A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

Study Overview
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Brief Summary
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RO7490677 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 RO7490677 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.

Detailed Description
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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 RO7490677 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 RO7490677 or RO7490677 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 RO7490677 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 RO7490677. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010.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.

Official Title
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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)

Conditions
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Primary Myelofibrosis, Polycythemia Vera, Post-Essential Thrombocythemia Myelofibrosis

Intervention / Treatment
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* Biological: RO7490677
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be ≥18 years of age at the time of signing the Informed Consent Form (ICF); Participants must voluntarily sign an ICF; Participants must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF; At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis; Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score; Participants must not be candidates for ruxolitinib based on EITHER: Platelet count < 50 x 10e9/L, OR 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; Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F); Life expectancy of at least twelve months; 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; Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia; 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. Ability to adhere to the study visit schedule and all protocol requirements; 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: White blood cell count > 25 x 10e9/L or > 10% peripheral blood blasts; Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer; History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months; Presence of active serious infection; 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; Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection; Organ transplant recipients other than bone marrow transplant; Women who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Cohort 1 Weekly<br>Participants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 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. | Biological: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;|
| Experimental: Stage 1: Cohort 1 Every 4 Weeks<br>Paricipants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 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. | Biological: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;|
| Experimental: Stage 1: Cohort 2 Weekly<br>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 RO7490677 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. | Biological: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;Drug: Ruxolitinib<br>* IV infusion<br>* Other names: Jakafi;|
| Experimental: Stage 1: Cohort 2 Every 4 Weeks<br>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 RO7490677 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. | Biological: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;Drug: Ruxolitinib<br>* IV infusion<br>* Other names: Jakafi;|
| Experimental: Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks<br>Participants will be treated with single agent RO7490677 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: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;|
| Experimental: Stage 2: Cohort 2 3mg/kg Every 4 Weeks<br>Participants will be treated with single agent RO7490677 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: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;|
| Experimental: Stage 2: Cohort 3 10mg /kg Every 4 Weeks<br>Participants will be treated with single agent RO7490677 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: RO7490677<br>* IV infusion<br>* Other names: originally called PRM-151, and also known as rhPTX-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1 Main Phase: Overall Response Rate (ORR) | ORR was defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This was defined as those participants who achieved clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR had 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. | Up until and including completion of 6 cycles. Each cycle is 28 days. | 
| Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) | Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria from baseline to any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. | Up until and including completion of 9 cycles. Each cycle is 28 days. | 
| Stage 1 Main + Open-Label Extension (OLE): ORR | ORR was defined as the percent of participants with a response according to the IWG-MRT criteria. This was defined as those participants who achieved CI, PR, or CR at a post-baseline assessment of treatment response OR had at least 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. Participants who achieved a clinical benefit in the main phase had the opportunity to remain on treatment. The determination of ORR in the main phase is outlined in the arms description below. Participants who didn't achieve a benefit had the opportunity to switch to a different dosing schedule in the OLE phase. The determination of ORR in the OLE phase is outlined in the arms descriptions below. | From cycle 1 day 1 up until cycle 6, day 29 (Main Phase). From cycle 7 day 1 up until study discontinuation or study termination, up to 83 cycles (OLE). Each cycle is 28 days. | 
| Stage 2 Main + Open-Label Extension (OLE): BMRR | 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. Participants in the main phase had the opportunity to remain on treatment (as outlined in the arms description below). Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment and receive PRM-151 10 mg/kg/Q4W (as outlined in the arms description below). | From cycle 1 day 1 up until cycle 9 day 29 (main phase). From cycle 10 day 1 up until study discontinuation or study termination, up to 51 cycles (OLE). Each cycle is 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1 Main Phase: BMRR | Bone marrow response was defined as a reduction in bone marrow fibrosis score by at least one grade from baseline at anytime during the study. | Baseline, Weeks 12 and 24 | 
| Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. The values reported are the change from baseline scores. | Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days. | 
| Stage 2 Main Phase: BMRR | Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria at any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. | Up until and including completion of 9 cycles. Each cycle is 28 days. | 
| Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | Reduction in bone marrow fibrosis score: Reduction of at least one grade from baseline. Bone marrow fibrosis grades according to WHO criteria (as determined by central adjudication). | Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days. | 
| Stage 2 Main Phase: Duration of Bone Marrow Improvement | Duration of response was defined as time from first decrease from baseline >= 1 grade to time of return to baseline levels. | From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles. | 
| Stage 2 Main Phase: Hemoglobin Improvement | Hemoglobin improvement was measured by the percent of participants with: Red cell transfusion independence (no transfusions for >= 12 consecutive weeks) OR 50% reduction in red blood cell (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 was dependent on baseline hemoglobin/transfusion status). | Up until and including completion of 9 cycles. Each cycle is 28 days. | 
| Stage 2 Main Phase: Platelet Improvement | Platelet improvement was measured by the percent of participants with: Platelet transfusion independence (no transfusions for >= 12 consecutive weeks) OR 50% reduction in platelets transfusions for >= 12 consecutive weeks OR 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 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). | Up until and including completion of 9 cycles. Each cycle is 28 days. | 
| Stage 2 Main Phase: Symptom Improvement | Symptom improvement was assessed as the percent of participants with 50% reduction in MPN-SAF TSS from baseline over time. The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. | Up until and including completion of 9 cycles. Each cycle is 28 days. | 
| Stage 2 Main Phase: Percentage of Participants With Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria | Best Overall Response: (CR, PR, CI), SD and PD according to the IWG-MRT Criteria. | Up until and including completion of 9 cycles. Each cycle is 28 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fibrosis