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

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ClinicalTrials.gov Identifier: NCT01981850
Recruitment Status : Completed
First Posted : November 13, 2013
Last Update Posted : November 24, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE October 29, 2013
First Posted Date  ICMJE November 13, 2013
Last Update Posted Date November 24, 2020
Actual Study Start Date  ICMJE October 1, 2013
Actual Primary Completion Date July 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2020)
  • Stage 1: Overall Response Rate (ORR) [ Time Frame: Up until and including completion of 6 cycles (each cycle is 28 days) ]
    ORR is defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This is defined as those participants who achieve clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR have at least stable disease (SD) for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease.
  • Stage 2: Bone Marrow Response Rate (BMRR) [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
    Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
  • Stage 1 Open-Label Extension (OLE): Overall Response Rate (ORR) [ Time Frame: From cycle 7 every third cycle (every 3 months) until study discontinuation. Each cycle is 28 days. ]
  • Stage 2 Open-Label Extension (OLE): Bone Marrow Response Rate (BMRR) [ Time Frame: From cycle 10 every third cycle (every 3 months) until study discontinuation. Each cycle is 28 days. ]
    Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2013)
Overall response rate according to International Working Group consensus criteria for treatment response in myelofibrosis with myeloid metaplasia [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2020)
  • Stage 1: Bone Marrow Myelofibrosis (MF) Grade Shifts [ Time Frame: Baseline, Weeks 12 and 24 ]
    Change in Bone Marrow Fibrosis According to European Consensus on Grading of Bone Marrow Fibrosis
  • Stage 1: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes [ Time Frame: Baseline, beginning of each cycle (Cycle 2 onward). A cycle is 28 days. ]
  • Stage 2: Bone Marrow Response Rate [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
  • Stage 2: Bone Marrow (BM) Response Rate (MF Grade) at Each Visit [ Time Frame: Day 1 on Cycles 2, 3, 4, 5, 6, 7, 8, 9 (28 day length cycles) and Cycle 9 Day 29 ]
  • Stage 2: Duration of Bone Marrow Response [ Time Frame: From first decrease from baseline of one grade to time of return to baseline levels ]
  • Stage 2: Hemoglobin Improvement [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
    As measured by percent of participants with : Red cell transfusion independence (no transfusions for ≥ 12 consecutive weeks) OR 50% reduction in RBC transfusions for ≥ 12 consecutive weeks OR Percent of participants 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)
  • Stage 2: Platelet Improvement [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
    Percent of participants with: Platelet transfusion independence (no transfusions for ≥ 12 consecutive weeks) OR 50% reduction in platelets transfusions for ≥ 12 consecutive weeks OR Percent of participants 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 participants 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)
  • Stage 2: Symptom Improvement [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
    Percent of participants with 50% reduction in MPN-SAF TSS from baseline over time
  • Stage 2: Percent of Participants with Complete Response, Partial Response, Clinical Improvement, Stable Disease, and Progressive Disease According to IWG-MRT Criteria [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
  • OLE: Secondary Endpoints as per the Analyses of the Main Phases in Stage 1 or Stage 2 [ Time Frame: From cycle 7 (Stage 1) or cycle 10 (Stage 2) every third cycle (every 3 months) until study discontinuation. Each cycle is 28 days. ]
    When applicable
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2013)
  • Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in laboratory test results [ Time Frame: up to 28 weeks ]
  • Change in bone marrow fibrosis according to European Consensus on Grading of Bone Marrow Fibrosis [ Time Frame: 6 months ]
  • Change in the modified Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) Score [ Time Frame: 6 months ]
  • Duration of response [ Time Frame: 6 months ]
  • Pharmacokinetic (PK) parameters including Cmax (maximum drug concentration), tmax (time to maximum concentration, area under the curve (AUC), clearance, and volume of distribution. [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures
 (submitted: November 20, 2020)
  • Stage 1: Maximum Drug Concentration (Cmax) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days. ]
  • Stage 1: Time to Maximum Concentration (Tmax) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days. ]
  • Stage 1: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days. ]
  • Stage 1: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days. ]
  • Stage 1: Terminal Elimination Half-Life (T1/2) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days. ]
  • Stage 1: Clearance (CL) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days ]
  • Stage 1: Volume of Distribution (Vd) [ Time Frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and at end of infusion, 1, 2, 4, and 8 hours post infusion; at pre-dose on C1D3 and 5; on C1D15 at any time, and any time on C6D29. A Cycle is 28 days ]
  • Stage 1: Incidence and Severity of Adverse Events (AEs) and Infusion Related Reactions (IRRs) [ Time Frame: Up until and including completion of 6 cycles (each cycle is 28 days) ]
  • Stage 1: Incidence of Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation [ Time Frame: Up until and including completion of 6 cycles (each cycle is 28 days) ]
  • Stage 1: Laboratory Abnormalities, Vital Signs, and ECG [ Time Frame: Up until and including completion of 6 cycles (each cycle is 28 days) ]
  • Stage 2: Incidence and Severity of AEs and IRRs [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
  • Stage 2: Incidence of SAEs and AEs Leading to Study Drug Discontinuation [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
  • Stage 2: Laboratory Abnormalities, Vital Signs, and ECG [ Time Frame: Up until and including completion of 9 cycles (each cycle is 28 days) ]
  • Open Label Extensions for Stages 1 & 2: Incidence and Severity of AEs and IRRs [ Time Frame: Stage 1: Days 1, 8, 15, 22 of Extension Cycles. Stage 2: Days 1, 3 and 5 on Cycle 10, Day 1 (Cycle 9, Day 29) and Day 1 on Extension Cycles. A cycle is 28 days. ]
  • Open Label Extensions for Stages 1 & 2: Incidence of SAEs and AEs Leading to Study Drug Discontinuation [ Time Frame: Stage 1: Days 1, 8, 15, 22 of Extension Cycles. Stage 2: Days 1, 3 and 5 on Cycle 10, Day 1 (Cycle 9, Day 29) and Day 1 on Extension Cycles. A cycle is 28 days. ]
  • Open Label Extensions for Stages 1 & 2: Laboratory Abnormalities, Vital Signs, and ECG [ Time Frame: Stage 1: Days 1, 8, 15, 22 of Extension Cycles. Stage 2: Days 1, 3 and 5 on Cycle 10, Day 1 (Cycle 9, Day 29) and Day 1 on Extension Cycles. A cycle is 28 days. ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study Of PRM-151 In Participants With Myelofibrosis
Official Title  ICMJE 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)
Brief Summary

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.

Detailed Description

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 participants with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules receiving either single-agent PRM-151 or PRM-151 in combination with ruxolitinib. Participants were assigned to a weekly or every four week dosing schedule by the investigator.

Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of PRM-151 in participants with PMF and post ET/PV MF. Participants 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Polycythemia Vera
  • Post-Essential Thrombocythemia Myelofibrosis
Intervention  ICMJE
  • Biological: PRM-151
    IV infusion
    Other Name: recombinant human pentraxin-2
  • Drug: Ruxolitinib
    IV infusion
    Other Name: Jakafi
Study Arms  ICMJE
  • Experimental: Stage 1: Cohort 1 Weekly
    Participants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.
    Intervention: Biological: PRM-151
  • Experimental: Stage 1: Cohort 1 Every 4 Weeks
    Paricipants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Intervention: Biological: PRM-151
  • Experimental: Stage 1: Cohort 2 Weekly
    Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive PRM-151 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.
    Interventions:
    • Biological: PRM-151
    • Drug: Ruxolitinib
  • Experimental: Stage 1: Cohort 2 Every 4 Weeks
    Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive PRM-151 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Interventions:
    • Biological: PRM-151
    • Drug: Ruxolitinib
  • Experimental: Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks
    Participants 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.
    Intervention: Biological: PRM-151
  • Experimental: Stage 2: Cohort 2 3mg/kg Every 4 Weeks
    Participants 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.
    Intervention: Biological: PRM-151
  • Experimental: Stage 2: Cohort 3 10mg /kg Every 4 Weeks
    Participants 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.
    Intervention: Biological: PRM-151
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 20, 2020)
125
Original Estimated Enrollment  ICMJE
 (submitted: November 5, 2013)
104
Actual Study Completion Date  ICMJE July 10, 2020
Actual Primary Completion Date July 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Participants must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
  2. Participants must voluntarily sign an ICF;
  3. Participants 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. Participants 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. Participants 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 participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Germany,   Israel,   Italy,   Netherlands,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01981850
Other Study ID Numbers  ICMJE BO42355
PRM-151G-101 ( Other Identifier: Promedior, Inc. )
2015-001718-80 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP