A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01981850
Collaborator
(none)
125
23
7
81.3
5.4
0.1

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010.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

Study Design

Study Type:
Interventional
Actual Enrollment :
125 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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)
Actual Study Start Date :
Oct 1, 2013
Actual Primary Completion Date :
Jul 10, 2020
Actual Study Completion Date :
Jul 10, 2020

Arms and Interventions

Arm Intervention/Treatment
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 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
IV infusion
Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • 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 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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • 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 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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • Drug: Ruxolitinib
    IV infusion
    Other Names:
  • Jakafi
  • 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 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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • Drug: Ruxolitinib
    IV infusion
    Other Names:
  • Jakafi
  • Experimental: Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks

    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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • Experimental: Stage 2: Cohort 2 3mg/kg Every 4 Weeks

    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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • Experimental: Stage 2: Cohort 3 10mg /kg Every 4 Weeks

    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
    IV infusion
    Other Names:
  • originally called PRM-151, and also known as rhPTX-2
  • Outcome Measures

    Primary Outcome Measures

    1. Stage 1 Main Phase: Overall Response Rate (ORR) [Up until and including completion of 6 cycles. Each cycle is 28 days.]

      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.

    2. Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      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.

    3. Stage 1 Main + Open-Label Extension (OLE): ORR [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.]

      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.

    4. Stage 2 Main + Open-Label Extension (OLE): BMRR [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.]

      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

    1. Stage 1 Main Phase: BMRR [Baseline, Weeks 12 and 24]

      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.

    2. Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes [Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.]

      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.

    3. Stage 2 Main Phase: BMRR [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      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.

    4. Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit [Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.]

      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).

    5. Stage 2 Main Phase: Duration of Bone Marrow Improvement [From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.]

      Duration of response was defined as time from first decrease from baseline >= 1 grade to time of return to baseline levels.

    6. Stage 2 Main Phase: Hemoglobin Improvement [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      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).

    7. Stage 2 Main Phase: Platelet Improvement [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      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).

    8. Stage 2 Main Phase: Symptom Improvement [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      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.

    9. 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 [Up until and including completion of 9 cycles. Each cycle is 28 days.]

      Best Overall Response: (CR, PR, CI), SD and PD according to the IWG-MRT Criteria.

    Other Outcome Measures

    1. Stage 1 Main Phase: Maximum Drug Concentration (Cmax) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

      Cmax is the maximum observed RO7490677 plasma concentration.

    2. Stage 1 Main Phase: Time to Maximum Concentration (Tmax) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

      Time at which the maximum plasma concentration was observed.

    3. Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

      Area under the plasma concentration time curve from time 0 to time of last measurable plasma concentration.

    4. Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

      Area under the plasma concentration-time curve from 0-time extrapolated to infinity.

    5. Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

      Apparent terminal elimination half-life of RO7490677.

    6. Stage 1 Main Phase: Clearance (CL) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

    7. Stage 1 Main Phase: Volume of Distribution (Vd) [Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days]

    8. Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) [Baseline up until 6.75 years]

      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.

    9. Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation [Baseline up until 6.75 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    8. Platelet count < 50 x 10e9/L, OR

    9. 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;

    10. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F);

    11. Life expectancy of at least twelve months;

    12. 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;

    13. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;

    14. 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.

    15. Ability to adhere to the study visit schedule and all protocol requirements;

    16. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic Cancer Center Phoenix Arizona United States 85054
    2 Stanford Cancer Institute Palo Alto California United States 94304
    3 Emory Hospital Atlanta Georgia United States 30322
    4 University of Maryland Medical Center Baltimore Maryland United States 21201
    5 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    6 University of Michigan Ann Arbor Michigan United States 48109-2800
    7 Mount Sinai Medical Center New York New York United States 10029
    8 Weill Cornell Medical Center New York New York United States 10065
    9 Wake Forest Baptist Medical Center Winston-Salem North Carolina United States 27157
    10 Vanderbilt University Medical Center Nashville Tennessee United States 37232
    11 MD Anderson Cancer Center Houston Texas United States 77030
    12 Providence Health Care Vancouver British Columbia Canada V6Z 2A5
    13 The Princess Margaret Cancer Centre Toronto Ontario Canada M5T 2M9
    14 Hospital Saint-Louis Paris France 75475
    15 University Medical Center RWTH Aachen Aachen Germany D-52074
    16 Johannes Wesling Academic Medical Center Minden Germany 32429
    17 Hadassah Medical Centre Jerusalem Israel 91120
    18 Meir Medical Centre Kfar Saba Israel 4428164
    19 Fondazione IRCCS Policlinico San Matteo Pavia Italy 27100
    20 Marche Nord Hospital Pesaro Italy 61122
    21 Erasmus Medical Center Rotterdam Zuid Holland Netherlands 3015 CE
    22 Radboud University Medical Center Nijmegen Netherlands 6525 GA
    23 Guy's and St. Thomas' Hospital London United Kingdom

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01981850
    Other Study ID Numbers:
    • BO42355
    • PRM-151G-101
    • 2015-001718-80
    First Posted:
    Nov 13, 2013
    Last Update Posted:
    Jan 5, 2022
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Hoffmann-La Roche
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details A total of 125 participants were enrolled at sites in 8 different countries.
    Pre-assignment Detail One randomized participant in Stage 2 did not receive the study treatment, bringing the total number of treated participants to 124.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants who completed the main phase of treatment moved to the open label extension. They were treated with single agent PRM-151 at a dose of 10 mg/kg administered as an IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle. Participants who completed the main phase of treatment moved to the open label extension. They were treated with PRM-151 at a dose of 10 mg/kg administered as an IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle. Participants who completed 9 cycles of the originally assigned treatment could switch to the open label extension. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on days 1, 3, and 5 of first cycle of the open label phase and Day 1 of each subsequent 28 day cycle.
    Period Title: Main Phase Stage 1
    STARTED 8 7 6 6 0 0 0 0 0 0
    COMPLETED 5 5 4 6 0 0 0 0 0 0
    NOT COMPLETED 3 2 2 0 0 0 0 0 0 0
    Period Title: Main Phase Stage 1
    STARTED 0 0 0 0 33 32 32 0 0 0
    COMPLETED 0 0 0 0 20 16 15 0 0 0
    NOT COMPLETED 0 0 0 0 13 16 17 0 0 0
    Period Title: Main Phase Stage 1
    STARTED 0 0 0 0 0 0 0 13 5 48
    COMPLETED 0 0 0 0 0 0 0 1 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 12 5 48

    Baseline Characteristics

    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W Total
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Total of all reporting groups
    Overall Participants 8 7 6 6 33 32 32 124
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    64.3
    (11.4)
    70.7
    (6.3)
    66.0
    (7.3)
    66.2
    (8.6)
    66.7
    (8.7)
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    70.6
    (7.1)
    70.2
    (6.5)
    69.4
    (8.9)
    70.1
    (7.5)
    Sex: Female, Male (Count of Participants)
    Female
    5
    62.5%
    2
    28.6%
    3
    50%
    5
    83.3%
    15
    45.5%
    Male
    3
    37.5%
    5
    71.4%
    3
    50%
    1
    16.7%
    12
    36.4%
    Sex: Female, Male (Count of Participants)
    Female
    16
    200%
    8
    114.3%
    11
    183.3%
    35
    583.3%
    Male
    17
    212.5%
    24
    342.9%
    21
    350%
    62
    1033.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    3%
    Not Hispanic or Latino
    8
    100%
    7
    100%
    4
    66.7%
    6
    100%
    25
    75.8%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    3%
    Asian
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    12.5%
    0
    0%
    1
    16.7%
    0
    0%
    2
    6.1%
    White
    7
    87.5%
    7
    100%
    3
    50%
    6
    100%
    23
    69.7%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    1
    14.3%
    2
    33.3%
    3
    50%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    14.3%
    0
    0%
    1
    16.7%
    White
    33
    412.5%
    29
    414.3%
    29
    483.3%
    91
    1516.7%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    1
    14.3%
    1
    16.7%
    2
    33.3%

    Outcome Measures

    1. Primary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants who received at least one dose of RO7490667.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    Number (90% Confidence Interval) [Percentage of Participants]
    37.5
    468.8%
    14.3
    204.3%
    33.3
    555%
    50.0
    833.3%
    2. Primary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Number (95% Confidence Interval) [Percentage of Participants]
    30.3
    378.8%
    31.3
    447.1%
    25.0
    416.7%
    3. Primary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population (main phase + OLE) included all participants who received at least one dose of RO7490667.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV QW; OLE: RO7490677 10 mg/kg IV Q4W Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W; OLE: RO7490677 10 mg/kg IV Q4W Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib; OLE: RO7490677 10 mg/kg IV Q4W + Ruxo. Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib; OLE: RO7490677 10 mg/kg IV Q4W + Ruxo.
    Arm/Group Description Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE). Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE). Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants could drop ruxolitinib in the OLE, but were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE). Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants could drop ruxolitinib in the OLE, but were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE).
    Measure Participants 8 7 6 6
    Number (90% Confidence Interval) [Percentage of Participants]
    50.0
    625%
    71.4
    1020%
    50.0
    833.3%
    66.7
    1111.7%
    4. Primary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population (main phase + OLE) included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W; OLE: RO7490677 10 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W; OLE: RO7490677 10 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W; OLE: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and PRM-151 at a dose of 10 mg/kg on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE). Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and PRM-151 at a dose of 10 mg/kg on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE). Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE).
    Measure Participants 33 32 32
    Number (95% Confidence Interval) [Percentage of Participants]
    30.3
    378.8%
    34.4
    491.4%
    25.0
    416.7%
    5. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants who received at least one dose of RO7490667.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    Number (95% Confidence Interval) [Percentage of Participants]
    37.5
    468.8%
    14.3
    204.3%
    16.7
    278.3%
    50.0
    833.3%
    6. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants who received at least one dose of RO7490667.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    Baseline
    23.1
    (19.1)
    16.9
    (7.2)
    26.8
    (17.1)
    15.3
    (10.4)
    Cycle(C)2 Day(D)1
    -5.3
    (12.6)
    5.7
    (11.8)
    0.5
    (8.8)
    -2.0
    (5.0)
    C3D1
    -9.1
    (10.9)
    1.9
    (5.3)
    -2.7
    (14.8)
    4.2
    (8.0)
    C4D1
    -8.7
    (10.7)
    1.0
    (8.0)
    -7.5
    (6.0)
    5.7
    (20.9)
    C5D1
    -13.2
    (13.2)
    2.6
    (6.9)
    -6.7
    (10.6)
    1.5
    (13.6)
    C6D1
    -12.2
    (9.5)
    -0.8
    (8.3)
    -5.4
    (6.2)
    4.3
    (11.5)
    C6D29
    -15.0
    (13.7)
    -2.2
    (5.3)
    -5.3
    (4.6)
    2.3
    (8.8)
    7. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Number (95% Confidence Interval) [Percentage of Participants]
    30.3
    378.8%
    31.3
    447.1%
    25.0
    416.7%
    8. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Cycle(C) 4 Day(D) 1
    10.7
    133.8%
    24.0
    342.9%
    19.2
    320%
    C7D1
    23.8
    297.5%
    11.8
    168.6%
    10.5
    175%
    C9D29/C10D1
    30.0
    375%
    21.4
    305.7%
    13.3
    221.7%
    9. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Median (95% Confidence Interval) [Weeks]
    NA
    12.0
    12.1
    10. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Number [Percentage of Participants]
    15.2
    190%
    15.6
    222.9%
    6.3
    105%
    11. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Number [Percentage of Participants]
    27.3
    341.3%
    34.4
    491.4%
    37.5
    625%
    12. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    Cycle(C) 2 Day(D) 1
    5
    62.5%
    2
    28.6%
    1
    16.7%
    C3D1
    6
    75%
    3
    42.9%
    2
    33.3%
    C4D1
    3
    37.5%
    4
    57.1%
    2
    33.3%
    C5D1
    5
    62.5%
    2
    28.6%
    1
    16.7%
    C6D1
    8
    100%
    3
    42.9%
    3
    50%
    C7D1
    8
    100%
    5
    71.4%
    0
    0%
    C8D1
    5
    62.5%
    3
    42.9%
    0
    0%
    C9D1
    5
    62.5%
    3
    42.9%
    1
    16.7%
    C9D29/C10D1
    5
    62.5%
    2
    28.6%
    0
    0%
    13. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The all treated population included all participants randomized and who received at least one administration of the drug.
    Arm/Group Title Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
    Measure Participants 33 32 32
    CR
    0
    0%
    0
    0%
    0
    0%
    PR
    0
    0%
    0
    0%
    0
    0%
    CI
    8
    100%
    6
    85.7%
    2
    33.3%
    SD
    20
    250%
    21
    300%
    26
    433.3%
    PD
    3
    37.5%
    3
    42.9%
    4
    66.7%
    Not evaluable
    2
    25%
    2
    28.6%
    0
    0%
    14. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    133
    (48.4)
    113
    (28.1)
    164
    (23.9)
    112
    (90.4)
    C1D15
    127
    (31.9)
    126
    (27.5)
    C2D1
    107
    (26.9)
    110
    (20.9)
    149
    (29.1)
    130
    (80.2)
    C6D1
    142
    (70.0)
    111
    (28.0)
    136
    (34.1)
    142
    (27.4)
    15. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    1.12
    1.10
    1.14
    1.13
    C1D15
    1.13
    1.65
    C2D1
    1.10
    1.08
    1.05
    1.44
    C6D1
    2.00
    1.07
    1.17
    1.01
    16. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    1810
    (72.0)
    1690
    (26.1)
    2590
    (28.7)
    1500
    (158.3)
    C1D15
    1460
    (142.0)
    2590
    (187.6)
    C2D1
    127.3
    (904)
    504
    (84.7)
    2990
    (92.0)
    663
    (79.5)
    C6D1
    698
    (63.0)
    570
    (44.8)
    764
    (28.9)
    703
    (33.8)
    17. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    2830
    (12.9)
    2050
    (29.5)
    2970
    (34.9)
    3130
    (8.6)
    C1D15
    3450
    (2.8)
    6060
    (23.2)
    C2D1
    2170
    (170.9)
    4230
    (34.8)
    C6D1
    819
    (NA)
    18. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    14.7
    (19.2)
    17.2
    (23.7)
    16.8
    (17.7)
    18.4
    (7.9)
    C1D15
    31.2
    (45.0)
    40.4
    (12.6)
    C2D1
    18.0
    (220.6)
    30.0
    (48.6)
    C6D1
    1.95
    (NA)
    19. Other Pre-specified Outcome
    Title Stage 1 Main Phase: Clearance (CL)
    Description
    Time Frame Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    0.258
    (9.0)
    0.362
    (31.5)
    0.269
    (32.9)
    0.233
    (33.3)
    C1D15
    0.233
    (24.9)
    0.147
    (35.0)
    C2D1
    0.382
    (229.9)
    0.189
    (55.5)
    C6D1
    1.42
    (NA)
    20. Other Pre-specified Outcome
    Title Stage 1 Main Phase: Volume of Distribution (Vd)
    Description
    Time Frame Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

    Outcome Measure Data

    Analysis Population Description
    The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
    Measure Participants 8 7 6 6
    C1D1
    5.47
    (10.9)
    9.00
    (28.8)
    6.52
    (26.4)
    6.17
    (38.9)
    C1D15
    10.5
    (62.4)
    8.57
    (47.6)
    C2D1
    9.93
    (63.0)
    8.18
    (24.5)
    C6D1
    4.01
    (NA)
    21. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The safety population included all participants who received at least one dose of study drug.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants who completed 9 cycles of the originally assigned treatment could switch to the open label extension. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on days 1, 3, and 5 of first cycle of the open label phase and Day 1 of each subsequent 28 day cycle.
    Measure Participants 8 7 6 6 33 32 32 13 5 48
    AEs
    100
    1250%
    85.7
    1224.3%
    100
    1666.7%
    100
    1666.7%
    100
    303%
    100
    312.5%
    100
    312.5%
    92.3
    74.4%
    100
    NaN
    89.6
    NaN
    IRRs
    0
    0%
    0
    0%
    0
    0%
    16.7
    278.3%
    3.0
    9.1%
    3.1
    9.7%
    6.3
    19.7%
    7.7
    6.2%
    20.0
    NaN
    2.1
    NaN
    22. Other Pre-specified Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    The safety population included all participants who received at least one dose of study drug.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants who completed 9 cycles of the originally assigned treatment could switch to the open label extension. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on days 1, 3, and 5 of first cycle of the open label phase and Day 1 of each subsequent 28 day cycle.
    Measure Participants 8 7 6 6 33 32 32 13 5 48
    SAEs
    25.0
    312.5%
    0
    0%
    0
    0%
    0
    0%
    15.2
    46.1%
    15.6
    48.8%
    28.1
    87.8%
    7.7
    6.2%
    0
    NaN
    22.9
    NaN
    AEs
    25.0
    312.5%
    0
    0%
    0
    0%
    0
    0%
    21.2
    64.2%
    34.4
    107.5%
    37.5
    117.2%
    30.8
    24.8%
    0
    NaN
    27.1
    NaN

    Adverse Events

    Time Frame Baseline up until 6.75 years
    Adverse Event Reporting Description Treatment-emergent adverse events (TEAEs) were defined as any AE that occurred after the administration of any amount of the study drug, or any event that was present at baseline.
    Arm/Group Title Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Arm/Group Description Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion 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 who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib 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 were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. Participants who completed the main phase of treatment moved to the open label extension. They were treated with single agent PRM-151 at a dose of 10 mg/kg administered as an IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle. Participants who completed the main phase of treatment moved to the open label extension. They were treated with PRM-151 at a dose of 10 mg/kg administered as an IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle. Participants who completed 9 cycles of the originally assigned treatment could switch to the open label extension. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on days 1, 3, and 5 of first cycle of the open label phase and Day 1 of each subsequent 28 day cycle.
    All Cause Mortality
    Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/8 (25%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 7/33 (21.2%) 6/32 (18.8%) 9/32 (28.1%) 0/13 (0%) 0/5 (0%) 7/48 (14.6%)
    Serious Adverse Events
    Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/8 (25%) 1/7 (14.3%) 2/6 (33.3%) 0/6 (0%) 11/33 (33.3%) 14/32 (43.8%) 14/32 (43.8%) 5/13 (38.5%) 2/5 (40%) 22/48 (45.8%)
    Blood and lymphatic system disorders
    Anaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Bone marrow failure 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Extramedullary haemopoiesis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Leukocytosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pancytopenia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Thrombocytopenia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cardiac disorders
    Acute coronary syndrome 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Acute myocardial infarction 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Aortic valve stenosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Cardiac failure 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 3 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cardiopulmonary failure 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Coronary artery disease 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pericardial effusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Cardiac arrest 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/8 (0%) 0 1/7 (14.3%) 3 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Femoral hernia, obstructive 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Intestinal ischaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Melaena 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Oesophageal varices haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 2
    Rectal haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Varices oesophageal 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Intestinal obstruction 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Mouth haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Upper gastrointestinal haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 2 0/48 (0%) 0
    General disorders
    Asthenia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Chest pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Death 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Disease progression 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Inflammation 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Peripheral swelling 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Unevaluable event 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 2
    Organ failure 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cholecystitis acute 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cholelithiasis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Portal hypertension 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Immune system disorders
    Anaphylactic reaction 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Infections and infestations
    Infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 1/48 (2.1%) 1
    Pneumonia 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 2/33 (6.1%) 3 1/32 (3.1%) 1 2/32 (6.3%) 2 0/13 (0%) 0 1/5 (20%) 2 3/48 (6.3%) 3
    Abscess limb 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cellulitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Endocarditis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Influenza 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Intervertebral discitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Osteomyelitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Pneumonia fungal 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pseudomonal sepsis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Sepsis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Septic shock 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Upper respiratory tract infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Urinary tract infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Urosepsis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 3 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Enterocolitis infectious 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Gastroenteritis 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pneumonia viral 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Respiratory syncytial virus infection 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sialoadenitis 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Wound infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 1/5 (20%) 1 0/48 (0%) 0
    Injury, poisoning and procedural complications
    Fall 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Infusion related reaction 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Osteoradionecrosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Procedural haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Subdural haematoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Multiple fractures 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Post procedural haematoma 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Rib fracture 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Hepatic enzyme increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Metabolism and nutrition disorders
    Cachexia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hyperkalaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hyperuricaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Chondrocalcinosis pyrophosphate 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Haemarthrosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Haematoma muscle 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Joint effusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Malignant neoplasm progression 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Myelofibrosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Primary myelofibrosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Transformation to acute myeloid leukaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hepatic cancer 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Metastatic squamous cell carcinoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Squamous cell carcinoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 2 0/48 (0%) 0
    Nervous system disorders
    Cerebral haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hepatic encephalopathy 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Subarachnoid haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Syncope 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Metabolic encephalopathy 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 2
    Nephrolithiasis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Renal failure 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Urinary bladder haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 3 0/5 (0%) 0 0/48 (0%) 0
    Urinary bladder rupture 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Epistaxis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Pleural effusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Skin and subcutaneous tissue disorders
    Eczema 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Skin ulcer 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Surgical and medical procedures
    Aortic valve replacement 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Vascular disorders
    Dry gangrene 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Haematoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Other (Not Including Serious) Adverse Events
    Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib OLE Stage 2: RO7490677 10 mg/kg IV Q4W
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/8 (100%) 6/7 (85.7%) 6/6 (100%) 6/6 (100%) 32/33 (97%) 30/32 (93.8%) 31/32 (96.9%) 12/13 (92.3%) 5/5 (100%) 32/48 (66.7%)
    Blood and lymphatic system disorders
    Anaemia 1/8 (12.5%) 1 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 5/33 (15.2%) 11 6/32 (18.8%) 8 3/32 (9.4%) 6 1/13 (7.7%) 2 1/5 (20%) 1 6/48 (12.5%) 12
    Leukocytosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Splenomegaly 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 2/32 (6.3%) 3 2/32 (6.3%) 3 3/13 (23.1%) 3 0/5 (0%) 0 7/48 (14.6%) 7
    Thrombocytopenia 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 5/33 (15.2%) 6 4/32 (12.5%) 5 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 3
    Leukopenia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Neutropenia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 3 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Increased tendency to bruise 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Cardiac disorders
    Tachycardia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Palpitations 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Supraventricular extrasystoles 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Endocrine disorders
    Hypothyroidism 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Eye disorders
    Dry eye 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 3 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Vision blurred 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 3 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 1/5 (20%) 1 1/48 (2.1%) 1
    Abdominal pain 1/8 (12.5%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 5/33 (15.2%) 7 6/32 (18.8%) 8 4/32 (12.5%) 5 1/13 (7.7%) 1 0/5 (0%) 0 3/48 (6.3%) 3
    Abdominal pain upper 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 2 1/32 (3.1%) 2 3/13 (23.1%) 4 0/5 (0%) 0 2/48 (4.2%) 2
    Diarrhoea 2/8 (25%) 2 0/7 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 2 8/33 (24.2%) 8 5/32 (15.6%) 5 3/32 (9.4%) 3 0/13 (0%) 0 1/5 (20%) 1 7/48 (14.6%) 7
    Nausea 2/8 (25%) 2 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 2/33 (6.1%) 2 2/32 (6.3%) 2 5/32 (15.6%) 5 4/13 (30.8%) 5 2/5 (40%) 3 3/48 (6.3%) 5
    Stomatitis 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 4
    Vomiting 0/8 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 3 5/32 (15.6%) 9 2/13 (15.4%) 2 2/5 (40%) 2 0/48 (0%) 0
    Constipation 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 4/33 (12.1%) 5 4/32 (12.5%) 4 4/32 (12.5%) 6 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Gingival bleeding 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 3 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Abdominal discomfort 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Abdominal pain lower 2/8 (25%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Abdominal tenderness 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Anal incontinence 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Aphthous ulcer 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Flatulence 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Gastrooesophageal reflux disease 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Gingival pain 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Oral disorder 1/8 (12.5%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Oral pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Retching 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    General disorders
    Asthenia 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 1/33 (3%) 1 4/32 (12.5%) 4 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Chest pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Chills 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 5 0/32 (0%) 0 1/13 (7.7%) 2 0/5 (0%) 0 0/48 (0%) 0
    Fatigue 3/8 (37.5%) 3 1/7 (14.3%) 1 1/6 (16.7%) 3 1/6 (16.7%) 1 8/33 (24.2%) 9 8/32 (25%) 10 11/32 (34.4%) 12 2/13 (15.4%) 2 0/5 (0%) 0 5/48 (10.4%) 5
    Oedema peripheral 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 6/33 (18.2%) 8 3/32 (9.4%) 4 9/32 (28.1%) 10 2/13 (15.4%) 2 0/5 (0%) 0 4/48 (8.3%) 5
    Peripheral swelling 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 2/6 (33.3%) 2 2/33 (6.1%) 3 1/32 (3.1%) 1 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pyrexia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 3/6 (50%) 3 4/33 (12.1%) 4 7/32 (21.9%) 8 3/32 (9.4%) 3 0/13 (0%) 0 1/5 (20%) 2 2/48 (4.2%) 3
    Chest discomfort 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 3 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Gait disturbance 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 1/32 (3.1%) 1 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Early satiety 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Extravasation 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Ill-defined disorder 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Injection site haemorrhage 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Pain 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Swelling 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Vessel puncture site bruise 0/8 (0%) 0 0/7 (0%) 0 2/6 (33.3%) 5 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hepatobiliary disorders
    Hepatomegaly 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Hepatosplenomegaly 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Hyperbilirubinaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Infections and infestations
    Bronchitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 5 0/32 (0%) 0 1/32 (3.1%) 1 0/13 (0%) 0 2/5 (40%) 2 0/48 (0%) 0
    Nasopharyngitis 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/33 (3%) 1 1/32 (3.1%) 1 2/32 (6.3%) 3 0/13 (0%) 0 1/5 (20%) 1 3/48 (6.3%) 3
    Oral herpes 1/8 (12.5%) 1 0/7 (0%) 0 2/6 (33.3%) 2 1/6 (16.7%) 1 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Pneumonia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 4 1/32 (3.1%) 1 3/32 (9.4%) 3 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Sinusitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 3 0/5 (0%) 0 1/48 (2.1%) 2
    Skin infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Upper respiratory tract infection 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 2/6 (33.3%) 2 2/33 (6.1%) 2 2/32 (6.3%) 2 0/32 (0%) 0 3/13 (23.1%) 4 0/5 (0%) 0 2/48 (4.2%) 5
    Urinary tract infection 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 2/33 (6.1%) 4 2/32 (6.3%) 2 1/32 (3.1%) 1 2/13 (15.4%) 3 0/5 (0%) 0 4/48 (8.3%) 4
    Cellulitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 1/32 (3.1%) 2 0/13 (0%) 0 0/5 (0%) 0 4/48 (8.3%) 5
    Folliculitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Diarrhoea infectious 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Gastroenteritis viral 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Laryngitis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Localised infection 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Lyme disease 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Respiratory syncytial virus infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Rhinitis 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sialoadenitis 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Subcutaneous abscess 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Tooth infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Urosepsis 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Viral upper respiratory tract infection 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Injury, poisoning and procedural complications
    Contusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 1/13 (7.7%) 1 1/5 (20%) 3 5/48 (10.4%) 5
    Eye contusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Fall 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 3/32 (9.4%) 7 2/32 (6.3%) 3 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 6
    Procedural pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 2/32 (6.3%) 3 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Ankle fracture 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Arthropod bite 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Foot fracture 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Infusion related reaction 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Post-traumatic pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Road traffic accident 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 3 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Transfusion reaction 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Wound 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Wrist fracture 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Investigations
    Alanine aminotransferase increased 3/8 (37.5%) 3 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 4/32 (12.5%) 7 1/32 (3.1%) 1 0/13 (0%) 0 2/5 (40%) 2 0/48 (0%) 0
    Aspartate aminotransferase increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 5/32 (15.6%) 9 1/32 (3.1%) 1 0/13 (0%) 0 2/5 (40%) 2 0/48 (0%) 0
    Blood bilirubin increased 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Weight increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 3/48 (6.3%) 3
    Blood alkaline phosphatase increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 6 2/32 (6.3%) 4 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Blood sodium decreased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Neutrophil count decreased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 3 3/32 (9.4%) 4 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Platelet count decreased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 4/33 (12.1%) 8 3/32 (9.4%) 3 1/32 (3.1%) 2 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Weight decreased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 6/33 (18.2%) 7 8/32 (25%) 8 8/32 (25%) 11 0/13 (0%) 0 0/5 (0%) 0 5/48 (10.4%) 6
    White blood cell count decreased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 5 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Blood creatine phosphokinase increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 2/5 (40%) 3 0/48 (0%) 0
    Blood creatinine increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Blood urea increased 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Blood uric acid increased 2/8 (25%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 4/33 (12.1%) 5 4/32 (12.5%) 5 4/32 (12.5%) 6 1/13 (7.7%) 1 0/5 (0%) 0 2/48 (4.2%) 2
    Gout 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 2 1/32 (3.1%) 1 1/13 (7.7%) 1 0/5 (0%) 0 1/48 (2.1%) 1
    Hyperglycaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 4 3/32 (9.4%) 5 1/32 (3.1%) 2 1/13 (7.7%) 1 0/5 (0%) 0 2/48 (4.2%) 3
    Hyperuricaemia 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 4/32 (12.5%) 5 4/32 (12.5%) 4 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hypocalcaemia 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Hypokalaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 1/5 (20%) 1 1/48 (2.1%) 2
    Cachexia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hyperphosphataemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Hypomagnesaemia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 3 0/48 (0%) 0
    Iron deficiency 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Iron overload 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Type 2 diabetes mellitus 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 3/33 (9.1%) 3 5/32 (15.6%) 5 2/32 (6.3%) 2 2/13 (15.4%) 2 4/5 (80%) 4 3/48 (6.3%) 3
    Back pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 3/32 (9.4%) 3 0/32 (0%) 0 1/13 (7.7%) 1 1/5 (20%) 1 1/48 (2.1%) 1
    Bone pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 3 3/32 (9.4%) 3 2/32 (6.3%) 2 1/13 (7.7%) 1 1/5 (20%) 1 0/48 (0%) 0
    Muscle spasms 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 3 2/32 (6.3%) 3 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 3/48 (6.3%) 3
    Muscular weakness 2/8 (25%) 2 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 2 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Myalgia 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 3 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 2
    Pain in extremity 0/8 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 2 0/6 (0%) 0 2/33 (6.1%) 3 5/32 (15.6%) 5 1/32 (3.1%) 1 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Musculoskeletal pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 3/32 (9.4%) 3 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 2/48 (4.2%) 2
    Groin pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Joint lock 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Joint swelling 1/8 (12.5%) 1 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Musculoskeletal chest pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 1/5 (20%) 1 0/48 (0%) 0
    Musculoskeletal stiffness 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Neck pain 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/33 (6.1%) 2 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 3/5 (60%) 3 0/48 (0%) 0
    Lipoma 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Neoplasm 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Nervous system disorders
    Dizziness 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 6/33 (18.2%) 9 3/32 (9.4%) 3 1/32 (3.1%) 1 0/13 (0%) 0 1/5 (20%) 1 2/48 (4.2%) 2
    Headache 0/8 (0%) 0 0/7 (0%) 0 2/6 (33.3%) 2 1/6 (16.7%) 1 4/33 (12.1%) 5 7/32 (21.9%) 8 3/32 (9.4%) 3 2/13 (15.4%) 3 2/5 (40%) 4 3/48 (6.3%) 3
    Hypoaesthesia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 2/33 (6.1%) 2 1/32 (3.1%) 1 1/32 (3.1%) 1 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Neuropathy peripheral 0/8 (0%) 0 2/7 (28.6%) 2 0/6 (0%) 0 0/6 (0%) 0 3/33 (9.1%) 3 1/32 (3.1%) 1 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Nerve compression 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sciatic nerve neuropathy 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sciatica 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Psychiatric disorders
    Depression 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 4/32 (12.5%) 4 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Insomnia 1/8 (12.5%) 1 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/33 (3%) 1 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Delirium 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 3 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sleep disorder 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Renal and urinary disorders
    Dysuria 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Haematuria 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Nocturia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Reproductive system and breast disorders
    Vaginal haemorrhage 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 1/8 (12.5%) 1 0/7 (0%) 0 2/6 (33.3%) 2 1/6 (16.7%) 1 10/33 (30.3%) 12 7/32 (21.9%) 8 5/32 (15.6%) 5 2/13 (15.4%) 3 3/5 (60%) 4 4/48 (8.3%) 4
    Dyspnoea 0/8 (0%) 0 2/7 (28.6%) 2 0/6 (0%) 0 0/6 (0%) 0 4/33 (12.1%) 7 8/32 (25%) 10 7/32 (21.9%) 8 0/13 (0%) 0 0/5 (0%) 0 4/48 (8.3%) 4
    Dyspnoea exertional 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 2 3/33 (9.1%) 3 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Epistaxis 0/8 (0%) 0 0/7 (0%) 0 2/6 (33.3%) 3 1/6 (16.7%) 1 5/33 (15.2%) 7 4/32 (12.5%) 4 4/32 (12.5%) 11 0/13 (0%) 0 1/5 (20%) 1 7/48 (14.6%) 16
    Oropharyngeal pain 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 4/32 (12.5%) 4 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 1/48 (2.1%) 1
    Pleural effusion 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Dysphonia 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hypoxia 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Nasal dryness 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Paranasal sinus discomfort 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Pneumothorax 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Rhinitis allergic 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Sleep apnoea syndrome 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Sneezing 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Upper-airway cough syndrome 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Skin and subcutaneous tissue disorders
    Ecchymosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Night sweats 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 4/32 (12.5%) 7 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 1/48 (2.1%) 1
    Pruritus 0/8 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 4/32 (12.5%) 6 3/32 (9.4%) 3 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Urticaria 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Erythema 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Hyperhidrosis 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hyperkeratosis 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0
    Lichen planus 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Petechiae 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Rash 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 1/5 (20%) 1 0/48 (0%) 0
    Rash erythematous 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Rash pruritic 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Skin induration 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Skin lesion 0/8 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Social circumstances
    Blood product transfusion dependent 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Vascular disorders
    Hypotension 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/33 (3%) 1 2/32 (6.3%) 2 1/32 (3.1%) 1 0/13 (0%) 0 0/5 (0%) 0 3/48 (6.3%) 3
    Haematoma 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 1/13 (7.7%) 1 0/5 (0%) 0 0/48 (0%) 0
    Hot flush 1/8 (12.5%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 0/5 (0%) 0 0/48 (0%) 0
    Hypertension 0/8 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/32 (0%) 0 0/13 (0%) 0 1/5 (20%) 1 0/48 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmann-La Roche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01981850
    Other Study ID Numbers:
    • BO42355
    • PRM-151G-101
    • 2015-001718-80
    First Posted:
    Nov 13, 2013
    Last Update Posted:
    Jan 5, 2022
    Last Verified:
    Dec 1, 2021