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A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

Primary Purpose

Primary Myelofibrosis, Polycythemia Vera, Post-Essential Thrombocythemia Myelofibrosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
RO7490677
Ruxolitinib
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring fibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Mayo Clinic Cancer Center
  • Stanford Cancer Institute
  • Emory Hospital
  • University of Maryland Medical Center
  • Dana-Farber Cancer Institute
  • University of Michigan
  • Mount Sinai Medical Center
  • Weill Cornell Medical Center
  • Wake Forest Baptist Medical Center
  • Vanderbilt University Medical Center
  • MD Anderson Cancer Center
  • Providence Health Care
  • The Princess Margaret Cancer Centre
  • Hospital Saint-Louis
  • University Medical Center RWTH Aachen
  • Johannes Wesling Academic Medical Center
  • Hadassah Medical Centre
  • Meir Medical Centre
  • Fondazione IRCCS Policlinico San Matteo
  • Marche Nord Hospital
  • Erasmus Medical Center
  • Radboud University Medical Center
  • Guy's and St. Thomas' Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Stage 1: Cohort 1 Weekly

Stage 1: Cohort 1 Every 4 Weeks

Stage 1: Cohort 2 Weekly

Stage 1: Cohort 2 Every 4 Weeks

Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks

Stage 2: Cohort 2 3mg/kg Every 4 Weeks

Stage 2: Cohort 3 10mg /kg Every 4 Weeks

Arm Description

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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).

Secondary Outcome Measures

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.
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.
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.
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).
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.
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).
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).
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.
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.

Full Information

First Posted
October 29, 2013
Last Updated
December 7, 2021
Sponsor
Hoffmann-La Roche
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1. Study Identification

Unique Protocol Identification Number
NCT01981850
Brief Title
A Phase 2 Study of RO7490677 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)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
October 1, 2013 (Actual)
Primary Completion Date
July 10, 2020 (Actual)
Study Completion Date
July 10, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Polycythemia Vera, Post-Essential Thrombocythemia Myelofibrosis
Keywords
fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
125 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Stage 1: Cohort 1 Weekly
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 1: Cohort 1 Every 4 Weeks
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 1: Cohort 2 Weekly
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 1: Cohort 2 Every 4 Weeks
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 2: Cohort 2 3mg/kg Every 4 Weeks
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 2: Cohort 3 10mg /kg Every 4 Weeks
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
RO7490677
Other Intervention Name(s)
originally called PRM-151, and also known as rhPTX-2
Intervention Description
IV infusion
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
Jakafi
Intervention Description
IV infusion
Primary Outcome Measure Information:
Title
Stage 1 Main Phase: Overall Response Rate (ORR)
Description
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.
Time Frame
Up until and including completion of 6 cycles. Each cycle is 28 days.
Title
Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)
Description
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.
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Title
Stage 1 Main + Open-Label Extension (OLE): ORR
Description
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.
Time Frame
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.
Title
Stage 2 Main + Open-Label Extension (OLE): BMRR
Description
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).
Time Frame
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 Measure Information:
Title
Stage 1 Main Phase: BMRR
Description
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.
Time Frame
Baseline, Weeks 12 and 24
Title
Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes
Description
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.
Time Frame
Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.
Title
Stage 2 Main Phase: BMRR
Description
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.
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Title
Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit
Description
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).
Time Frame
Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.
Title
Stage 2 Main Phase: Duration of Bone Marrow Improvement
Description
Duration of response was defined as time from first decrease from baseline >= 1 grade to time of return to baseline levels.
Time Frame
From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.
Title
Stage 2 Main Phase: Hemoglobin Improvement
Description
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).
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Title
Stage 2 Main Phase: Platelet Improvement
Description
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).
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Title
Stage 2 Main Phase: Symptom Improvement
Description
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.
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Title
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
Description
Best Overall Response: (CR, PR, CI), SD and PD according to the IWG-MRT Criteria.
Time Frame
Up until and including completion of 9 cycles. Each cycle is 28 days.
Other Pre-specified Outcome Measures:
Title
Stage 1 Main Phase: Maximum Drug Concentration (Cmax)
Description
Cmax is the maximum observed RO7490677 plasma concentration.
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Time to Maximum Concentration (Tmax)
Description
Time at which the maximum plasma concentration was observed.
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)
Description
Area under the plasma concentration time curve from time 0 to time of last measurable plasma concentration.
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)
Description
Area under the plasma concentration-time curve from 0-time extrapolated to infinity.
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)
Description
Apparent terminal elimination half-life of RO7490677.
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Clearance (CL)
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Stage 1 Main Phase: Volume of Distribution (Vd)
Time Frame
Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Title
Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs)
Description
An AE was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. Pre-existing conditions which worsened during the study were also considered as adverse events. IRRs were considerd to be Adverse Events of Special Interest (AESI). Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.
Time Frame
Baseline up until 6.75 years
Title
Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation
Description
An SAE was defined as any AE that occurred at any dose the resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalizations; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly or birth defect. An AE was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. Pre-existing conditions which worsened during the study were also considered as adverse events. Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.
Time Frame
Baseline up until 6.75 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic Cancer Center
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Stanford Cancer Institute
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Emory Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-2800
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Wake Forest Baptist Medical Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Providence Health Care
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 2A5
Country
Canada
Facility Name
The Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 2M9
Country
Canada
Facility Name
Hospital Saint-Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
University Medical Center RWTH Aachen
City
Aachen
ZIP/Postal Code
D-52074
Country
Germany
Facility Name
Johannes Wesling Academic Medical Center
City
Minden
ZIP/Postal Code
32429
Country
Germany
Facility Name
Hadassah Medical Centre
City
Jerusalem
ZIP/Postal Code
91120
Country
Israel
Facility Name
Meir Medical Centre
City
Kfar Saba
ZIP/Postal Code
4428164
Country
Israel
Facility Name
Fondazione IRCCS Policlinico San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Marche Nord Hospital
City
Pesaro
ZIP/Postal Code
61122
Country
Italy
Facility Name
Erasmus Medical Center
City
Rotterdam
State/Province
Zuid Holland
ZIP/Postal Code
3015 CE
Country
Netherlands
Facility Name
Radboud University Medical Center
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
Facility Name
Guy's and St. Thomas' Hospital
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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).

Learn more about this trial

A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

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