Description:
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.
Title
- Brief Title: A Phase 2 Study Of PRM-151 In Participants With Myelofibrosis
- 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)
Clinical Trial IDs
- ORG STUDY ID:
BO42355
- SECONDARY ID:
PRM-151G-101
- SECONDARY ID:
2015-001718-80
- NCT ID:
NCT01981850
Conditions
- Primary Myelofibrosis
- Polycythemia Vera
- Post-Essential Thrombocythemia Myelofibrosis
Interventions
Drug | Synonyms | Arms |
---|
PRM-151 | recombinant human pentraxin-2 | Stage 1: Cohort 1 Every 4 Weeks |
Ruxolitinib | Jakafi | Stage 1: Cohort 2 Every 4 Weeks |
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.
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is the second stage of an adaptive design study as defined in FDA Draft Guidance for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.
Trial Arms
Name | Type | Description | Interventions |
---|
Stage 1: Cohort 1 Weekly | Experimental | 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. | |
Stage 1: Cohort 1 Every 4 Weeks | Experimental | 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. | |
Stage 1: Cohort 2 Weekly | Experimental | 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. | |
Stage 1: Cohort 2 Every 4 Weeks | Experimental | 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. | |
Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks | Experimental | 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. | |
Stage 2: Cohort 2 3mg/kg Every 4 Weeks | Experimental | 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. | |
Stage 2: Cohort 3 10mg /kg Every 4 Weeks | Experimental | 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. | |
Eligibility Criteria
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Stage 1: Overall Response Rate (ORR) |
Time Frame: | Up until and including completion of 6 cycles (each cycle is 28 days) |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Stage 1: Bone Marrow Myelofibrosis (MF) Grade Shifts |
Time Frame: | Baseline, Weeks 12 and 24 |
Safety Issue: | |
Description: | Change in Bone Marrow Fibrosis According to European Consensus on Grading of Bone Marrow Fibrosis |
Measure: | 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. |
Safety Issue: | |
Description: | |
Measure: | Stage 2: Bone Marrow Response Rate |
Time Frame: | Up until and including completion of 9 cycles (each cycle is 28 days) |
Safety Issue: | |
Description: | |
Measure: | 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 |
Safety Issue: | |
Description: | |
Measure: | Stage 2: Duration of Bone Marrow Response |
Time Frame: | From first decrease from baseline of one grade to time of return to baseline levels |
Safety Issue: | |
Description: | |
Measure: | Stage 2: Hemoglobin Improvement |
Time Frame: | Up until and including completion of 9 cycles (each cycle is 28 days) |
Safety Issue: | |
Description: | 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) |
Measure: | Stage 2: Platelet Improvement |
Time Frame: | Up until and including completion of 9 cycles (each cycle is 28 days) |
Safety Issue: | |
Description: | 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) |
Measure: | Stage 2: Symptom Improvement |
Time Frame: | Up until and including completion of 9 cycles (each cycle is 28 days) |
Safety Issue: | |
Description: | Percent of participants with 50% reduction in MPN-SAF TSS from baseline over time |
Measure: | 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) |
Safety Issue: | |
Description: | |
Measure: | 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. |
Safety Issue: | |
Description: | When applicable |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Hoffmann-La Roche |
Trial Keywords
Last Updated
November 24, 2020