Clinical Trials /

Assess the Safety, Tolerability Oral PU-H71 in Subjects Taking Ruxolitinib

NCT03935555

Description:

This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in subjects with PMF, Post-PV MF, Post-ET MF, taking stable doses of ruxolitinib.

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Assess the Safety, Tolerability Oral PU-H71 in Subjects Taking Ruxolitinib
  • Official Title: Phase 1b Study of PU-H71 for the Treatment of Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), Treated With Ruxolitinib

Clinical Trial IDs

  • ORG STUDY ID: PU-H71-01-003
  • NCT ID: NCT03935555

Conditions

  • Primary Myelofibrosis (PMF)
  • Post-Polycythemia Vera Myelofibrosis (Post-PV MF)
  • Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF)

Interventions

DrugSynonymsArms
PU-H71Oral - 50mg

Purpose

This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in subjects with PMF, Post-PV MF, Post-ET MF, taking stable doses of ruxolitinib.

Detailed Description

      The study will employ a standard 3+3 dose escalation design to determine maximum tolerated
      dose (MTD) and recommended Phase 2 dose (RP2D), with additional subjects treated in a dose
      expansion cohort. The time period for collecting dose limiting toxicities (DLTs) is 1 cycle
      (21 days).
    

Trial Arms

NameTypeDescriptionInterventions
Oral - 50mgExperimentalPU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
  • PU-H71
Oral -100 mgExperimentalPU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
  • PU-H71
Oral - 200 mgExperimentalPU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
  • PU-H71
Oral - 300 mgExperimentalPU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
  • PU-H71

Eligibility Criteria

        Inclusion Criteria:

          1. Subject is willing and able to provide written informed consent before any
             study-specific procedures are performed.

          2. Subject is willing to comply with all study procedures and restrictions.

          3. Subject is ≥18 years of age.

          4. Subject has confirmed diagnosis of PMF, Post-PV MF, or Post-ET MF.

          5. Subject has been receiving ruxolitinib therapy meeting the following criteria:

               -  Receiving ruxolitinib >3 months prior to enrollment.

               -  Stable dose for 8 weeks before starting therapy with PU-H71.

          6. Subject with evidence of evaluable residual burden of disease following ruxolitinib
             monotherapy treatment, consisting of:

             • Persistent or worsening disease-related symptoms, including but not limited to
             fatigue, pruritus, night sweats, early satiety, and other symptoms as determined by a
             Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
             score of >12 points.

             AND

             • Documented splenomegaly of at least 5 cm below the costal margin as measured on
             inspiration by physical examination.

          7. Subject has an Eastern Cooperative Oncology Group performance status of 0 to 2.

          8. Acceptable pre-study organ function during screening defined as:

               -  Absolute neutrophil count (ANC) ≥1000/µL.

               -  Platelet count ≥50,000/µL.

               -  Alanine aminotransferase or aspartate aminotransferase ≤2×upper limit of normal.

               -  Direct serum bilirubin ≤ 1.5×upper limit of normal.

               -  Creatinine clearance >50 mL/min/1.73 m2 based on the Cockcroft Gault equation.

          9. If female and of childbearing potential (premenopausal and not surgically sterile),
             the subject:

               -  Must have a negative serum or urine pregnancy test at screening. The serum
                  pregnancy test must be obtained prior to the first administration of PU-H71 (≤72
                  hours prior to dosing) in all premenopausal women and women <2 years after the
                  onset of menopause.

               -  Must agree to use an acceptable method of effective contraception for the
                  duration of the study and for 13 weeks after receiving the last dose of study
                  treatment.

         10. If male, the subject agrees to:

               -  Use an acceptable method of effective contraception for the duration of the study
                  and for 13 weeks after receiving study treatment.

               -  Agrees to abstain from sperm donation for the duration of the study and for 13
                  weeks after receiving the last dose of study treatment

        Exclusion Criteria:

          1. Subject has known active liver disease, including viral hepatitis or cirrhosis.

          2. Subject has known or suspected human immunodeficiency virus (HIV) or other active
             infections requiring acute or chronic treatment with systemic antibiotics. Conditions
             requiring topical antibiotics are acceptable.

          3. Subject has a QT interval corrected using Fridericia's formula (QTcF) >480 ms
             (corrected) in the screening or baseline ECG based on median value of ECG's obtained.

          4. Subject has left ventricular ejection fraction (LVEF) ≤50%, or below institution's
             lower limit of normal (whichever is lower), by echocardiogram or multigated
             acquisition (MUGA) scan.

          5. Subject has a history (or family history) of long QT syndrome.

          6. Subject has coronary artery disease with an ischemic event within 6 months prior to
             screening.

          7. Subject has a permanent cardiac pacemaker.

          8. Subject has history of a second primary malignancy within the past 2 years, except for
             the following (if appropriately treated and considered cured): Stage I endometrial,
             surgically treated cervical or prostate carcinoma, and non-melanoma skin cancer.

          9. Subject has significant uncontrolled medical condition within 6 months prior to
             screening, as determined by the Investigator.

         10. Subject has planned use of antineoplastic agents (chemotherapy or cytotoxic drugs),
             immunotherapy, experimental therapy, or biologic therapy for treatment of MPN with the
             exception of ruxolitinib.

         11. Subject uses systemic corticosteroids (ie, prednisone >12.5 mg/day or dexamethasone >2
             mg/day) within 2 weeks prior to Cycle 1 Day 1.

         12. Subject has planned or current use of strong CYP3A4/5, CYP2D6, or CYP2C19 inhibitors
             or inducers within 1 week or 5 half-lives (whichever is longer) prior to Cycle 1 Day
             1.

         13. Subject has planned or current use of medications that carry a risk for Torsades de
             Pointes within 1 week or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.

         14. Subject has planned or current use of herbal preparations/medications at least 7 days
             prior to Cycle 1 Day 1.

         15. Subject has previously received PU-H71.

         16. Subject has concurrent participation in any interventional studies (except
             PU-H71-Positive Emission Tomography (PET) Scan Studies) within 14 days or 5 half-lives
             (whichever duration is longer) of Cycle 1 Day 1.

         17. Subject has uncontrolled diabetes mellitus, in the judgment of the Investigator.

         18. Subject has any other condition or laboratory abnormality or receives any other
             treatment(s) that may increase the risk associated with study participation or may
             interfere with the interpretation of study results in the judgment of the
             Investigator.

         19. Subject has an active ocular condition that in the opinion of the Investigator, may
             alter visual acuity during the course of the study (ie, ocular inflammatory disease,
             etc.) or a history or anticipation of major ocular surgery (including cataract
             extraction, intraocular surgery, etc.) during the study.

         20. Women who are pregnant or breastfeeding or plan to become pregnant.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assess Safety, Tolerability and Pharmacokinetics of PU-H71
Time Frame:24 weeks
Safety Issue:
Description:Determine the human exposure PK including Cmax

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Samus Therapeutics, Inc.

Trial Keywords

  • Primary Myelofibrosis (PMF)
  • Post-Polycythemia Vera Myelofibrosis (Post-PV MF)
  • Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF)

Last Updated

August 12, 2019