Polycythemia Vera, Post-Essential Thrombocythemia Myelofibrosis, Primary Myelofibrosis
Conditions
Keywords
fibrosis
Brief summary
RO7490677 is an investigational drug that is being developed for possible use in the treatment of myelofibrosis (MF), a disease in which the bone marrow, which is the organ in the body that makes blood cells, is replaced by fibrosis, or excess scar tissue. The purpose of this study is to gather information on whether RO7490677 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.
Detailed description
Stage 1 of this study has completed. Stage 1 was an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of two different dose schedules of RO7490677 in participants with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules receiving either single-agent RO7490677 or RO7490677 in combination with ruxolitinib. Participants were assigned to a weekly or every four week dosing schedule by the investigator. Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of RO7490677 in participants with PMF and post ET/PV MF. Participants will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of RO7490677. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. Modifications to dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1.
Interventions
BIOLOGICALRO7490677
IV infusion
DRUGRuxolitinib
IV infusion
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 1. Platelet count \< 50 x 10e9/L, OR 2. Hgb \< 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study entry, and be intolerant of or had inadequate response to ruxolitinib; 8. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F); 9. Life expectancy of at least twelve months; 10. At least four weeks must have elapsed between the last dose of any MF- directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment; 11. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia; 12. Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 years or 12 months if \>55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception are outlined in the protocol. 13. Ability to adhere to the study visit schedule and all protocol requirements; 14. Must have adequate organ function as demonstrated by the following: * ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis \[EMH\] related to MF); * Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF); * Serum creatinine ≤ 2.5 mg/dL x ULN.
Exclusion criteria
1. White blood cell count \> 25 x 10e9/L or \> 10% peripheral blood blasts; 2. Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer; 3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months; 4. Presence of active serious infection; 5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study; 6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection; 7. Organ transplant recipients other than bone marrow transplant; 8. Women who are pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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). |
| 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). |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 | — |
| 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 | — |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, France, Germany, Israel, Italy, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
A total of 125 participants were enrolled at sites in 8 different countries.
Pre-assignment details
One randomized participant in Stage 2 did not receive the study treatment, bringing the total number of treated participants to 124.
Participants by arm
| Arm | Count |
|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) 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. | 8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) 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. | 7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib 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. | 6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib 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. | 6 |
| Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W 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. | 33 |
| Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W 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. | 32 |
| Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W 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. | 32 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Main Phase Stage 1 | Death | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Phase Stage 1 | Informed Consent Withdrawn | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Phase Stage 1 | Lack of Efficacy | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Phase Stage 1 | Various reasons | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Phase Stage 2 | Adverse Event | 0 | 0 | 0 | 0 | 6 | 5 | 7 | 0 | 0 | 0 |
| Main Phase Stage 2 | Informed Consent Withdrawn | 0 | 0 | 0 | 0 | 4 | 3 | 3 | 0 | 0 | 0 |
| Main Phase Stage 2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Main Phase Stage 2 | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 6 | 6 | 0 | 0 | 0 |
| Main Phase Stage 2 | Various reasons | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 0 |
| Open Label Extension (OLE) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 8 |
| Open Label Extension (OLE) | Informed Consent Withdrawn | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 8 |
| Open Label Extension (OLE) | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 1 | 19 |
| Open Label Extension (OLE) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Open Label Extension (OLE) | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 2 | 9 |
| Open Label Extension (OLE) | Various reasons | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 3 |
Baseline characteristics
| Characteristic | Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 70.7 Years STANDARD_DEVIATION 6.3 | 70.6 Years STANDARD_DEVIATION 7.1 | 70.2 Years STANDARD_DEVIATION 6.5 | 69.4 Years STANDARD_DEVIATION 8.9 | 66.7 Years STANDARD_DEVIATION 8.7 | 64.3 Years STANDARD_DEVIATION 11.4 | 66.2 Years STANDARD_DEVIATION 8.6 | 66.0 Years STANDARD_DEVIATION 7.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | — | — | — | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | — | — | — | 25 Participants | 8 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | — | — | — | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 33 Participants | 29 Participants | 29 Participants | 23 Participants | 7 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 16 Participants | 8 Participants | 11 Participants | 15 Participants | 5 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 17 Participants | 24 Participants | 21 Participants | 12 Participants | 3 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 0 / 7 | 1 / 6 | 0 / 6 | 7 / 33 | 6 / 32 | 9 / 32 | 0 / 13 | 0 / 5 | 7 / 48 |
| other Total, other adverse events | 8 / 8 | 6 / 7 | 6 / 6 | 6 / 6 | 32 / 33 | 30 / 32 | 31 / 32 | 12 / 13 | 5 / 5 | 32 / 48 |
| serious Total, serious adverse events | 2 / 8 | 1 / 7 | 2 / 6 | 0 / 6 | 11 / 33 | 14 / 32 | 14 / 32 | 5 / 13 | 2 / 5 | 22 / 48 |
Outcome results
Primary
Stage 1 Main + Open-Label Extension (OLE): ORR
ORR was defined as the percent of participants with a response according to the IWG-MRT criteria. This was defined as those participants who achieved CI, PR, or CR at a post-baseline assessment of treatment response OR had at least SD for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease. Participants who achieved a clinical benefit in the main phase had the opportunity to remain on treatment. The determination of ORR in the main phase is outlined in the arms description below. Participants who didn't achieve a benefit had the opportunity to switch to a different dosing schedule in the OLE phase. The determination of ORR in the OLE phase is outlined in the arms descriptions below.
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.
Population: The all treated population (main phase + OLE) included all participants who received at least one dose of RO7490667.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main + Open-Label Extension (OLE): ORR | 50.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main + Open-Label Extension (OLE): ORR | 71.4 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main + Open-Label Extension (OLE): ORR | 50.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main + Open-Label Extension (OLE): ORR | 66.7 Percentage of Participants |
Primary
Stage 1 Main Phase: Overall Response Rate (ORR)
ORR was defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This was defined as those participants who achieved clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR had at least stable disease (SD) for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease.
Time frame: Up until and including completion of 6 cycles. Each cycle is 28 days.
Population: The all treated population included all participants who received at least one dose of RO7490667.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Overall Response Rate (ORR) | 37.5 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Overall Response Rate (ORR) | 14.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Overall Response Rate (ORR) | 33.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Overall Response Rate (ORR) | 50.0 Percentage of Participants |
Primary
Stage 2 Main + Open-Label Extension (OLE): BMRR
Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. Participants in the main phase had the opportunity to remain on treatment (as outlined in the arms description below). Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment and receive PRM-151 10 mg/kg/Q4W (as outlined in the arms description below).
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.
Population: The all treated population (main phase + OLE) included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main + Open-Label Extension (OLE): BMRR | 30.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main + Open-Label Extension (OLE): BMRR | 34.4 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main + Open-Label Extension (OLE): BMRR | 25.0 Percentage of Participants |
Primary
Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)
Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria from baseline to any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) | 30.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) | 31.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) | 25.0 Percentage of Participants |
Secondary
Stage 1 Main Phase: BMRR
Bone marrow response was defined as a reduction in bone marrow fibrosis score by at least one grade from baseline at anytime during the study.
Time frame: Baseline, Weeks 12 and 24
Population: The all treated population included all participants who received at least one dose of RO7490667.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: BMRR | 37.5 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: BMRR | 14.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: BMRR | 16.7 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: BMRR | 50.0 Percentage of Participants |
Secondary
Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes
The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. The values reported are the change from baseline scores.
Time frame: Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.
Population: The all treated population included all participants who received at least one dose of RO7490667.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Baseline | 23.1 Score on a scale | Standard Deviation 19.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D29 | -15.0 Score on a scale | Standard Deviation 13.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C3D1 | -9.1 Score on a scale | Standard Deviation 10.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D1 | -12.2 Score on a scale | Standard Deviation 9.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C4D1 | -8.7 Score on a scale | Standard Deviation 10.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C5D1 | -13.2 Score on a scale | Standard Deviation 13.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Cycle(C)2 Day(D)1 | -5.3 Score on a scale | Standard Deviation 12.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C3D1 | 1.9 Score on a scale | Standard Deviation 5.3 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D29 | -2.2 Score on a scale | Standard Deviation 5.3 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Cycle(C)2 Day(D)1 | 5.7 Score on a scale | Standard Deviation 11.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Baseline | 16.9 Score on a scale | Standard Deviation 7.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D1 | -0.8 Score on a scale | Standard Deviation 8.3 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C4D1 | 1.0 Score on a scale | Standard Deviation 8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C5D1 | 2.6 Score on a scale | Standard Deviation 6.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C5D1 | -6.7 Score on a scale | Standard Deviation 10.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C4D1 | -7.5 Score on a scale | Standard Deviation 6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Cycle(C)2 Day(D)1 | 0.5 Score on a scale | Standard Deviation 8.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D29 | -5.3 Score on a scale | Standard Deviation 4.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D1 | -5.4 Score on a scale | Standard Deviation 6.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Baseline | 26.8 Score on a scale | Standard Deviation 17.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C3D1 | -2.7 Score on a scale | Standard Deviation 14.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D29 | 2.3 Score on a scale | Standard Deviation 8.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Baseline | 15.3 Score on a scale | Standard Deviation 10.4 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | Cycle(C)2 Day(D)1 | -2.0 Score on a scale | Standard Deviation 5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C3D1 | 4.2 Score on a scale | Standard Deviation 8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C4D1 | 5.7 Score on a scale | Standard Deviation 20.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C6D1 | 4.3 Score on a scale | Standard Deviation 11.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes | C5D1 | 1.5 Score on a scale | Standard Deviation 13.6 |
Secondary
Stage 2 Main Phase: BMRR
Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria at any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: BMRR | 30.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: BMRR | 31.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: BMRR | 25.0 Percentage of Participants |
Secondary
Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit
Reduction in bone marrow fibrosis score: Reduction of at least one grade from baseline. Bone marrow fibrosis grades according to WHO criteria (as determined by central adjudication).
Time frame: Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C7D1 | 23.8 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | Cycle(C) 4 Day(D) 1 | 10.7 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C9D29/C10D1 | 30.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C7D1 | 11.8 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | Cycle(C) 4 Day(D) 1 | 24.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C9D29/C10D1 | 21.4 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | Cycle(C) 4 Day(D) 1 | 19.2 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C9D29/C10D1 | 13.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit | C7D1 | 10.5 Percentage of Participants |
Secondary
Stage 2 Main Phase: Duration of Bone Marrow Improvement
Duration of response was defined as time from first decrease from baseline \>= 1 grade to time of return to baseline levels.
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.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Duration of Bone Marrow Improvement | NA Weeks |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Duration of Bone Marrow Improvement | 12.0 Weeks |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Duration of Bone Marrow Improvement | 12.1 Weeks |
Secondary
Stage 2 Main Phase: Hemoglobin Improvement
Hemoglobin improvement was measured by the percent of participants with: Red cell transfusion independence (no transfusions for \>= 12 consecutive weeks) OR 50% reduction in red blood cell (RBC) transfusions for \>= 12 consecutive weeks OR percent of participants with \>= 10 g/L and \>= 20 g/L increase in hemoglobin for \>= 12 consecutive weeks without transfusions (outcome parameter assessed was dependent on baseline hemoglobin/transfusion status).
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Hemoglobin Improvement | 15.2 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Hemoglobin Improvement | 15.6 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Hemoglobin Improvement | 6.3 Percentage of Participants |
Secondary
Stage 2 Main Phase: Percentage of Participants With Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria
Best Overall Response: (CR, PR, CI), SD and PD according to the IWG-MRT Criteria.
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | PD | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | Not evaluable | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | CR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | CI | 8 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | PR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | 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 | SD | 20 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | CI | 6 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | PD | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | PR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | SD | 21 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | Not evaluable | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | 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 | CR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | Not evaluable | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | CR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | SD | 26 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | PR | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | CI | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | 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 | PD | 4 Participants |
Secondary
Stage 2 Main Phase: Platelet Improvement
Platelet improvement was measured by the percent of participants with: Platelet transfusion independence (no transfusions for \>= 12 consecutive weeks) OR 50% reduction in platelets transfusions for \>= 12 consecutive weeks OR doubling of baseline platelet count for \>= 12 consecutive weeks without platelet transfusions OR platelet count \> 50 x 10e9/L for \>=12 consecutive weeks without platelet transfusions OR doubling of baseline platelet count for \>= 12 consecutive weeks without platelet transfusions OR platelet count \> 25 x 10e9/L for \>= 12 consecutive weeks without platelet transfusions (outcome parameter assessed is dependent on baseline platelet status).
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Platelet Improvement | 27.3 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Platelet Improvement | 34.4 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Platelet Improvement | 37.5 Percentage of Participants |
Secondary
Stage 2 Main Phase: Symptom Improvement
Symptom improvement was assessed as the percent of participants with 50% reduction in MPN-SAF TSS from baseline over time. The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable.
Time frame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Population: The all treated population included all participants randomized and who received at least one administration of the drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C8D1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | Cycle(C) 2 Day(D) 1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C5D1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C4D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C3D1 | 6 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C6D1 | 8 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C9D29/C10D1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C9D1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 2 Main Phase: Symptom Improvement | C7D1 | 8 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C7D1 | 5 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C8D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C9D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C9D29/C10D1 | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C4D1 | 4 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C5D1 | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C6D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | C3D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 2 Main Phase: Symptom Improvement | Cycle(C) 2 Day(D) 1 | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C9D29/C10D1 | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C8D1 | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | Cycle(C) 2 Day(D) 1 | 1 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C3D1 | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C4D1 | 2 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C5D1 | 1 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C6D1 | 3 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C7D1 | 0 Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 2 Main Phase: Symptom Improvement | C9D1 | 1 Participants |
Other Pre-specified
Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs)
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
Population: The safety population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 85.7 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 16.7 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 3.0 Percentage of Participants |
| Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 3.1 Percentage of Participants |
| Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 6.3 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 7.7 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 92.3 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 100 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 20.0 Percentage of Participants |
| OLE Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | IRRs | 2.1 Percentage of Participants |
| OLE Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs) | AEs | 89.6 Percentage of Participants |
Other Pre-specified
Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation
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
Population: The safety population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 25.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 25.0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 Percentage of Participants |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 0 Percentage of Participants |
| Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 21.2 Percentage of Participants |
| Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 15.2 Percentage of Participants |
| Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 34.4 Percentage of Participants |
| Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 15.6 Percentage of Participants |
| Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 37.5 Percentage of Participants |
| Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 28.1 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 7.7 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 30.8 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 Percentage of Participants |
| OLE Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 0 Percentage of Participants |
| OLE Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 22.9 Percentage of Participants |
| OLE Stage 2: RO7490677 10 mg/kg IV Q4W | Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 27.1 Percentage of Participants |
Other Pre-specified
Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D1 | 2830 ug*hour/mL | Geometric Coefficient of Variation 12.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D15 | 3450 ug*hour/mL | Geometric Coefficient of Variation 2.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C2D1 | 2170 ug*hour/mL | Geometric Coefficient of Variation 170.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D1 | 2050 ug*hour/mL | Geometric Coefficient of Variation 29.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C2D1 | 4230 ug*hour/mL | Geometric Coefficient of Variation 34.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D15 | 6060 ug*hour/mL | Geometric Coefficient of Variation 23.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C6D1 | 819 ug*hour/mL | — |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D1 | 2970 ug*hour/mL | Geometric Coefficient of Variation 34.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) | C1D1 | 3130 ug*hour/mL | Geometric Coefficient of Variation 8.6 |
Other Pre-specified
Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C2D1 | 127.3 ug*hour/mL | Geometric Coefficient of Variation 904 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D15 | 1460 ug*hour/mL | Geometric Coefficient of Variation 142 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D1 | 1810 ug*hour/mL | Geometric Coefficient of Variation 72 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C6D1 | 698 ug*hour/mL | Geometric Coefficient of Variation 63 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C6D1 | 570 ug*hour/mL | Geometric Coefficient of Variation 44.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D1 | 1690 ug*hour/mL | Geometric Coefficient of Variation 26.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C2D1 | 504 ug*hour/mL | Geometric Coefficient of Variation 84.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D1 | 2590 ug*hour/mL | Geometric Coefficient of Variation 28.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D15 | 2590 ug*hour/mL | Geometric Coefficient of Variation 187.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C6D1 | 764 ug*hour/mL | Geometric Coefficient of Variation 28.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C2D1 | 2990 ug*hour/mL | Geometric Coefficient of Variation 92 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C2D1 | 663 ug*hour/mL | Geometric Coefficient of Variation 79.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C6D1 | 703 ug*hour/mL | Geometric Coefficient of Variation 33.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) | C1D1 | 1500 ug*hour/mL | Geometric Coefficient of Variation 158.3 |
Other Pre-specified
Stage 1 Main Phase: Clearance (CL)
Time frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Clearance (CL) | C1D1 | 0.258 Litres per hour (L/hr) | Geometric Coefficient of Variation 9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Clearance (CL) | C1D15 | 0.233 Litres per hour (L/hr) | Geometric Coefficient of Variation 24.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Clearance (CL) | C2D1 | 0.382 Litres per hour (L/hr) | Geometric Coefficient of Variation 229.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Clearance (CL) | C1D1 | 0.362 Litres per hour (L/hr) | Geometric Coefficient of Variation 31.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Clearance (CL) | C2D1 | 0.189 Litres per hour (L/hr) | Geometric Coefficient of Variation 55.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Clearance (CL) | C1D15 | 0.147 Litres per hour (L/hr) | Geometric Coefficient of Variation 35 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Clearance (CL) | C6D1 | 1.42 Litres per hour (L/hr) | — |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Clearance (CL) | C1D1 | 0.269 Litres per hour (L/hr) | Geometric Coefficient of Variation 32.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Clearance (CL) | C1D1 | 0.233 Litres per hour (L/hr) | Geometric Coefficient of Variation 33.3 |
Other Pre-specified
Stage 1 Main Phase: Maximum Drug Concentration (Cmax)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C6D1 | 142 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 70 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D1 | 133 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 48.4 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C2D1 | 107 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 26.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D15 | 127 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 31.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C2D1 | 110 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 20.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C6D1 | 111 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 28 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D1 | 113 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 28.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C6D1 | 136 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 34.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D1 | 164 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 23.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D15 | 126 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 27.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C2D1 | 149 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 29.1 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C2D1 | 130 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 80.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C1D1 | 112 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 90.4 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Maximum Drug Concentration (Cmax) | C6D1 | 142 Micrograms per Milliliter (ug/mL) | Geometric Coefficient of Variation 27.4 |
Other Pre-specified
Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D1 | 14.7 hr | Geometric Coefficient of Variation 19.2 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D15 | 31.2 hr | Geometric Coefficient of Variation 45 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C2D1 | 18.0 hr | Geometric Coefficient of Variation 220.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D1 | 17.2 hr | Geometric Coefficient of Variation 23.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C2D1 | 30.0 hr | Geometric Coefficient of Variation 48.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D15 | 40.4 hr | Geometric Coefficient of Variation 12.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C6D1 | 1.95 hr | — |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D1 | 16.8 hr | Geometric Coefficient of Variation 17.7 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) | C1D1 | 18.4 hr | Geometric Coefficient of Variation 7.9 |
Other Pre-specified
Stage 1 Main Phase: Time to Maximum Concentration (Tmax)
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D1 | 1.12 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D15 | 1.13 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C2D1 | 1.10 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C6D1 | 2.00 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C2D1 | 1.08 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C6D1 | 1.07 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D1 | 1.10 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C2D1 | 1.05 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D1 | 1.14 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C6D1 | 1.17 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D15 | 1.65 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C2D1 | 1.44 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C6D1 | 1.01 Hour (hr) |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Time to Maximum Concentration (Tmax) | C1D1 | 1.13 Hour (hr) |
Other Pre-specified
Stage 1 Main Phase: Volume of Distribution (Vd)
Time frame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Volume of Distribution (Vd) | C2D1 | 9.93 Litres (L) | Geometric Coefficient of Variation 63 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D15 | 10.5 Litres (L) | Geometric Coefficient of Variation 62.4 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW) | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D1 | 5.47 Litres (L) | Geometric Coefficient of Variation 10.9 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W) | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D1 | 9.00 Litres (L) | Geometric Coefficient of Variation 28.8 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Volume of Distribution (Vd) | C6D1 | 4.01 Litres (L) | — |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D1 | 6.52 Litres (L) | Geometric Coefficient of Variation 26.4 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D15 | 8.57 Litres (L) | Geometric Coefficient of Variation 47.6 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib | Stage 1 Main Phase: Volume of Distribution (Vd) | C2D1 | 8.18 Litres (L) | Geometric Coefficient of Variation 24.5 |
| Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib | Stage 1 Main Phase: Volume of Distribution (Vd) | C1D1 | 6.17 Litres (L) | Geometric Coefficient of Variation 38.9 |