, Shulgina V, Hochhaus A, Ottmann O, Cortes J, Gale RP, Chilov G. Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia. Ann Hematol. 2025 May;104(5):2707-2715. doi: 10.1007/s00277-025-06239-8. Epub 2025 Apr 29.

  PMID: 40298994 DERIVED

Related Links

• doi:10.1038/leu.2014.326

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase

Interventions

PF-114

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Anna Turkina, Professor

  Federal Haematological Scientific Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2016
• First Posted: August 31, 2016
• Study Start: July 1, 2016
• Primary Completion: June 1, 2018
• Study Completion: May 1, 2020
• Last Updated: February 17, 2020

Record last verified: 2020-02

Locations

RU (3)