A Phase 2 Study Of PRM-151 In Subjects With Myelofibrosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by Promedior, Inc.
Sponsor:
Information provided by (Responsible Party):
Promedior, Inc.
ClinicalTrials.gov Identifier:
NCT01981850
First received: October 29, 2013
Last updated: July 20, 2016
Last verified: July 2016
  Purpose

PRM-151 is an investigational drug that is being developed for possible use in the treatment of myelofibrosis (MF), a disease in which the bone marrow, which is the organ in the body that makes blood cells, is replaced by fibrosis, or excess scar tissue.

The purpose of this study is to gather information on whether PRM-151 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.


Condition Intervention Phase
Primary Myelofibrosis
Polycythemia Vera
Post-Essential Thrombocythemia Myelofibrosis
Biological: PRM-151
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV MF), Or Post-Essential Thrombocythemia MF (Post-ET MF)

Resource links provided by NLM:


Further study details as provided by Promedior, Inc.:

Primary Outcome Measures:
  • Bone marrow response rate, defined as the percent of subjects with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    As determined by a central adjudication panel of expert hematopathologists, blinded to subject, treatment, and time of biopsy


Secondary Outcome Measures:
  • Comparison of primary and secondary efficacy parameters between doses [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in laboratory test results [ Time Frame: up to 40 weeks ] [ Designated as safety issue: No ]
  • Bone marrow improvement: Bone marrow response rate at weeks 12, 24, and 36; Duration of bone marrow response [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • Hemoglobin improvement [ Time Frame: 9 months ] [ Designated as safety issue: No ]

    As measured by Percent of subjects with : Red cell transfusion independence (no transfusions for ≥ 12 consecutive weeks)

    OR

    50% reduction in RBC transfusions for ≥ 12 consecutive weeks

    OR

    Percent of subjects with ≥ 10 g/L and ≥ 20 g/L increase in hemoglobin for ≥ 12 consecutive weeks without transfusions

    (Outcome parameter assessed is dependent on baseline hemoglobin/transfusion status)


  • Platelet improvement [ Time Frame: 9 months ] [ Designated as safety issue: No ]

    Percent of subjects with:

    Platelet transfusion independence (no transfusions for ≥ 12 consecutive weeks)

    OR

    50% reduction in platelets transfusions for ≥ 12 consecutive weeks

    OR

    Percent of subjects with:

    Doubling of baseline platelet count for ≥ 12 consecutive weeks without platelet transfusions

    OR

    Platelet count > 50 x 10e9/L for ≥ 12 consecutive weeks without platelet transfusions

    OR

    Percent of subjects with:

    Doubling of baseline platelet count for ≥ 12 consecutive weeks without platelet transfusions

    OR

    Platelet count > 25 x 10e9/L for ≥ 12 consecutive weeks without platelet transfusions

    (Outcome parameter assessed is dependent on baseline platelet status)


  • Hematologic improvement [ Time Frame: 9 months ] [ Designated as safety issue: No ]

    Percent of subjects who have EITHER Hemoglobin improvement OR Platelet improvement as described above and no worsening of hemoglobin or platelets from baseline

    OR

    Percent of subjects who have Hemoglobin improvement as described above AND Did not develop platelets < 50 x 10e9/L Percent of subjects who have Platelet improvement as described above

    AND

    Did not develop Hemoglobin < 100 g/L or new transfusion dependence

    (Outcome parameter assessed is dependent on baseline hematology status)


  • Symptom improvement [ Time Frame: 9 months ] [ Designated as safety issue: No ]

    Percent of subjects with 25% and 50% reduction in MPN-SAF Total Symptom Score from baseline at Week 36

    Mean change from baseline in EORTC QLQ-C30 at 36 weeks

    Duration of all improvement parameters listed above


  • Percent of subjects with complete response, partial response, clinical improvement, stable disease, and progressive disease according to IWG-MRT criteria [ Time Frame: 9 months ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Exploratory Outcome: Bone marrow [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    • Percent of subjects with Grade 0-1 bone marrow fibrosis grade at any time during the study and at weeks 12, 24, and 36
    • Duration of Grade 0-1 bone marrow fibrosis grade
    • Mean change from baseline to 12, 24, and 36 weeks in bone marrow fibrosis by quantitative image analysis
    • Changes from baseline to weeks 12, 24, and 36 in bone marrow metabolism by FDG or FLT PET scan (where feasible)
    • Assessment of changes in bone marrow morphology at 12, 24, and 36 weeks

  • Exploratory Outcome: Hematologic and other disease related laboratory parameters [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    • Mean change from baseline to 36 weeks in: hemoglobin, # RBC units transfused in previous 12 weeks, platelet count, # platelet transfusions in previous 12 weeks, white blood cell count, absolute neutrophil count, reticulocyte count, peripheral blood blast count, and lactic dehydrogenase (LDH)
    • Percent of subjects with increase in Hgb from < 100 g/L to > 100 g/L without transfusions, increase in platelets from < 50 x 10e9/L to > 100 x 10e9/L, decrease in WBC from > 25 to < 25, increase in ANC from < 1500 to ≥ 1500, decrease in peripheral blood blasts from > 1% to < 1%, and disappearance of leukoerythroblastosis, at 36 weeks and for ≥ 12 weeks at any time during the study
    • Duration of increase in Hgb from < 100 g/L to > 100 g/L without transfusions, increase in platelets from < 50 x 10e9/L to > 100 x 10e9/L, decrease in WBC from > 25 to < 25, increase in ANC from < 1500 to ≥ 1500, decrease in peripheral blood blasts from > 1% to < 1%, and disappearance of leukoerythroblastosis

  • Exploratory Outcome: • Spleen improvement (subjects with palpable spleen at baseline) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    • Percent of subjects with 10% and 35% reduction in spleen size from baseline by CT at 36 weeks
    • Duration of 10% and 35% reduction in spleen size from baseline
    • Mean change from baseline in spleen size by CT at 36 weeks
    • Change in spleen and liver metabolism by FDG or FLT PET scan at 12, 24, and 36 weeks

  • Exploratory Outcome: DIPSS [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    • Percent of subjects with a reduction in DIPSS score and category at week 36
    • Mean change in DIPSS score from baseline to Week 36

  • Exploratory Outcome: Mutational Status and Cytogentics [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    • Association of baseline mutational status of JAK2V617F, MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 with selected primary and secondary endpoints
    • Changes in allele burden of JAK2V617F at week 36. Changes in allele burden of MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 at week 36 will be measured as commercially available assays become available
    • Association of baseline cytogenetic abnormalities and selected primary and secondary endpoints

  • Exploratory Outcome: Association of baseline PTX-2 levels with selected primary and secondary endpoints [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • Exploratory Outcome: • Evaluation of potential biomarkers of PRM-151 activity in bone marrow biopsies taken at baseline, weeks 12, 24, and 36 [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • Exploratory Outcome: Survival [ Time Frame: ongoing ] [ Designated as safety issue: No ]
    Measurement of progression-free and overall survival


Estimated Enrollment: 84
Study Start Date: October 2013
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1 0.3mg/kg Every 4 Weeks
Subjects will be treated with single agent PRM-151 at a dose of 0.3 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
Biological: PRM-151
IV infusion
Experimental: Cohort 2 3 mg/kg Every 4 Weeks
Subjects will be treated with single agent PRM-151 at a dose of 3.0 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles
Biological: PRM-151
IV infusion
Experimental: Cohort 3 10mg /kg Every 4 Weeks
Subjects will be treated with single agent PRM-151 at a dose of 10 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles
Biological: PRM-151
IV infusion

Detailed Description:

Stage 2 of this study is ongoing. Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of PRM-151 in subjects with PMF and post ET/PV MF. Subjects will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of PRM-151. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. Modifications to dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1.

Stage 1 of this study has completed. Stage 1 was an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of two different dose schedules of PRM-151 in subjects with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules of PRM-151. Subjects were assigned to a weekly or every four week dosing schedule by the investigator.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
  2. Subjects must voluntarily sign an ICF;
  3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF;
  4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis;
  5. Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System
  6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score;
  7. Subjects must not be candidates for ruxolitinib based on EITHER:

    1. Platelet count < 50 x 10e9/L, OR
    2. Hgb < 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study entry, and be intolerant of or had inadequate response to ruxolitinib;
  8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F);
  9. Life expectancy of at least twelve months;
  10. At least four weeks must have elapsed between the last dose of any MF- directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment;
  11. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;
  12. Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 years or 12 months if >55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception are outlined in the protocol.
  13. Ability to adhere to the study visit schedule and all protocol requirements;
  14. Must have adequate organ function as demonstrated by the following:

    • ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF);
    • Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF);
    • Serum creatinine ≤ 2.5 mg/dL x ULN.

Exclusion Criteria:

  1. White blood cell count > 25 x 10e9/L or > 10% peripheral blood blasts;
  2. Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer;
  3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months;
  4. Presence of active serious infection;
  5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study;
  6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection;
  7. Organ transplant recipients other than bone marrow transplant;
  8. Women who are pregnant or lactating.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01981850

Locations
United States, Arizona
Mayo Clinic Cancer Center Recruiting
Phoenix, Arizona, United States, 85054
Contact: Megan Altschuler, RN    480-342-6066    altschuler.megan@mayo.edu   
Contact: Chris Reed-Pease    480-342-6068    reedpease.christine@mayo.edu   
Principal Investigator: Ruben Mesa, MD         
United States, California
Stanford Cancer Institute Recruiting
Palo Alto, California, United States, 94304
Contact: Jason Gotlib, MD    650-725-0744      
Contact: Isabel Reyes    650-725-4047    ilreyes@stanford.edu   
Principal Investigator: Jason Gotlib, MD         
United States, Maryland
University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Christina Shehata    410-462-3178    christinashehata@umm.edu   
Principal Investigator: Maria Baer, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Matthew Jacobs    617-632-5157    mjacobs5@partners.org   
Principal Investigator: Martha Wadleigh, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109-2800
Contact: Roxana Taralunga    734-232-0773    roxanat@med.umich.edu   
Principal Investigator: Moshe Talpaz, MD         
United States, New York
Mount Sinai Medical Center Not yet recruiting
New York, New York, United States, 10029
Contact: Sarah Han    212-241-9185    Sarah.han@mssm.edu   
Contact: Carrie Newsom, RN    212-241-9185    Carrie.newsom@mssm.edu   
Principal Investigator: John Mascarenhas, MD         
Weill Cornell Medical Center Recruiting
New York, New York, United States, 10065
Contact: Ariella Barel    646-962-2700      
Contact: Ellen Ritchie, MD    646-962-2700    ritchie@med.cornell.edu   
Principal Investigator: Ellen Ritchie, MD         
United States, North Carolina
Wake Forest Baptist Medical Center Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Jennifer MacLean    336-713-3539    jemaclea@wakehealth.edu   
Principal Investigator: Dmitriy Berenzon, MD         
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Michael Savona, MD    800-811-8480      
Contact: Clinical Trials Information Program    1-800-811-8480      
Principal Investigator: Michael Savona, MD         
United States, Texas
MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Srdan Verstovsek, MD    713-745-3429      
Contact: Stephanie Van Derbur, RN    713-745-4525    sjrivers@mdanderson.org   
Principal Investigator: Srdan Verstovsek, MD         
Canada, British Columbia
Providence Health Care Recruiting
Vancouver, British Columbia, Canada, V6Z 2A5
Contact: Lynda Foltz, MD    604-684-5794      
Contact: Gail Vicente    604-682-2344 ext 64987    grvicente@providencehealth.bc.ca   
Principal Investigator: Lynda Foltz, MD         
Canada, Ontario
The Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5T 2M9
Contact: Vikas Gupta, MD    416-946-4521      
Contact: Kelly Foley    416-946-4501 ext 5745    kelly.foley@uhn.ca   
Principal Investigator: Vikas Gupta, MD         
Germany
University Medical Center RWTH Aachen Not yet recruiting
Aachen, Germany, D-52074
Contact: Christian Hasenbank    0049-241-803-7031    chasenbank@ukaachen.de   
Principal Investigator: Steffen Koschmieder, MD         
Italy
Marche Nord Hospital Recruiting
Pesaro, Italy, 61122
Contact: Federica Loscocco    0039-072-136-4022    federica.loscocco@gmail.com   
Principal Investigator: Alessandro Isidori, MD         
Netherlands
Erasmus Medical Center Recruiting
Rotterdam, Zuid Holland, Netherlands, 3015 CE
Contact: Els P.M. van der Graaf    +31 10 703 2324    p.vandergraaf@erasmusmc.nl   
Principal Investigator: Peter A. W. te Boekhorst, MD         
United Kingdom
Guy's and St. Thomas' Hospital Recruiting
London, United Kingdom
Contact: Sarah El Farhi       sarah.elfarhi@gstt.nhs.uk   
Principal Investigator: Claire Harrison, MD         
Sponsors and Collaborators
Promedior, Inc.
Investigators
Study Director: Bernt van den Blink, MD, PhD Promedior, Inc.
  More Information

Responsible Party: Promedior, Inc.
ClinicalTrials.gov Identifier: NCT01981850     History of Changes
Other Study ID Numbers: PRM-151G-101 
Study First Received: October 29, 2013
Last Updated: July 20, 2016
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Promedior, Inc.:
fibrosis

Additional relevant MeSH terms:
Primary Myelofibrosis
Polycythemia
Polycythemia Vera
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders

ClinicalTrials.gov processed this record on July 21, 2016