Back to resultsEvaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis
Primary Purpose
Myelofibrosis, Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PU-H71
Ruxolitinib
Sponsored by
About this trial
This is an interventional treatment trial for Myelofibrosis
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Sites / Locations
- Yale Cancer Center
- Ochsner Clinic Foundation
- University of Michigan
- Karmanos Cancer Institute
- University of Nebraska Medical Center
- Duke University Medical Center
- Cleveland Clinic - Taussig Cancer Institute
- Abramson Cancer Center - University of Pennsylvania
- MD Anderson Cancer Center
- Mays Cancer Center UT Health San Antonio
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
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
Arm Description
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Outcomes
Primary Outcome Measures
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.
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.
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
Pharmacokinetic profile of PU-H71: Area under the plasma concentration versus time curve (AUC)
Area under the plasma concentration versus time curve (AUC)
Pharmacokinetic profile of PU-H71: Trough plasma concentration (Cmin)
Trough plasma concentration (Cmin)
Pharmacokinetic profile of PU-H71: Peak plasma concentration (Cmax)
Peak plasma concentration (Cmax)
Pharmacokinetic profile of PU-H71: Time to maximum plasma concentration (Tmax)
Time to maximum plasma concentration (Tmax)
Pharmacokinetic profile of PU-H71: Plasma half-life (T1/2)
Plasma half-life (T1/2)
Secondary Outcome Measures
Treatment Response
Treatment response is to be evaluated using the revised IWG-MRT response criteria.
Symptom Burden Assessment
The symptomatic burden will be serially evaluated using the MPN-SAF TSS.
Biological Markers
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).
Full Information
NCT ID
NCT03373877
First Posted
November 29, 2017
Last Updated
November 14, 2022
Sponsor
Samus Therapeutics, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03373877
Brief Title
Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis
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)
Study Type
Interventional
2. Study Status
Record Verification Date
November 2022
Overall Recruitment Status
Terminated
Why Stopped
Samus is focusing all of their efforts in myelofibrosis on the new oral formulation of PU-H71.
Study Start Date
May 24, 2018 (Actual)
Primary Completion Date
October 17, 2019 (Actual)
Study Completion Date
March 10, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Samus Therapeutics, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelofibrosis, Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
4 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose 1: PU-H71 225 mg/m2 + ruxolitinib
Arm Type
Experimental
Arm Description
Cohort 1
Arm Title
Dose 2: PU-H71 300 mg/m2 + ruxolitinib
Arm Type
Experimental
Arm Description
Cohort 2
Arm Title
Dose 3: PU-H71 400 mg/m2 + ruxolitinib
Arm Type
Experimental
Arm Description
Cohort 3
Arm Title
Dose 4: PU-H71 600 mg/m2 + ruxolitinib
Arm Type
Experimental
Arm Description
Cohort 4
Intervention Type
Drug
Intervention Name(s)
PU-H71
Intervention Description
PU-H71 treatments will be administered by IV infusion on days 1, 8, and 15 of each 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
Jakafi
Intervention Description
Dosing will be in accordance with current package insert and dose subject was on during study entry.
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
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.
Time Frame
12 months
Title
Maximum Tolerated Dose of PU-H71 (MTD)
Description
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.
Time Frame
7 months
Title
Recommended Phase 2 Dose of PU-H71 (RP2D)
Description
The RP2D is the dose with an acceptable risk/benefit ratio that warrant study in future trials
Time Frame
12 months
Title
Pharmacokinetic profile of PU-H71: Area under the plasma concentration versus time curve (AUC)
Description
Area under the plasma concentration versus time curve (AUC)
Time Frame
12 months
Title
Pharmacokinetic profile of PU-H71: Trough plasma concentration (Cmin)
Description
Trough plasma concentration (Cmin)
Time Frame
12 months
Title
Pharmacokinetic profile of PU-H71: Peak plasma concentration (Cmax)
Description
Peak plasma concentration (Cmax)
Time Frame
12 months
Title
Pharmacokinetic profile of PU-H71: Time to maximum plasma concentration (Tmax)
Description
Time to maximum plasma concentration (Tmax)
Time Frame
12 months
Title
Pharmacokinetic profile of PU-H71: Plasma half-life (T1/2)
Description
Plasma half-life (T1/2)
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Treatment Response
Description
Treatment response is to be evaluated using the revised IWG-MRT response criteria.
Time Frame
12 months
Title
Symptom Burden Assessment
Description
The symptomatic burden will be serially evaluated using the MPN-SAF TSS.
Time Frame
12 months
Title
Biological Markers
Description
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).
Time Frame
12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Exclusion Criteria:
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Morgan, MS, JD
Organizational Affiliation
Sponsor GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Yale Cancer Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06511
Country
United States
Facility Name
Ochsner Clinic Foundation
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cleveland Clinic - Taussig Cancer Institute
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Abramson Cancer Center - University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Mays Cancer Center UT Health San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-3900
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis
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