Myelofibrosis
Conditions
Keywords
Hematology, Myelofibrosis, Thrombocythemia Myelofibrosis, Bone Marrow Diseases, Hematologic Diseases, Blood Diseases, Leukemia, Blood Disorders
Brief summary
This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with primary myelofibrosis (PMF) and post polycythemia vera or post essential thrombocythemia myelofibrosis (ET/PV MF). The study is designed as a two-stage trial. In the stage 1, participants will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, participants on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.
Interventions
DRUGSimtuzumab
Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks
DRUGRuxolitinib
In Stage 2, participants will be on a stable dose of ruxolitinib
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be diagnosed with PMF or post ET/PV MF with intermediate-1, intermediate-2 or high risk disease according to the international working group (IWG) prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is ≥ 10 cm below left costal margin by physical exam. * Must have adequate organ function as demonstrated by the following: * Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5x upper limit of normal (ULN), or ≤ 4x 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 extramedullary hematopoiesis \[EMH\] related to MF); * Serum creatinine ≤ 2.5 mg/dL. * In Stage 2, participants must be on ruxolitinib for at least 8 weeks and on a stable dose for at least 4 weeks. * Eastern cooperative oncology group (ECOG) performance status (PS) ≤ 2 * Treatment-related toxicities from prior therapies must have resolved to Grade ≤ 1 * Women of childbearing potential and men must agree to using one medically approved (ie, mechanical or pharmacological) contraceptive measure and have their partners agree to an additional barrier method of contraception for the duration of the study and for 90 days after the last administration of study drug. Definition of female of child bearing potential and a list of acceptable contraceptive methods for this study applies per protocol.
Exclusion criteria
* Any serious medical condition or psychiatric illness that would prevent, (as judged by the treating physician) 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. * Pregnant or lactating. * Known history of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B. * History or presence of any form of cancer within the 3 years prior to enrollment, with the exception of excised basal cell or squamous cell carcinoma of the skin, or cervical carcinoma in situ or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis. * Participation in an investigational drug or device trial within 2 weeks prior to study Day 1 or within 5 times the half-life of the investigational agent in the other clinical study, if known. * Use of any cytotoxic chemotherapeutic agents (eg, hydroxyurea), corticosteroids (prednisone ≤ 10 mg/day or corticosteroid equivalent is allowed), or immune modulators (eg, thalidomide) within 2 weeks and interferon use within 4 weeks prior to study Day 1. * Symptomatic congestive heart failure (New York Heart Association Classification \> Class II), unstable angina, or unstable cardiac arrhythmia requiring medication. * History of surgery within 2 weeks prior to enrollment or anticipated surgery during the study period. * Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | Baseline; Week 24 | Overall response for the study drug is defined by the reduction in bone marrow fibrosis score which is on a scale of 0-3 where 0 indicates the scattered linear reticulin with no fiber intersections representing normal marrow and 3 indicates dense increase in reticulin fibrosis with fiber intersections, often with osteosclerosis. Reduction from baseline of score indicates improvement in clinical condition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Baseline; Weeks 12, 24 and any time post baseline (enrollment up to 94 weeks) | Overall response for the study drug was defined by the rate of clinical improvement in hemoglobin, platelet or ANC. Clinical improvement in hemoglobin was defined as a ≥ 2 g/dL increase from baseline in hemoglobin level and transfusion independent (absence of red blood cell (RBC) transfusions in prior 8 weeks and applicable only for participants with baseline hemoglobin level of \< 10 g/dL); clinical improvement in platelets was defined as a ≥ 100% increase from baseline in platelet count and an absolute platelet count of ≥ 50 x 10\^9/L (applicable only for participants with baseline platelet count \< 50 x 10\^9/L); clinical improvement in ANC is defined as a ≥ 100% increase from baseline in ANC and an ANC of ≥ 0.5 x 10\^9/L (applicable only for participants with baseline ANC \< 1 x 10\^9/L). |
| Percentage of Participants With Adverse Events (AEs) | First dose date up to the last dose date (maximum: 94 weeks) plus 28 days | — |
| Change From Baseline in Myelofibrosis Symptoms Assessment Score | Baseline; Days 43 and 85 of Cycles 1-7 (cycle=12 weeks) | Myelofibrosis symptom assessment was performed using myeloproliferative neoplasm symptoms assessment form (MPN-SAF) which is a 27-item questionnaire to address symptom burden and quality of life. The form consists of 27 questions which are scored on a scale of 0-10 by participants based on how symptoms are affecting them, where 0 indicates less symptoms while 10 indicated more severe symptoms and greater inactivity. The MPN-SAF score was calculated at each visit for each participant as an average of the scales for each question and all answered questions. If the number of questions not answered at 1 visit was \> 10, then the MPN-SAF score for that visit was taken as missing. A negative change from Baseline indicated improvement. |
| Change From Baseline in Cytokine Levels | Baseline; Week 24 | Biomarker samples were collected to evaluate the effects of SIM treatment on markers of serum and plasma cytokines. |
| Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline; Day 85 of Cycles 1 to 5 (cycle=12 weeks) | Blood samples were collected for the presence of anti-SIM antibodies which was determined using a validated electro-chemiluminescent (ECL) assay screening test. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 30 June 2011. The last study visit occurred on 24 September 2014.
Pre-assignment details
62 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: SIM 200 mg Participants were administered simtuzumab (SIM) 200 mg intravenous (IV) infusion over 30 minutes once every 2 weeks for a total of 6 infusions per 12-week cycle for up to 94 weeks. | 12 |
| Stage 1: SIM 700 mg Participants were administered SIM 700 mg IV infusion over 30 minutes once every 2 weeks for a total of 6 infusions per 12-week cycle for up to 40 weeks. | 12 |
| Stage 2: SIM 200 mg+Ruxolitinib Participants on a stable dose of ruxolitinib were administered SIM 200 mg IV infusion over 30 minutes once every 2 weeks for up to 91 weeks. | 15 |
| Stage 2: SIM 700 mg+Ruxolitinib Participants on a stable dose of ruxolitinib were administered SIM 700 mg IV infusion over 30 minutes once every 2 weeks for up to 86 weeks. | 15 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 0 | 0 | 0 | 1 |
| Overall Study | Investigator's Discretion | 1 | 0 | 1 | 3 |
| Overall Study | Lack of Efficacy | 9 | 9 | 1 | 3 |
| Overall Study | Unknown Reason | 1 | 0 | 11 | 6 |
| Overall Study | Withdrawal of Consent | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Stage 1: SIM 200 mg | Total | Stage 2: SIM 700 mg+Ruxolitinib | Stage 2: SIM 200 mg+Ruxolitinib | Stage 1: SIM 700 mg |
|---|---|---|---|---|---|
| Age, Customized Age ≤ 65 years | 3 Participants | 16 Participants | 6 Participants | 3 Participants | 4 Participants |
| Age, Customized Age > 65 years | 9 Participants | 38 Participants | 9 Participants | 12 Participants | 8 Participants |
| Bone Marrow Fibrosis Score MF-0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Bone Marrow Fibrosis Score MF-1 | 2 Participants | 7 Participants | 3 Participants | 1 Participants | 1 Participants |
| Bone Marrow Fibrosis Score MF-2 | 4 Participants | 17 Participants | 5 Participants | 6 Participants | 2 Participants |
| Bone Marrow Fibrosis Score MF-3 | 5 Participants | 28 Participants | 7 Participants | 8 Participants | 8 Participants |
| Bone Marrow Fibrosis Score Missing | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 52 Participants | 14 Participants | 15 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African Heritage | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 12 Participants | 50 Participants | 14 Participants | 13 Participants | 11 Participants |
| Sex: Female, Male Female | 6 Participants | 23 Participants | 4 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 31 Participants | 11 Participants | 6 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 1 / 12 | 1 / 15 | 0 / 15 |
| other Total, other adverse events | 12 / 12 | 12 / 12 | 15 / 15 | 15 / 15 |
| serious Total, serious adverse events | 8 / 12 | 1 / 12 | 5 / 15 | 4 / 15 |
Outcome results
Primary
Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score
Overall response for the study drug is defined by the reduction in bone marrow fibrosis score which is on a scale of 0-3 where 0 indicates the scattered linear reticulin with no fiber intersections representing normal marrow and 3 indicates dense increase in reticulin fibrosis with fiber intersections, often with osteosclerosis. Reduction from baseline of score indicates improvement in clinical condition.
Time frame: Baseline; Week 24
Population: The Per Protocol Analysis Set included participants who were randomized, received at least 1 dose of study drug, did not violate any major entry criteria, and had at least 80% adherence with study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: SIM 200 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | 0 percentage of participants |
| Stage 1: SIM 700 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | 16.7 percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | 6.7 percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | 13.3 percentage of participants |
Secondary
Change From Baseline in Cytokine Levels
Biomarker samples were collected to evaluate the effects of SIM treatment on markers of serum and plasma cytokines.
Time frame: Baseline; Week 24
Population: The cytokine analysis was not performed.
Secondary
Change From Baseline in Myelofibrosis Symptoms Assessment Score
Myelofibrosis symptom assessment was performed using myeloproliferative neoplasm symptoms assessment form (MPN-SAF) which is a 27-item questionnaire to address symptom burden and quality of life. The form consists of 27 questions which are scored on a scale of 0-10 by participants based on how symptoms are affecting them, where 0 indicates less symptoms while 10 indicated more severe symptoms and greater inactivity. The MPN-SAF score was calculated at each visit for each participant as an average of the scales for each question and all answered questions. If the number of questions not answered at 1 visit was \> 10, then the MPN-SAF score for that visit was taken as missing. A negative change from Baseline indicated improvement.
Time frame: Baseline; Days 43 and 85 of Cycles 1-7 (cycle=12 weeks)
Population: Participants in the Per Protocol Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 85 | 1.2 score on a scale | — |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Baseline | 2.5 score on a scale | Standard Deviation 1.75 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 6 - Day 43 | 1.4 score on a scale | — |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 85 | 1.0 score on a scale | — |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 43 | 1.1 score on a scale | Standard Deviation 2.81 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 43 | 1.8 score on a scale | — |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 43 | -0.3 score on a scale | Standard Deviation 0.99 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 85 | -0.3 score on a scale | Standard Deviation 1.59 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 85 | 0.1 score on a scale | Standard Deviation 1.1 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 85 | 0.3 score on a scale | Standard Deviation 0.89 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 43 | -0.2 score on a scale | Standard Deviation 0.58 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Best Change from Baseline | -0.9 score on a scale | Standard Deviation 1.11 |
| Stage 1: SIM 200 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 43 | 0 score on a scale | — |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 85 | -0.9 score on a scale | Standard Deviation 1.67 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 85 | -0.8 score on a scale | Standard Deviation 1.44 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 43 | -1.2 score on a scale | Standard Deviation 2.33 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 85 | 0.6 score on a scale | Standard Deviation 1.55 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Baseline | 3.7 score on a scale | Standard Deviation 1.86 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Best Change from Baseline | -1.3 score on a scale | Standard Deviation 1.6 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 43 | -1.0 score on a scale | Standard Deviation 1.66 |
| Stage 1: SIM 700 mg | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 43 | -1.0 score on a scale | Standard Deviation 1.26 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 85 | -0.8 score on a scale | Standard Deviation 1.46 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 6 - Day 43 | -0.4 score on a scale | Standard Deviation 0.65 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 6 - Day 85 | -1.5 score on a scale | Standard Deviation 0.84 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 7 - Day 43 | -1.4 score on a scale | — |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 7 - Day 85 | -1.3 score on a scale | — |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 43 | -0.4 score on a scale | Standard Deviation 1.35 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Baseline | 3.2 score on a scale | Standard Deviation 2.06 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Best Change from Baseline | -1.1 score on a scale | Standard Deviation 1.25 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 85 | -0.5 score on a scale | Standard Deviation 1.22 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 85 | -0.5 score on a scale | Standard Deviation 1.42 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 43 | -0.2 score on a scale | Standard Deviation 0.81 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 85 | 0.5 score on a scale | Standard Deviation 1.36 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 43 | -0.5 score on a scale | Standard Deviation 1.16 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 43 | -0.7 score on a scale | Standard Deviation 1.3 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 43 | -0.6 score on a scale | Standard Deviation 1.22 |
| Stage 2: SIM 200 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 85 | -1.2 score on a scale | Standard Deviation 1.24 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 43 | -0.6 score on a scale | Standard Deviation 1.29 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Best Change from Baseline | -0.6 score on a scale | Standard Deviation 0.98 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 6 - Day 43 | -0.5 score on a scale | Standard Deviation 0.32 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 85 | 0.4 score on a scale | Standard Deviation 0.74 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 6 - Day 85 | -0.9 score on a scale | — |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 4 - Day 85 | -0.2 score on a scale | Standard Deviation 0.68 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 7 - Day 43 | -1.4 score on a scale | — |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 85 | -0.9 score on a scale | Standard Deviation 0.91 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 1 - Day 43 | 0.2 score on a scale | Standard Deviation 1 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 43 | 0.4 score on a scale | Standard Deviation 1.43 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 43 | -0.3 score on a scale | Standard Deviation 0.58 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Baseline | 2.2 score on a scale | Standard Deviation 1.34 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 3 - Day 85 | -0.8 score on a scale | Standard Deviation 0.39 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 2 - Day 85 | 0.7 score on a scale | Standard Deviation 1.61 |
| Stage 2: SIM 700 mg+Ruxolitinib | Change From Baseline in Myelofibrosis Symptoms Assessment Score | Change from Baseline at Cycle 5 - Day 43 | -0.9 score on a scale | Standard Deviation 0.53 |
Secondary
Percentage of Participants With Adverse Events (AEs)
Time frame: First dose date up to the last dose date (maximum: 94 weeks) plus 28 days
Population: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: SIM 200 mg | Percentage of Participants With Adverse Events (AEs) | 100 percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Adverse Events (AEs) | 100 percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Adverse Events (AEs) | 100 percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Adverse Events (AEs) | 100 percentage of participants |
Secondary
Percentage of Participants With Anti-Simtuzumab Antibody Formation
Blood samples were collected for the presence of anti-SIM antibodies which was determined using a validated electro-chemiluminescent (ECL) assay screening test.
Time frame: Baseline; Day 85 of Cycles 1 to 5 (cycle=12 weeks)
Population: Participants in Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Positive | 25.0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Negative | 75.0 Percentage of participants |
| Stage 1: SIM 200 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Positive | 36.4 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Negative | 63.6 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Positive | 14.3 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Positive | 10.0 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Negative | 90.0 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 1: SIM 700 mg | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Negative | 85.7 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Negative | 57.1 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Negative | 73.3 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Positive | 26.7 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 5 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 5 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Positive | 42.9 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Negative | 69.2 Percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Positive | 30.8 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Positive | 9.1 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Positive | 7.7 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Negative | 100.0 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Positive | 25.0 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Negative | 78.6 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 2 - Day 85 : Screened Negative | 90.9 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 3 - Day 85 : Screened Negative | 75.0 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Baseline : Screened Positive | 21.4 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 4 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 1 - Day 85 : Screened Negative | 92.3 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 5 - Day 85 : Screened Positive | 0 Percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Percentage of Participants With Anti-Simtuzumab Antibody Formation | Cycle 5 - Day 85 : Screened Negative | 100.0 Percentage of participants |
Secondary
Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC)
Overall response for the study drug was defined by the rate of clinical improvement in hemoglobin, platelet or ANC. Clinical improvement in hemoglobin was defined as a ≥ 2 g/dL increase from baseline in hemoglobin level and transfusion independent (absence of red blood cell (RBC) transfusions in prior 8 weeks and applicable only for participants with baseline hemoglobin level of \< 10 g/dL); clinical improvement in platelets was defined as a ≥ 100% increase from baseline in platelet count and an absolute platelet count of ≥ 50 x 10\^9/L (applicable only for participants with baseline platelet count \< 50 x 10\^9/L); clinical improvement in ANC is defined as a ≥ 100% increase from baseline in ANC and an ANC of ≥ 0.5 x 10\^9/L (applicable only for participants with baseline ANC \< 1 x 10\^9/L).
Time frame: Baseline; Weeks 12, 24 and any time post baseline (enrollment up to 94 weeks)
Population: Participants in Per Protocol Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 1: SIM 200 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 12 | 0 percentage of participants |
| Stage 1: SIM 200 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Any Time Post-Baseline | 0 percentage of participants |
| Stage 1: SIM 200 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 24 | 0 percentage of participants |
| Stage 1: SIM 700 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 12 | 0 percentage of participants |
| Stage 1: SIM 700 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Any Time Post-Baseline | 0 percentage of participants |
| Stage 1: SIM 700 mg | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 24 | 0 percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 24 | 0 percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 12 | 0 percentage of participants |
| Stage 2: SIM 200 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Any Time Post-Baseline | 11.1 percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 12 | 0 percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Any Time Post-Baseline | 0 percentage of participants |
| Stage 2: SIM 700 mg+Ruxolitinib | Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Week 24 | 0 percentage of participants |