Synopsis of PRM-151 Stage 2 Study

The following synopsis was provided by Promedior, the sponsor of PRM-151. This description is for the study "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)" currently enrolling patients.

PRM-151G-101 SYNOPSIS: STAGE 2

Sponsor: Promedior, Inc
Name of Finished Product: Recombinant human Pentraxin-2; PRM-151

Primary Objective(s):

To determine the effect size of three different doses of PRM-151 on reduction in bone marrow fibrosis by ≥ 1 grade in intermediate-1, intermediate-2, and high risk subjects with PMF, post-PV MF, or post ET-MF who are anemic or thrombocytopenic and who are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib.

Secondary Objective(s):

  • To determine if there is a difference in efficacy between the three doses of PRM-151 used in the study
  • To evaluate the safety and tolerability of three different doses of PRM-151
  • To assess the duration of effect of three doses of PRM-151 on reduction in bone marrow fibrosis
  • To assess the effect and duration of effect of three doses of PRM-151 on disease related anemia, thrombocytopenia, and constitutional symptoms
  • To assess IWG-MRT response (Complete Response, Partial Response, Clinical Improvement), stable and progressive disease in subjects treated with three doses of PRM-151

Exploratory Objectives

  • To measure changes in bone marrow fibrosis by quantitative image analysis and evaluate changes in bone marrow morphology in subjects receiving PRM-151
  • To assess the effect of PRM-151 on other disease related parameters, including hematologic abnormalities and spleen size
  • To assess the effect of PRM-151 on prognostic factors associated with increased mortality as measured by the DIPSS (Dynamic International Prognostic Scoring System)
  • To evaluate the interaction between selected genetic mutations and cytogenetic abnormalities and response to PRM-151
  • To explore potential biomarkers of PRM-151 activity in bone marrow samples
  • To assess the effect of PRM-151 on bone marrow metabolism by PET imaging (at selected institutions)
  • To evaluate the correlation of baseline PTX-2 levels with outcomes
  • To evaluate the relationship between bone marrow fibrosis reduction and hematologic improvements in subjects treated with PRM-151
  • To measure progression-free and overall survival in subjects receiving PRM-151

Stage 2 Study Design:

This 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.

Approximately 84 subjects with intermediate-1, intermediate-2, or high risk MF who meet study eligibility requirements will be enrolled and randomized to treatment with single agent PRM-151 at doses of 0.3, 3, or 10 mg/kg IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. The randomization will be stratified according to type of subject (subjects with Hgb < 100 g/L and having received ≥ 2 units PRBC in the 12 weeks prior to study entry OR subjects with platelet count < 50 x 109/L) and will ensure that the final study population will include at least 50% of subjects from the second stratum (platelet count < 50 x 109/L). All subjects may switch to an open label extension and receive PRM-151 10mg/kg every 4 weeks after completing 9 cycles of the originally assigned treatment. After study completion and data analysis, all subjects remaining on PRM-151 will switch to the dose that has been selected for future development based on study results.

Enrolled subjects will be considered evaluable for response if they are on study drug for at least twelve weeks.

Study Duration: Each subject will participate in the study for approximately 44 weeks. Participation will include a screening evaluation within four weeks prior to the first PRM-151 administration, nine study cycles of four weeks each, and an end of study visit four weeks after the end of the last cycle. After completion of 9 cycles, subjects may continue with PRM-151 dosing in the open label extension in the absence of disease progression or toxicity warranting discontinuation of therapy.
It is estimated that the study will be completed in approximately 18 months.

Study Inclusion and Exclusion 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 (Appendix C) or post ET/PV MF;
  4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis (Appendix D);
  5. Intermediate-1, intermediate -2, or high risk disease according to the IWG-MRT Dynamic International Prognostic Scoring System (Appendix E);
  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 109/L, OR
    2. b. 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 include use of oral contraceptives or Depo-Provera, with an additional barrier method (diaphragm with spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence;
  13. Ability to adhere to the study visit schedule and all protocol requirements;
  14. Must have adequate organ function as demonstrated by the following:
    1. 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);
    2. 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);
    3. Serum creatinine ≤ 2.5 mg/dL x ULN.

Exclusion Criteria:

  1. White blood cell count > 25 x 109/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.

Efficacy Assessments:

Efficacy will be assessed by evaluation of WHO bone marrow fibrosis grade, changes in hemoglobin, platelets, peripheral blood blasts, disease related symptoms, and spleen size.

Safety Assessments:

Safety will be evaluated from reported adverse events, scheduled physical examinations, vital signs, and clinical laboratory test results.

A blinded DMC will be established to review safety data from this study, thereby better ensuring the safety of study participants. Consistent with US Food and Drug Administration (FDA) recommendations (FDA Guidance for Industry, Establishment and Operation of Clinical Trial Data Monitoring Committees, 2006), the DMC will be constituted of independent clinicians expert in the field of MF and clinical research. A formal charter will be established for the conduct of the DMC.

The committee is planned to review the safety data in a blinded manner, but a procedure will be in place to allow the committee an immediate unblinding of either specific cases or of the whole study in case of detection of a potential safety signal necessitating an unblinded review of some (or all) subjects.

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