MPN (Myeloproliferative Neoplasms)
Conditions
Keywords
Myelofibrosis, Janus kinase (JAK) inhibitor, itacitinib, ruxolitinib
Brief summary
The purpose of this study is to evaluate the efficacy and safety of itacitinib combined with low-dose ruxolitinib or itacitinib alone in participants with myelofibrosis (MF).
Interventions
DRUGItacitinib
Itacitinib self-administered orally once daily .
DRUGRuxolitinib
Ruxolitinib self-administered orally at the stable dose of \< 20 mg daily established before entering the study.
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort A only •Receiving ruxolitinib dose of less than 20 mg daily with no dose increase or no dose modification in the last 8 weeks before screening visit. Cohort B only •Must have had initial reduction in spleen on ruxolitinib treatment: * Followed by documented evidence of progression in spleen length or volume OR * Discontinued ruxolitinib for hematologic toxicities, after the initial reduction in spleen length or volume. All participants * Confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis according to revised World Health Organization 2016 criteria. * Must have palpable spleen of greater than or equal to (≥) 5 centimeter (cm) below the left subcostal margin on physical examination at the screening visit. * Eastern Cooperative Oncology Group performance status of 0, 1, or 2. * Screening bone marrow biopsy specimen available or willingness to undergo a bone marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at Week 24. * Life expectancy of at least 24 weeks. * Willingness to avoid pregnancy or fathering children
Exclusion criteria
* Lack of recovery from all toxicities from previous therapy (except ruxolitinib) to Grade 1 or better. * Previous treatment with itacitinib or Janus kinase (JAK1) inhibitors (JAK1/JAK2 inhibitor ruxolitinib is permitted). * Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications. * Recent history of inadequate bone marrow reserve as demonstrated by protocol-defined criteria. * Inadequate liver function at screening and baseline visits as demonstrated by protocol-defined criteria. * Inadequate renal function at screening and baseline visits as demonstrated by protocol-defined criteria. * Active bacterial, fungal, parasitic, or viral infection that requires therapy. * Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of reactivation: HBV deoxyribonucleic acid (DNA) and HCV ribonucleic acid (RNA) must be undetectable. Participants cannot be positive for hepatitis B surface antigen or anti-hepatitis B core antibodies. Participants who have positive anti-HBs as the only evidence of prior exposure may participate in the study provided that there is both 1) no known history of HBV infection and 2) verified receipt of hepatitis B vaccine. * Known human immunodeficiency virus infection. * Clinically significant or uncontrolled cardiac disease. * Active invasive malignancy over the previous 2 years except treated basal or squamous carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary thyroid and follicular thyroid cancers. Participants with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery may be enrolled as long as they have a reasonable expectation to have been cured with the treatment modality received. * Splenic irradiation within 6 months before receiving the first dose of itacitinib. * Use of any prohibited concomitant medications. * Active alcohol or drug addiction that would interfere with their ability to comply with the study requirements. * Use of any potent/strong cytochrome P450 3A4 inhibitors within 14 days or 5 half-lives (whichever is longer) before the first dose of itacitinib or anticipated during the study. * Use of concomitant treatment of fluconazole at a dose \> 200 mg (for ruxolitinib participants treated in Cohort A only). * Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy. * Currently breastfeeding or pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Spleen Volume at Week 24 Compared to Baseline | Baseline and Week 24 | Spleen volume was measured using magnetic resonance imaging (MRI) or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. |
| Percentage Change in Spleen Volume at Week 24 Compared to Baseline | Baseline and Week 24 | Spleen volume was measured using MRI or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | up to approximately 40 months (3.3 years) | Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported. |
| Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | Baseline through Week 12 | Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. |
| Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | Baseline through Week 12 | Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. |
| Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Baseline through Weeks 12 and 24 | Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. |
| Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Baseline through Weeks 12 and 24 | Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. |
| Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary | Baseline through Weeks 12 and 24 | Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. |
| Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary | Baseline through Weeks 12 and 24 | Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. |
| Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) | Baseline through Week 12 and Week 24 | Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms. |
| Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF | Baseline through Week 12 and Week 24 | Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms. Note that the mean percentage change can vary in direction from the mean absolute change because percent increases (but not decreases) can exceed 100%. |
| Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 168 | Symptoms of myelofibrosis were assessed using the PGIC questionnaire. Using the questionnaire, participants rated the overall sense of treatment effect on their symptoms on a scale of 1 (very much improved)- 7(very much worse). The specific wording was: Since the start of the treatment you have received in this study, your myelofibrosis symptoms are: 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse. A higher score indicates worse symptoms. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | up to approximately 40 months (3.3 years) | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether considered drug related, that occurs after a participant provides informed consent. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug. An SAE is an AE resulting in: death; initial/prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly. |
| Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | AUCtau defined as area under the concentration-time curve over a dosing interval for Itacitinib. The concentrations of itacitinib in plasma were determined using a validated Liquid Chromatography with tandem mass spectrometry (LC/MS/MS) method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Itacitinib PK data for Cohort A on Week 2 were not available as itacitinib was to be held until the completion of PK sample collection. |
| Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | AUCtau defined as area under the concentration-time curve over a dosing interval for ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). |
| Apparent Oral Dose Clearance (CL/F) of Itacitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. |
| Apparent Oral Dose Clearance (CL/F) of Ruxolitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). |
| Maximum Observed Plasma Concentration (Cmax) of Itacitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. |
| Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). |
| Time to Maximum Concentration (Tmax) of Itacitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. |
| Time to Maximum Concentration (Tmax) of Ruxolitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). |
| Concentration at the End of the Dosing Interval (Ctau) of Itacitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4 | Ctau is defined as concentration at the end of the dosing interval of ruxolitinib.The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. |
| Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib | 0 (pre-dose), 1, 2, 5 and 8 hours post-dose Week 2 and Week 4 | Ctau is defined as concentration at the end of the dosing interval of ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). |
| Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response | up to approximately 40 months (3.3 years) | Treatment response (complete remission \[CR\] or partial remission \[PR\]) graded per IWG-MRT. CR: Bone marrow (BM): \< 5% blasts; ≤ Grade 1 MF, Peripheral blood: Hemoglobin (Hb) ≥ 100 grams per liter (g/L), \< upper normal limit (UNL); neutrophil count ≥ 1 × 10\^9/L and \< UNL; Platelet count ≥ 100 × 10\^9/L and \< UNL; \< 2% immature myeloid cells (IMCs) and Clinical: Resolution of disease symptoms; spleen, liver not palpable; no evidence of extramedullary hematopoeisis (EMH). PR: Peripheral blood: Hb ≥ 100 g/L and \< UNL; neutrophil count ≥ 1 × 10\^9/L and \< UNL; platelet count ≥ 100 × 10\^9/L and \< UNL; \< 2% IMCs and Clinical: Resolution of symptoms; spleen and liver not palpable; no evidence of EMH or BM: \< 5% blasts; ≤ Grade 1 MF; and peripheral blood: Hb≥ 85 g/L but \< 100 g/L and \< UNL; neutrophil count ≥ 1 × 10\^9/L and \< UNL; platelet count ≥ 50 × 10\^9/L but \< 100 × 10\^9/L and \< UNL; \< 2% IMCs and Clinical: Resolution of symptoms; spleen, liver not palpable; no evidence of EMH. |
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | up to approximately 40 months (3.3 years) | Laboratory investigation included hematology, clinical chemistry, coagulation and urinalysis. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. |
Countries
Austria, Netherlands, United States
Participant flow
Recruitment details
The study was conducted at 9 study centers in the United States, 1 study center in Austria, and 1 study center in the Netherlands.
Pre-assignment details
A total of 23 participants with Myelofibrosis (MF) were enrolled in the study and received itacitinib + ruxolitinib (Cohort A) or itacitinib monotherapy (Cohort B).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been \< 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met. | 13 |
| Cohort B Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met. | 10 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not Reported | 2 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Cohort B | Total | Cohort A |
|---|---|---|---|
| Age, Continuous | 72.0 years STANDARD_DEVIATION 7.33 | 70.8 years STANDARD_DEVIATION 6.65 | 69.8 years STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 21 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White/Caucasian | 8 Participants | 21 Participants | 13 Participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 2 / 10 | 2 / 23 |
| other Total, other adverse events | 13 / 13 | 10 / 10 | 23 / 23 |
| serious Total, serious adverse events | 3 / 13 | 5 / 10 | 8 / 23 |
Outcome results
Primary
Change in Spleen Volume at Week 24 Compared to Baseline
Spleen volume was measured using magnetic resonance imaging (MRI) or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Time frame: Baseline and Week 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, Overall Number of participants analyzed (N) signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change in Spleen Volume at Week 24 Compared to Baseline | 88.7 cubic centimeter (cm^3) | Standard Deviation 563.5 |
| Cohort B | Change in Spleen Volume at Week 24 Compared to Baseline | -207 cubic centimeter (cm^3) | Standard Deviation 571.3 |
Primary
Percentage Change in Spleen Volume at Week 24 Compared to Baseline
Spleen volume was measured using MRI or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Time frame: Baseline and Week 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Percentage Change in Spleen Volume at Week 24 Compared to Baseline | 6.9 percentage change | Standard Deviation 27.49 |
| Cohort B | Percentage Change in Spleen Volume at Week 24 Compared to Baseline | -3.0 percentage change | Standard Deviation 34.67 |
Secondary
Apparent Oral Dose Clearance (CL/F) of Itacitinib
Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection.
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of itacitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Apparent Oral Dose Clearance (CL/F) of Itacitinib | Week 4 | 203 liters per hour (L/h) | Standard Deviation 97.4 |
| Cohort B | Apparent Oral Dose Clearance (CL/F) of Itacitinib | Week 4 | 42.4 liters per hour (L/h) | Standard Deviation 15.8 |
| Cohort B | Apparent Oral Dose Clearance (CL/F) of Itacitinib | Week 2 | 48.5 liters per hour (L/h) | Standard Deviation 14.9 |
Secondary
Apparent Oral Dose Clearance (CL/F) of Ruxolitinib
Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ).
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of ruxolitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure. Only the data from 15mg QD is shown as it is the only dose level with at least three participants at both week 2 and week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Apparent Oral Dose Clearance (CL/F) of Ruxolitinib | Week 2 | 17.0 L/h | Standard Deviation 3.12 |
| Cohort A | Apparent Oral Dose Clearance (CL/F) of Ruxolitinib | Week 4 | 22.2 L/h | Standard Deviation 6.82 |
Secondary
Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib
AUCtau defined as area under the concentration-time curve over a dosing interval for Itacitinib. The concentrations of itacitinib in plasma were determined using a validated Liquid Chromatography with tandem mass spectrometry (LC/MS/MS) method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Itacitinib PK data for Cohort A on Week 2 were not available as itacitinib was to be held until the completion of PK sample collection.
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of itacitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib | Week 4 | 2540 nanomolar* hour (nM*h) | Standard Deviation 2020 |
| Cohort B | Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib | Week 2 | 24100 nanomolar* hour (nM*h) | Standard Deviation 6600 |
| Cohort B | Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib | Week 4 | 28900 nanomolar* hour (nM*h) | Standard Deviation 11200 |
Secondary
Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib
AUCtau defined as area under the concentration-time curve over a dosing interval for ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ).
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of ruxolitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure. Only the data from 15mg QD is shown as it is the only dose level with at least three participants at both week 2 and week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib | Week 2 | 2930 nM*h | Standard Deviation 486 |
| Cohort A | Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib | Week 4 | 2350 nM*h | Standard Deviation 635 |
Secondary
Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary
Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms.
Time frame: Baseline through Weeks 12 and 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary | Change at Week 12 | 1.4 score on scale | Standard Deviation 6.06 |
| Cohort A | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary | Change at Week 24 | -1.0 score on scale | Standard Deviation 9.88 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary | Change at Week 12 | -4.7 score on scale | Standard Deviation 12.5 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary | Change at Week 24 | -0.3 score on scale | Standard Deviation 10.14 |
Secondary
Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF)
Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms.
Time frame: Baseline through Week 12 and Week 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. . Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) | Change at Week 12 | 2.0 score on scale | Standard Deviation 9.76 |
| Cohort A | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) | Change at Week 24 | -1.6 score on scale | Standard Deviation 11.11 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) | Change at Week 12 | -3.7 score on scale | Standard Deviation 12.91 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) | Change at Week 24 | -6.0 score on scale | Standard Deviation 8.76 |
Secondary
Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Time frame: Baseline through Weeks 12 and 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 12 | -0.2 cm | Standard Deviation 2.17 |
| Cohort A | Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 24 | -0.4 cm | Standard Deviation 5.41 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 12 | -3.6 cm | Standard Deviation 6.73 |
| Cohort B | Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 24 | -2.6 cm | Standard Deviation 3.44 |
Secondary
Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred.
Time frame: Baseline through Week 12
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -29.2 cm^3 | Standard Deviation 349.3 |
| Cohort B | Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -608 cm^3 | Standard Deviation 669.6 |
Secondary
Concentration at the End of the Dosing Interval (Ctau) of Itacitinib
Ctau is defined as concentration at the end of the dosing interval of ruxolitinib.The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection.
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of itacitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Concentration at the End of the Dosing Interval (Ctau) of Itacitinib | Week 4 | 10.2 nM | Standard Deviation 8.67 |
| Cohort B | Concentration at the End of the Dosing Interval (Ctau) of Itacitinib | Week 2 | 102 nM | Standard Deviation 120 |
| Cohort B | Concentration at the End of the Dosing Interval (Ctau) of Itacitinib | Week 4 | 108 nM | Standard Deviation 85.4 |
Secondary
Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib
Ctau is defined as concentration at the end of the dosing interval of ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ).
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of ruxolitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure. Only the data from 15mg QD is shown as it is the only dose level with at least three participants at both week 2 and week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib | Week 2 | 16.6 nM | Standard Deviation 14.5 |
| Cohort A | Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib | Week 4 | 19.7 nM | Standard Deviation 28.6 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Itacitinib
The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection.
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of itacitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Maximum Observed Plasma Concentration (Cmax) of Itacitinib | Week 4 | 559 nanometer (nM) | Standard Deviation 518 |
| Cohort B | Maximum Observed Plasma Concentration (Cmax) of Itacitinib | Week 4 | 4460 nanometer (nM) | Standard Deviation 2470 |
| Cohort B | Maximum Observed Plasma Concentration (Cmax) of Itacitinib | Week 2 | 3570 nanometer (nM) | Standard Deviation 1280 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ).
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of ruxolitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure. Only the data from 15mg QD is shown as it is the only dose level with at least three participants at both week 2 and week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib | Week 2 | 695 nM | Standard Deviation 111 |
| Cohort A | Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib | Week 4 | 677 nM | Standard Deviation 118 |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
Laboratory investigation included hematology, clinical chemistry, coagulation and urinalysis. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.
Time frame: up to approximately 40 months (3.3 years)
Population: Safety Population included all enrolled participants who received at least 1 dose of itacitinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Neutrophils | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Hemoglobin: Low Direction | 4 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Leukocytes: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Leukocytes: Low Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Lymphocytes: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Lymphocytes: Low Direction | 3 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Hemoglobin: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Platelets | 3 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Alanine Aminotransferase | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Albumin | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Alkaline Phosphatase | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Aspartate Aminotransferase | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Bilirubin | 1 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Calcium: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Calcium: Low Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Cholesterol | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Creatinine | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Glucose: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Glucose: Low Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Phosphate | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Potassium: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Potassium: Low Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Sodium: High Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Sodium: Low Direction | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Triglycerides | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Urate | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Phosphate | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Hemoglobin: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Calcium: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Hemoglobin: Low Direction | 4 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Triglycerides | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Leukocytes: High Direction | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Calcium: Low Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Leukocytes: Low Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Potassium: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Lymphocytes: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Cholesterol | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Lymphocytes: Low Direction | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Sodium: Low Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Neutrophils | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Creatinine | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Platelets | 4 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Potassium: Low Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Alanine Aminotransferase | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Glucose: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Albumin | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Urate | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Alkaline Phosphatase | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Glucose: Low Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Aspartate Aminotransferase | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Sodium: High Direction | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Bilirubin | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.
Time frame: up to approximately 40 months (3.3 years)
Population: Safety Population included all enrolled participants who received at least 1 dose of itacitinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 36 | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Diastolic blood pressure, Week 12 | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 24 | 0 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Pulse, Week 84 | 1 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, End of Treatment | 1 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Pulse, Follow-up | 1 Participants |
| Cohort A | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 12 | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Pulse, Follow-up | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 12 | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 24 | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, Week 36 | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Systolic blood pressure, End of Treatment | 0 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Diastolic blood pressure, Week 12 | 1 Participants |
| Cohort B | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Pulse, Week 84 | 0 Participants |
Secondary
Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response
Treatment response (complete remission \[CR\] or partial remission \[PR\]) graded per IWG-MRT. CR: Bone marrow (BM): \< 5% blasts; ≤ Grade 1 MF, Peripheral blood: Hemoglobin (Hb) ≥ 100 grams per liter (g/L), \< upper normal limit (UNL); neutrophil count ≥ 1 × 10\^9/L and \< UNL; Platelet count ≥ 100 × 10\^9/L and \< UNL; \< 2% immature myeloid cells (IMCs) and Clinical: Resolution of disease symptoms; spleen, liver not palpable; no evidence of extramedullary hematopoeisis (EMH). PR: Peripheral blood: Hb ≥ 100 g/L and \< UNL; neutrophil count ≥ 1 × 10\^9/L and \< UNL; platelet count ≥ 100 × 10\^9/L and \< UNL; \< 2% IMCs and Clinical: Resolution of symptoms; spleen and liver not palpable; no evidence of EMH or BM: \< 5% blasts; ≤ Grade 1 MF; and peripheral blood: Hb≥ 85 g/L but \< 100 g/L and \< UNL; neutrophil count ≥ 1 × 10\^9/L and \< UNL; platelet count ≥ 50 × 10\^9/L but \< 100 × 10\^9/L and \< UNL; \< 2% IMCs and Clinical: Resolution of symptoms; spleen, liver not palpable; no evidence of EMH.
Time frame: up to approximately 40 months (3.3 years)
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response | 0 Participants |
| Cohort B | Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether considered drug related, that occurs after a participant provides informed consent. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug. An SAE is an AE resulting in: death; initial/prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly.
Time frame: up to approximately 40 months (3.3 years)
Population: Safety Population included all enrolled participants who received at least 1 dose of itacitinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 13 Participants |
| Cohort A | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 3 Participants |
| Cohort B | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 10 Participants |
| Cohort B | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 5 Participants |
Secondary
Patient Global Impression of Change (PGIC) Score at Each Visit
Symptoms of myelofibrosis were assessed using the PGIC questionnaire. Using the questionnaire, participants rated the overall sense of treatment effect on their symptoms on a scale of 1 (very much improved)- 7(very much worse). The specific wording was: Since the start of the treatment you have received in this study, your myelofibrosis symptoms are: 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse. A higher score indicates worse symptoms.
Time frame: Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 168
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 48 | 2.5 score on scale | Standard Deviation 1 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 84 | 2.0 score on scale | — |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Week 4 | 3.6 score on scale | Standard Deviation 0.81 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 24 | 3.2 score on scale | Standard Deviation 1.09 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 60 | 3.0 score on scale | Standard Deviation 1.73 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 12 | 3.2 score on scale | Standard Deviation 0.98 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 36 | 3.2 score on scale | Standard Deviation 0.98 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 16 | 3.0 score on scale | Standard Deviation 1 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 72 | 3.3 score on scale | Standard Deviation 1.5 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 20 | 3.3 score on scale | Standard Deviation 0.71 |
| Cohort A | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 8 | 3.3 score on scale | Standard Deviation 0.9 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Week 168 | 3.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Week 4 | 3.5 score on scale | Standard Deviation 0.93 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 8 | 3.3 score on scale | Standard Deviation 1.22 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 12 | 3.6 score on scale | Standard Deviation 0.98 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 16 | 4.2 score on scale | Standard Deviation 1.47 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 36 | 3.0 score on scale | Standard Deviation 1 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 20 | 3.2 score on scale | Standard Deviation 0.75 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 24 | 2.8 score on scale | Standard Deviation 0.96 |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 48 | 2.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 60 | 3.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 72 | 3.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 84 | 3.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 96 | 2.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Weeks 108 | 4.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Week 120 | 3.0 score on scale | — |
| Cohort B | Patient Global Impression of Change (PGIC) Score at Each Visit | Week 132 | 3.0 score on scale | — |
Secondary
Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary
Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms.
Time frame: Baseline through Weeks 12 and 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary | Percentage Change at Week 24 | -5.6 percentage change | Standard Deviation 95.56 |
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary | Percentage Change at Week 12 | 0.7 percentage change | Standard Deviation 69.57 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary | Percentage Change at Week 24 | 33.7 percentage change | Standard Deviation 142.3 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary | Percentage Change at Week 12 | -1.8 percentage change | Standard Deviation 116.6 |
Secondary
Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF
Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms. Note that the mean percentage change can vary in direction from the mean absolute change because percent increases (but not decreases) can exceed 100%.
Time frame: Baseline through Week 12 and Week 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF | Percentage Change at Week 12 | 3.8 percentage change | Standard Deviation 47.25 |
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF | Percentage Change at Week 24 | 5.8 percentage change | Standard Deviation 46.85 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF | Percentage Change at Week 12 | -6.1 percentage change | Standard Deviation 51.24 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF | Percentage Change at Week 24 | -22.7 percentage change | Standard Deviation 29.62 |
Secondary
Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Time frame: Baseline through Weeks 12 and 24
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies number of participants analyzed for this outcome measure and n signifies number of participants with data available at a particular time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 12 | 8.8 percentage change | Standard Deviation 40.83 |
| Cohort A | Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 24 | 2.5 percentage change | Standard Deviation 50.72 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 12 | -14.4 percentage change | Standard Deviation 49.89 |
| Cohort B | Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation | Week 24 | -21.3 percentage change | Standard Deviation 27.94 |
Secondary
Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred.
Time frame: Baseline through Week 12
Population: Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib. Here, N signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -1.6 percentage change | Standard Deviation 14.69 |
| Cohort B | Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -24.6 percentage change | Standard Deviation 21.72 |
Secondary
Time to Maximum Concentration (Tmax) of Itacitinib
The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection.
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of itacitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Time to Maximum Concentration (Tmax) of Itacitinib | Week 4 | 2.0 hour (hr) |
| Cohort B | Time to Maximum Concentration (Tmax) of Itacitinib | Week 2 | 2.0 hour (hr) |
| Cohort B | Time to Maximum Concentration (Tmax) of Itacitinib | Week 4 | 2.0 hour (hr) |
Secondary
Time to Maximum Concentration (Tmax) of Ruxolitinib
The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ).
Time frame: 0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
Population: Pharmacokinetic evaluable population included all participants who received at least 1 dose of ruxolitinib and provided at least 1 post-dose plasma sample for PK. Here, N signifies number of participants analyzed for this outcome measure. Only the data from 15mg QD is shown as it is the only dose level with at least three participants at both week 2 and week 4.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Time to Maximum Concentration (Tmax) of Ruxolitinib | Week 2 | 1.0 hr |
| Cohort A | Time to Maximum Concentration (Tmax) of Ruxolitinib | Week 4 | 1.0 hr |