Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis

NCT03373877 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: PU-H71-01-002
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 10

Brief Summary

This is a multicenter 2-part, Phase 1b study designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PU-H71 in subjects taking concomitant ruxolitinib. The first part (Dose Escalation) will employ a standard 3+3 dose escalation design to determine Maximum Tolerated Dose (MTD). The second part of the study (Dose Confirmation) will confirm the recommended Phase 2 dose (RP2D) in an expanded population.

Conditions

Myelofibrosis; Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis

Outcome Measures

Primary Outcomes (8)

• Incidence of adverse events

  Safety of PU-H71 in combination with ruxolitinib as assessed by the incidence and severity of adverse events (AEs) and serious AEs as determined by the NCI CTCAE v4.03.

  12 months

• Maximum Tolerated Dose of PU-H71 (MTD)

  MTD as assessed by the occurrences of dose limiting toxicities of PU-H71 in combination with ruxolitinib. The MTD will be defined as the dose that does not exceed an acceptable threshold of toxicity.

  7 months

• Recommended Phase 2 Dose of PU-H71 (RP2D)

  The RP2D is the dose with an acceptable risk/benefit ratio that warrant study in future trials

  12 months

• Pharmacokinetic profile of PU-H71: Area under the plasma concentration versus time curve (AUC)

  Area under the plasma concentration versus time curve (AUC)

  12 months

• Pharmacokinetic profile of PU-H71: Trough plasma concentration (Cmin)

  Trough plasma concentration (Cmin)

  12 months

• Pharmacokinetic profile of PU-H71: Peak plasma concentration (Cmax)

  Peak plasma concentration (Cmax)

  12 months

• Pharmacokinetic profile of PU-H71: Time to maximum plasma concentration (Tmax)

  Time to maximum plasma concentration (Tmax)

  12 months

• Pharmacokinetic profile of PU-H71: Plasma half-life (T1/2)

  Plasma half-life (T1/2)

  12 months

Secondary Outcomes (3)

• Treatment Response

  12 months

• Symptom Burden Assessment

  12 months

• Biological Markers

  12 months

Study Arms (4)

Dose 1: PU-H71 225 mg/m2 + ruxolitinib

EXPERIMENTAL

Cohort 1

Drug: PU-H71; Drug: Ruxolitinib

Dose 2: PU-H71 300 mg/m2 + ruxolitinib

EXPERIMENTAL

Cohort 2

Drug: PU-H71; Drug: Ruxolitinib

Dose 3: PU-H71 400 mg/m2 + ruxolitinib

EXPERIMENTAL

Cohort 3

Drug: PU-H71; Drug: Ruxolitinib

Dose 4: PU-H71 600 mg/m2 + ruxolitinib

EXPERIMENTAL

Cohort 4

Drug: PU-H71; Drug: Ruxolitinib

Interventions

PU-H71 DRUG

PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.

Dose 1: PU-H71 225 mg/m2 + ruxolitinib; Dose 2: PU-H71 300 mg/m2 + ruxolitinib; Dose 3: PU-H71 400 mg/m2 + ruxolitinib; Dose 4: PU-H71 600 mg/m2 + ruxolitinib

Ruxolitinib DRUG

Dosing will be in accordance with current package insert and dose subject was on during study entry.

Also known as: Jakafi

Dose 1: PU-H71 225 mg/m2 + ruxolitinib; Dose 2: PU-H71 300 mg/m2 + ruxolitinib; Dose 3: PU-H71 400 mg/m2 + ruxolitinib; Dose 4: PU-H71 600 mg/m2 + ruxolitinib

Eligibility Criteria

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

You may qualify if:

• Subject has a confirmed diagnosis of myelofibrosis, including PMF, post-PV MF, and post-ET MF.
• Subject has been receiving ruxolitinib therapy for intermediate or high-risk myelofibrosis for \>6 months prior to enrollment with no more than 1 dose reduction of ruxolitinib in the 2-8 weeks prior to enrollment and a stable daily dose ≥5 mg twice daily (BID) \>2 months prior to enrollment.
• Subject has MF with evidence of persistent disease despite 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 MPN-SAF TSS score of \>20 points; AND
• Documented splenomegaly of at least 5 cm below the costal margin as measured on inspiration by physical exam.
• Subject has an Eastern Cooperative Oncology Group performance status of 0-2.
• Acceptable pre-study organ function during screening defined as:
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Hemoglobin (hgb) ≥ 8.0 g/dL (may be supported with transfusion)
• Platelets (plt) ≥ 75,000/uL
• AST/SGOT and ALT/SGPT ≤2 x Upper Limit of Normal (ULN)
• Direct serum bilirubin ≤ 1.5 x ULN
• Creatinine clearance \>50 mL/min/1.73 m2 based on Cockcroft Gault equation.

You may not qualify if:

• Subject has known active liver disease, including viral hepatitis or cirrhosis.
• Subject has known or suspected HIV or other active infections requiring acute or chronic treatment with systemic antibiotics. Conditions requiring topical antibiotics are acceptable.
• Subject has a QTcF \> 480 ms (corrected) in the screening or baseline ECG.
• Subject has left ventricular ejection fraction (LVEF) ≤ 50%, or below institution's lower limit of normal (whichever is lower) by echocardiogram (ECHO) 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 enrollment.
• Subject has a permanent cardiac pacemaker.
• Subject has history of a second primary malignancy within the past 2 year 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 enrollment, as determined by the investigator.
• Subject has concurrent participation in any interventional studies within 14 days of first dose of study drug.
• Subject has uncontrolled diabetes mellitus, in the judgment of the Principal Investigator.
• Subject has an active ocular condition that in the opinion of the investigator may alter visual acuity during the course of the study (i.e., ocular inflammatory disease etc.) or a history or anticipation of major ocular surgery (including cataract extraction, intraocular surgery, etc.) during the study.

Sponsors & Collaborators

• Samus Therapeutics, Inc.: lead

Study Sites (10)

Yale Cancer Center

New Haven, Connecticut, 06511, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic - Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Abramson Cancer Center - University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Mays Cancer Center UT Health San Antonio

San Antonio, Texas, 78229-3900, 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)-; ruxolitinib

Condition Hierarchy (Ancestors)

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

Study Officials

• Robert Morgan, MS, JD

  Sponsor GmbH

  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

Study Record Dates

• First Submitted: November 29, 2017
• First Posted: December 14, 2017
• Study Start: May 24, 2018
• Primary Completion: October 17, 2019
• Study Completion: March 10, 2020
• Last Updated: November 15, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)