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

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ClinicalTrials.gov Identifier: NCT03935555
Recruitment Status : Recruiting
First Posted : May 2, 2019
Last Update Posted : October 20, 2020
Sponsor:
Information provided by (Responsible Party):
Samus Therapeutics, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Primary Myelofibrosis (PMF) Post-Polycythemia Vera Myelofibrosis (Post-PV MF) Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF) Drug: PU-H71 Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model 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).
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 12, 2019
Estimated Primary Completion Date : May 15, 2021
Estimated Study Completion Date : May 15, 2021


Arm Intervention/treatment
Experimental: Oral - 50mg
PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
Drug: PU-H71
PU-H71 is a synthetic purine-scaffold stress chaperome inhibitor, which specifically targets HSP90 in the tumor-specific epichaperome

Experimental: Oral -100 mg
PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
Drug: PU-H71
PU-H71 is a synthetic purine-scaffold stress chaperome inhibitor, which specifically targets HSP90 in the tumor-specific epichaperome

Experimental: Oral - 200 mg
PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
Drug: PU-H71
PU-H71 is a synthetic purine-scaffold stress chaperome inhibitor, which specifically targets HSP90 in the tumor-specific epichaperome

Experimental: Oral - 300 mg
PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).
Drug: PU-H71
PU-H71 is a synthetic purine-scaffold stress chaperome inhibitor, which specifically targets HSP90 in the tumor-specific epichaperome




Primary Outcome Measures :
  1. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including Cmax

  2. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including Tmax

  3. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including AUC0-t

  4. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including AUC0-inf

  5. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including CL

  6. Assess Safety, Tolerability and Pharmacokinetics of PU-H71 [ Time Frame: 24 weeks ]
    Determine the human exposure PK including t1/2

  7. Assess Safety and Tolerability of PU-H71 [ Time Frame: 24 weeks ]
    Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in physical examinations

  8. Assess Safety and Tolerability of PU-H71 [ Time Frame: 24 weeks ]
    Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in electrocardiograms (ECGs)

  9. Assess Safety and Tolerability of PU-H71 [ Time Frame: 24 weeks ]
    Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in vital signs

  10. Assess Safety and Tolerability of PU-H71 [ Time Frame: 24 weeks ]
    Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in clinical laboratory evaluations

  11. Assess treatment response of PU H71 [ Time Frame: 24 weeks ]
    Treatment response in myelofibrosis (MF) is to be evaluated using the revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

  12. Assess treatment response of PU H71 [ Time Frame: 24 weeks ]
    Treatment response in myelofibrosis (MF) is to be evaluated using the revised European LeukemiaNet (ELN) response criteria.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

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): NCT03935555


Contacts
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Contact: Carol Becker 646-902-9376 beckerc@samustherapeutics.com

Locations
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United States, California
Marin Cancer Care - Greenbrae (California Cancer Care A Medical Group, Inc. - Greenbrae) Recruiting
Larkspur, California, United States, 94904
Contact: Peter Eisenberg, MD    415-925-5000    peisenberg@marincancercare.com   
Ronald Reagan UCLA Medical Center Recruiting
Los Angeles, California, United States, 90095
Contact: Gary Schiller, MD    310-267-6810    GSchiller@mednet.ucla.edu   
Contact: Vladamir Kustanovich       VKustanovich@mednet.ucla.edu   
United States, Texas
MD Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Naveen Pemmaraju, MD    713-792-4956    npemmaraju@mdanderson.org   
Contact: Romany Gergis, MPH    713-792-9116    RGergis@mdanderson.org   
Sponsors and Collaborators
Samus Therapeutics, Inc.
Investigators
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Study Director: Hagop Youssoufian, M.D. Samus Therapeutics
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Responsible Party: Samus Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03935555    
Other Study ID Numbers: PU-H71-01-003
First Posted: May 2, 2019    Key Record Dates
Last Update Posted: October 20, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Samus Therapeutics, Inc.:
Primary Myelofibrosis (PMF)
Post-Polycythemia Vera Myelofibrosis (Post-PV MF)
Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF)
Additional relevant MeSH terms:
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Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
Antineoplastic Agents