Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03373877
Recruitment Status : Active, not recruiting
First Posted : December 14, 2017
Last Update Posted : April 29, 2019
Sponsor:
Information provided by (Responsible Party):
Samus Therapeutics, Inc.

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.

Condition or disease Intervention/treatment Phase
Myelofibrosis Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Drug: PU-H71 Drug: Ruxolitinib Phase 1

Detailed Description:

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

Up to 30 subjects who have active disease despite having received a minimum of 6 months of ruxolitinib therapy (including last 2 months at a daily dose of ≥5 mg twice daily and no more than one dose reduction 2-8 weeks prior to the baseline visit)stable dose will be enrolled to evaluate the safety, PK, and MTD of IV PU-H71 administered in combination ruxolitinib. Four ascending dose levels are planned. The planned dose levels of PU-H71 are 225 mg/m2, 300 mg/m2, 400 mg/m2, and 600 mg/m2. Additional dosing cohorts may be added at the discretion of the Safety Review Committee (SRC).

Following a 28-day screening period, eligible subjects will receive PU-H71 once weekly intravenously for three consecutive weeks, followed by one week off on a 28-day cycle (D1, D8, D15, every 28 days). Ruxolitinib will be administered twice daily per the package insert at the stable dose the subject had been receiving prior to enrolling in the study.

Subjects will have pk samples taken and ECGs performed at various time points throughout the study. Subjects will have safety evaluations including physical examinations, vital signs, laboratory assessments, and AE reporting. If deemed necessary, additional safety measurements will be performed at the discretion of the Investigator or the SRC.

Subjects will be treated until disease progression, DLT, death, or study termination.

At each dose level, a 3+3 dose escalation design will be employed. If none of the initial 3 subjects in the cohort experience a DLT within the first cycle, a new cohort of 3 subjects will be treated at the next higher dose level. If 1 of the 3 subjects in a cohort experiences a DLT, then 3 additional subjects will be treated at the same dose level as described under Dose Limiting Toxicities.

Once the MTD has been determined in the dose escalation portion of the study, up to 15 patients may be enrolled for further evaluation of safety, PK, and preliminary clinical activity in a dose confirmation phase.

A safety review committee (SRC) will assess the safety, tolerability, and available PK information collected for each dose level, decide whether to proceed to the next cohort, and determine the dose for the cohort.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Study of Ruxolitinib in Combination With PU-H71 for the Treatment of Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV MF), and Post-EssentialThrombocythemia MF (Post-ET MF)
Actual Study Start Date : May 24, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Dose 1: PU-H71 225 mg/m2 + ruxolitinib
Cohort 1
Drug: PU-H71
PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.

Drug: Ruxolitinib
Dosing will be in accordance with current package insert and dose subject was on during study entry.
Other Name: Jakafi

Experimental: Dose 2: PU-H71 300 mg/m2 + ruxolitinib
Cohort 2
Drug: PU-H71
PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.

Drug: Ruxolitinib
Dosing will be in accordance with current package insert and dose subject was on during study entry.
Other Name: Jakafi

Experimental: Dose 3: PU-H71 400 mg/m2 + ruxolitinib
Cohort 3
Drug: PU-H71
PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.

Drug: Ruxolitinib
Dosing will be in accordance with current package insert and dose subject was on during study entry.
Other Name: Jakafi

Experimental: Dose 4: PU-H71 600 mg/m2 + ruxolitinib
Cohort 4
Drug: PU-H71
PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.

Drug: Ruxolitinib
Dosing will be in accordance with current package insert and dose subject was on during study entry.
Other Name: Jakafi




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 12 months ]
    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.

  2. Maximum Tolerated Dose of PU-H71 (MTD) [ Time Frame: 7 months ]
    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.

  3. Recommended Phase 2 Dose of PU-H71 (RP2D) [ Time Frame: 12 months ]
    The RP2D is the dose with an acceptable risk/benefit ratio that warrant study in future trials

  4. Pharmacokinetic profile of PU-H71: Area under the plasma concentration versus time curve (AUC) [ Time Frame: 12 months ]
    Area under the plasma concentration versus time curve (AUC)

  5. Pharmacokinetic profile of PU-H71: Trough plasma concentration (Cmin) [ Time Frame: 12 months ]
    Trough plasma concentration (Cmin)

  6. Pharmacokinetic profile of PU-H71: Peak plasma concentration (Cmax) [ Time Frame: 12 months ]
    Peak plasma concentration (Cmax)

  7. Pharmacokinetic profile of PU-H71: Time to maximum plasma concentration (Tmax) [ Time Frame: 12 months ]
    Time to maximum plasma concentration (Tmax)

  8. Pharmacokinetic profile of PU-H71: Plasma half-life (T1/2) [ Time Frame: 12 months ]
    Plasma half-life (T1/2)


Secondary Outcome Measures :
  1. Treatment Response [ Time Frame: 12 months ]
    Treatment response is to be evaluated using the revised IWG-MRT response criteria.

  2. Symptom Burden Assessment [ Time Frame: 12 months ]
    The symptomatic burden will be serially evaluated using the MPN-SAF TSS.

  3. Biological Markers [ Time Frame: 12 months ]
    Assess the effects of treatment on biological markers of the disease (i.e., bone marrow histology; JAK2V617F, CALR, or MPLW515L/K allele burden; cytogenetic response; serum cytokine profiles; and other biomarkers of disease activity).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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 has a confirmed diagnosis of myelofibrosis, including PMF, post-PV MF, and post-ET MF.
  2. 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.
  3. Subject has MF with evidence of persistent disease despite ruxolitinib monotherapy treatment, consisting of:

    1. 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
    2. Documented splenomegaly of at least 5 cm below the costal margin as measured on inspiration by physical exam.
  4. Subject has an Eastern Cooperative Oncology Group performance status of 0-2.
  5. Acceptable pre-study organ function during screening defined as:

    1. Absolute neutrophil count (ANC) ≥ 1000/uL
    2. Hemoglobin (hgb) ≥ 8.0 g/dL (may be supported with transfusion)
    3. Platelets (plt) ≥ 75,000/uL
    4. AST/SGOT and ALT/SGPT ≤2 x Upper Limit of Normal (ULN)
    5. Direct serum bilirubin ≤ 1.5 x ULN
    6. Creatinine clearance >50 mL/min/1.73 m2 based on Cockcroft Gault equation.

Exclusion Criteria:

  1. Subject has known active liver disease, including viral hepatitis or cirrhosis.
  2. Subject has known or suspected HIV or other active infections requiring acute or chronic treatment with systemic antibiotics. Conditions requiring topical antibiotics are acceptable.
  3. Subject has a QTcF > 480 ms (corrected) in the screening or baseline ECG.
  4. 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.
  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 enrollment.
  7. Subject has a permanent cardiac pacemaker.
  8. 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.
  9. Subject has significant uncontrolled medical condition within 6 months prior to enrollment, as determined by the investigator.
  10. Subject has concurrent participation in any interventional studies within 14 days of first dose of study drug.
  11. Subject has uncontrolled diabetes mellitus, in the judgment of the Principal Investigator.
  12. 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.

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): NCT03373877


Locations
Layout table for location information
United States, Connecticut
Yale Cancer Center
New Haven, Connecticut, United States, 06511
United States, Louisiana
Ochsner Clinic Foundation
New Orleans, Louisiana, United States, 70121
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Cleveland Clinic - Taussig Cancer Institute
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Abramson Cancer Center - University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Mays Cancer Center UT Health San Antonio
San Antonio, Texas, United States, 78229-3900
Sponsors and Collaborators
Samus Therapeutics, Inc.
Investigators
Layout table for investigator information
Study Director: Robert Morgan, MS, JD Sponsor GmbH

Layout table for additonal information
Responsible Party: Samus Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03373877     History of Changes
Other Study ID Numbers: PU-H71-01-002
First Posted: December 14, 2017    Key Record Dates
Last Update Posted: April 29, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
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