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

NCT03935555 | Terminated Phase 1 FDA Drug

• 1 other identifier: PU-H71-01-003
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 3

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (12)

• 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

Study Arms (4)

Oral - 50mg

EXPERIMENTAL

PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).

Drug: PU-H71

Oral -100 mg

EXPERIMENTAL

PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).

Drug: PU-H71

Oral - 200 mg

EXPERIMENTAL

PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).

Drug: PU-H71

Oral - 300 mg

EXPERIMENTAL

PU-H71 (a small molecule purine-scaffold epichaperome inhibitor selective for stress-induced HSP90 in epichaperomes).

Drug: PU-H71

Interventions

PU-H71 DRUG

PU-H71 is a synthetic purine-scaffold stress chaperome inhibitor, which specifically targets HSP90 in the tumor-specific epichaperome

Oral - 200 mg; Oral - 300 mg; Oral - 50mg; Oral -100 mg

Eligibility Criteria

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

You may qualify if:

• Subject is willing and able to provide written informed consent before any study-specific procedures are performed.
• Subject is willing to comply with all study procedures and restrictions.
• Subject is ≥18 years of age.
• Subject has confirmed diagnosis of PMF, Post-PV MF, or Post-ET MF.
• 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.
• 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.
• Subject has an Eastern Cooperative Oncology Group performance status of 0 to 2.
• Acceptable pre-study organ function during screening defined as:
• Absolute neutrophil count (ANC) ≥1000/µL.
• Platelet count ≥50,000/µL.

You may not qualify if:

• Subject has known active liver disease, including viral hepatitis or cirrhosis.
• 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.
• 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.
• 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.
• Subject has a history (or family history) of long QT syndrome.
• Subject has coronary artery disease with an ischemic event within 6 months prior to screening.
• Subject has a permanent cardiac pacemaker.
• 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.
• Subject has significant uncontrolled medical condition within 6 months prior to screening, as determined by the Investigator.
• 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.
• Subject uses systemic corticosteroids (ie, prednisone \>12.5 mg/day or dexamethasone \>2 mg/day) within 2 weeks prior to Cycle 1 Day 1.
• 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.
• 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.
• Subject has planned or current use of herbal preparations/medications at least 7 days prior to Cycle 1 Day 1.
• Subject has previously received PU-H71.

Sponsors & Collaborators

• Samus Therapeutics, Inc.: lead

Study Sites (3)

Marin Cancer Care - Greenbrae (California Cancer Care A Medical Group, Inc. - Greenbrae)

Larkspur, California, 94904, United States

Location

Ronald Reagan UCLA Medical Center

Los Angeles, California, 90095, United States

Location

MD Anderson

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Michael Silverman, M.D.

  Samus Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 Record Dates

• First Submitted: March 14, 2019
• First Posted: May 2, 2019
• Study Start: August 12, 2019
• Primary Completion: October 19, 2022
• Study Completion: November 4, 2022
• Last Updated: November 17, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)