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

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

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.

Study Overview

• Status: Terminated
• Conditions: Primary Myelofibrosis (PMF); Post-Polycythemia Vera Myelofibrosis (Post-PV MF); Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF)
• Intervention / Treatment: Drug: PU-H71

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).

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Larkspur, California, United States, 94904
      • Marin Cancer Care - Greenbrae (California Cancer Care A Medical Group, Inc. - Greenbrae)
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including Cmax	24 weeks
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including Tmax	24 weeks
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including AUC0-t	24 weeks
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including AUC0-inf	24 weeks
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including CL	24 weeks
Assess Safety, Tolerability and Pharmacokinetics of PU-H71	Determine the human exposure PK including t1/2	24 weeks
Assess Safety and Tolerability of PU-H71	Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in physical examinations	24 weeks
Assess Safety and Tolerability of PU-H71	Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in electrocardiograms (ECGs)	24 weeks
Assess Safety and Tolerability of PU-H71	Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in vital signs	24 weeks
Assess Safety and Tolerability of PU-H71	Determine the Incidence and severity of AEs as determined by the NCI-CTCAE Version 5.0 and by changes in clinical laboratory evaluations	24 weeks
Assess treatment response of PU H71	Treatment response in myelofibrosis (MF) is to be evaluated using the revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)	24 weeks
Assess treatment response of PU H71	Treatment response in myelofibrosis (MF) is to be evaluated using the revised European LeukemiaNet (ELN) response criteria.	24 weeks

Collaborators and Investigators

• Sponsor: Samus Therapeutics, Inc.
• Investigators: Study Director: Michael Silverman, M.D., Samus Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2019
• Primary Completion (Actual): October 19, 2022
• Study Completion (Actual): November 4, 2022

Study Registration Dates

• First Submitted: March 14, 2019
• First Submitted That Met QC Criteria: April 30, 2019
• First Posted (Actual): May 2, 2019

Study Record Updates

• Last Update Posted (Actual): November 17, 2022
• Last Update Submitted That Met QC Criteria: November 14, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Primary Myelofibrosis (PMF); Post-Polycythemia Vera Myelofibrosis (Post-PV MF); Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF)
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Myelofibrosis; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia; Antineoplastic Agents; 9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
• Other Study ID Numbers: PU-H71-01-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No