A Phase 2 interventional study of Itacitinib and Ruxolitinib in MPN (Myeloproliferative Neoplasms), sponsored by Incyte Corporation. Completed at 26 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-06-16.
Sponsored by Incyte Corporation · Phase 2, Interventional, and Treatment
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).
419 studies on the registry are indexed under Primary Myelofibrosis; 117 are open to participants now.
This study's enrollment of 23 is below the median of 44 across 347 interventional studies indexed under Primary Myelofibrosis.
Browse Primary Myelofibrosis studies →Incyte Corporation is the lead sponsor of 286 studies on the registry; 37 are open to participants now.
Of its 144 completed or terminated interventional studies of FDA-regulated products, 93 (65%) have results posted.
Counted across the registry records on this site, refreshed daily.
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:
All participants
Exclusion Criteria:
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 the 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 are met.
Drug: Itacitinib · Drug: Ruxolitinib
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 are met.
Drug: Itacitinib
Itacitinib self-administered orally once daily .
Also known as: INCB039110
Ruxolitinib self-administered orally at the stable dose of \< 20 mg daily established before entering the study.
Also known as: INCB018424, Jakafi, Jakavi
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
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
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)
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)
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)
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
The study was conducted at 9 study centers in the United States, 1 study center in Austria, and 1 study center in the Netherlands.
| Milestone | Cohort A | Cohort B |
|---|---|---|
| Started | 13 | 10 |
| Completed | 10 | 3 |
| Not completed | 3 | 7 |
| Withdrew: Death | 0 | 2 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Physician decision | 0 | 1 |
| Withdrew: Withdrawal by subject | 1 | 3 |
| Withdrew: Not reported | 2 | 0 |
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.
| cubic centimeter (cm^3) | Cohort A | Cohort B |
|---|---|---|
| Change in Spleen Volume at Week 24 Compared to Baseline | 88.7 ± 563.5 | -207 ± 571.3 |
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.
| percentage change | Cohort A | Cohort B |
|---|---|---|
| Percentage Change in Spleen Volume at Week 24 Compared to Baseline | 6.9 ± 27.49 | -3.0 ± 34.67 |
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.
| Participants | Cohort A | Cohort B |
|---|---|---|
| TEAE | 13 | 10 |
| SAE | 3 | 5 |
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.
| Participants | Cohort A | Cohort B |
|---|---|---|
| Hemoglobin: High Direction | 0 | 0 |
| Hemoglobin: Low Direction | 4 | 4 |
| Leukocytes: High Direction | 0 | 1 |
| Leukocytes: Low Direction | 0 | 0 |
| Lymphocytes: High Direction | 0 | 0 |
| Lymphocytes: Low Direction | 3 | 1 |
| Neutrophils | 0 | 1 |
| Platelets | 3 | 4 |
| Alanine Aminotransferase | 0 | 0 |
| Albumin | 0 | 0 |
| Alkaline Phosphatase | 0 | 0 |
| Aspartate Aminotransferase | 0 | 0 |
| Bilirubin | 1 | 0 |
| Calcium: High Direction | 0 | 0 |
| Calcium: Low Direction | 0 | 0 |
| Cholesterol | 0 | 0 |
| Creatinine | 0 | 0 |
| Glucose: High Direction | 0 | 0 |
| Glucose: Low Direction | 0 | 0 |
| Phosphate | 0 | 1 |
| Potassium: High Direction | 0 | 0 |
| Potassium: Low Direction | 0 | 0 |
| Sodium: High Direction | 0 | 0 |
| Sodium: Low Direction | 0 | 0 |
| Triglycerides | 0 | 1 |
| Urate | 1 | 1 |
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.
| Participants | Cohort A | Cohort B |
|---|---|---|
| Systolic blood pressure, Week 12 | 1 | 1 |
| Systolic blood pressure, Week 24 | 0 | 1 |
| Systolic blood pressure, Week 36 | 0 | 1 |
| Systolic blood pressure, End of Treatment | 1 | 0 |
| Diastolic blood pressure, Week 12 | 0 | 1 |
| Pulse, Week 84 | 1 | 0 |
| Pulse, Follow-up | 1 | 0 |
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.
| cm^3 | Cohort A | Cohort B |
|---|---|---|
| Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -29.2 ± 349.3 | -608 ± 669.6 |
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 | Cohort A | Cohort B |
|---|---|---|
| Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants) | -1.6 ± 14.69 | -24.6 ± 21.72 |
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.
| cm | Cohort A | Cohort B |
|---|---|---|
| Week 12 | -0.2 ± 2.17 | -3.6 ± 6.73 |
| Week 24 | -0.4 ± 5.41 | -2.6 ± 3.44 |
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 | Cohort A | Cohort B |
|---|---|---|
| Week 12 | 8.8 ± 40.83 | -14.4 ± 49.89 |
| Week 24 | 2.5 ± 50.72 | -21.3 ± 27.94 |
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.
| score on scale | Cohort A | Cohort B |
|---|---|---|
| Change at Week 12 | 1.4 ± 6.06 | -4.7 ± 12.50 |
| Change at Week 24 | -1.0 ± 9.88 | -0.3 ± 10.14 |
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 | Cohort A | Cohort B |
|---|---|---|
| Percentage Change at Week 12 | 0.7 ± 69.57 | -1.8 ± 116.6 |
| Percentage Change at Week 24 | -5.6 ± 95.56 | 33.7 ± 142.3 |
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.
| score on scale | Cohort A | Cohort B |
|---|---|---|
| Change at Week 12 | 2.0 ± 9.76 | -3.7 ± 12.91 |
| Change at Week 24 | -1.6 ± 11.11 | -6.0 ± 8.76 |
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%.
| percentage change | Cohort A | Cohort B |
|---|---|---|
| Percentage Change at Week 12 | 3.8 ± 47.25 | -6.1 ± 51.24 |
| Percentage Change at Week 24 | 5.8 ± 46.85 | -22.7 ± 29.62 |
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.
| score on scale | Cohort A | Cohort B |
|---|---|---|
| Week 4 | 3.6 ± 0.81 | 3.5 ± 0.93 |
| Weeks 8 | 3.3 ± 0.90 | 3.3 ± 1.22 |
| Weeks 12 | 3.2 ± 0.98 | 3.6 ± 0.98 |
| Weeks 16 | 3.0 ± 1.00 | 4.2 ± 1.47 |
| Weeks 20 | 3.3 ± 0.71 | 3.2 ± 0.75 |
| Weeks 24 | 3.2 ± 1.09 | 2.8 ± 0.96 |
| Weeks 36 | 3.2 ± 0.98 | 3.0 ± 1.00 |
| Weeks 48 | 2.5 ± 1.00 | 2.0 ± NA |
| Weeks 60 | 3.0 ± 1.73 | 3.0 ± NA |
| Weeks 72 | 3.3 ± 1.50 | 3.0 ± NA |
| Weeks 84 | 2.0 ± NA | 3.0 ± NA |
| Weeks 96 | — | 2.0 ± NA |
| Weeks 108 | — | 4.0 ± NA |
| Week 120 | — | 3.0 ± NA |
| Week 132 | — | 3.0 ± NA |
| Week 168 | — | 3.0 ± NA |
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.
| Participants | Cohort A | 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 | 0 |
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.
| nanomolar* hour (nM*h) | PK: Cohort A (Itacitinib) | PK: Cohort B (Itacitinib) |
|---|---|---|
| Week 2 | — | 24100 ± 6600 |
| Week 4 | 2540 ± 2020 | 28900 ± 11200 |
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).
| nM*h | PK: Cohort A (Ruxolitinib) |
|---|---|
| Week 2 | 2930 ± 486 |
| Week 4 | 2350 ± 635 |
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.
| liters per hour (L/h) | PK: Cohort A (Itacitinib) | PK: Cohort B (Itacitinib) |
|---|---|---|
| Week 2 | — | 48.5 ± 14.9 |
| Week 4 | 203 ± 97.4 | 42.4 ± 15.8 |
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).
| L/h | PK: Cohort A (Ruxolitinib) |
|---|---|
| Week 2 | 17.0 ± 3.12 |
| Week 4 | 22.2 ± 6.82 |
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.
| nanometer (nM) | PK: Cohort A (Itacitinib) | PK: Cohort B (Itacitinib) |
|---|---|---|
| Week 2 | — | 3570 ± 1280 |
| Week 4 | 559 ± 518 | 4460 ± 2470 |
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).
| nM | PK: Cohort A (Ruxolitinib) |
|---|---|
| Week 2 | 695 ± 111 |
| Week 4 | 677 ± 118 |
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.
| hour (hr) | PK: Cohort A (Itacitinib) | PK: Cohort B (Itacitinib) |
|---|---|---|
| Week 2 | — | 2.0 (1.0 to 5.0) |
| Week 4 | 2.0 (1.0 to 2.3) | 2.0 (2.0 to 4.6) |
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).
| hr | PK: Cohort A (Ruxolitinib) |
|---|---|
| Week 2 | 1.0 (1.0 to 1.1) |
| Week 4 | 1.0 (1.0 to 1.1) |
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.
| nM | PK: Cohort A (Itacitinib) | PK: Cohort B (Itacitinib) |
|---|---|---|
| Week 2 | — | 102 ± 120 |
| Week 4 | 10.2 ± 8.67 | 108 ± 85.4 |
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).
| nM | PK: Cohort A (Ruxolitinib) |
|---|---|
| Week 2 | 16.6 ± 14.5 |
| Week 4 | 19.7 ± 28.6 |
Collected over up to approximately 40 months (3.3 years). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort A | 0/13 (0%) | 3/13 (23.1%) | 13/13 (100%) |
| Cohort B | 2/10 (20%) | 5/10 (50%) | 10/10 (100%) |
| Total | 2/23 (8.7%) | 8/23 (34.8%) | 23/23 (100%) |
| Event | Cohort A | Cohort B | Total |
|---|---|---|---|
| Atrial fibrillationCardiac disorders | 0/13 | 1/10 | 1/23 |
| BronchitisInfections and infestations | 0/13 | 1/10 | 1/23 |
| CellulitisInfections and infestations | 0/13 | 1/10 | 1/23 |
| Clostridium difficile infectionInfections and infestations | 0/13 | 1/10 | 1/23 |
| CoughRespiratory, thoracic and mediastinal disorders | 0/13 | 1/10 | 1/23 |
| Disseminated intravascular coagulationBlood and lymphatic system disorders | 0/13 | 1/10 | 1/23 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 0/13 | 1/10 | 1/23 |
| Haematoma muscleMusculoskeletal and connective tissue disorders | 0/13 | 1/10 | 1/23 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 0/13 | 1/10 | 1/23 |
| NephrolithiasisRenal and urinary disorders | 0/13 | 1/10 | 1/23 |
| Event | Cohort A | Cohort B | Total |
|---|---|---|---|
| FatigueGeneral disorders | 3/13 | 5/10 | 8/23 |
| AnaemiaBlood and lymphatic system disorders | 4/13 | 4/10 | 8/23 |
| DiarrhoeaGastrointestinal disorders | 4/13 | 4/10 | 8/23 |
| PyrexiaGeneral disorders | 1/13 | 4/10 | 5/23 |
| Abdominal painGastrointestinal disorders | 4/13 | 3/10 | 7/23 |
| DizzinessNervous system disorders | 4/13 | 2/10 | 6/23 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 2/13 | 3/10 | 5/23 |
| FallInjury, poisoning and procedural complications | 1/13 | 3/10 | 4/23 |
| NauseaGastrointestinal disorders | 2/13 | 3/10 | 5/23 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 3/13 | 0/10 | 3/23 |
Full Analysis Set included all enrolled participants who received at least 1 dose of itacitinib.
| Age, Continuous(years) | Cohort A | Cohort B | Total |
|---|---|---|---|
| Mean | 69.8 ± 6.20 | 72.0 ± 7.33 | 70.8 ± 6.65 |
| Sex: Female, Male(Participants) | Cohort A | Cohort B | Total |
|---|---|---|---|
| Female | 6 | 7 | 13 |
| Male | 7 | 3 | 10 |
| Ethnicity (NIH/OMB)(Participants) | Cohort A | Cohort B | Total |
|---|---|---|---|
| Hispanic or Latino | 1 | 0 | 1 |
| Not Hispanic or Latino | 12 | 9 | 21 |
| Unknown or Not Reported | 0 | 1 | 1 |
| Race/Ethnicity, Customized(Participants) | Cohort A | Cohort B | Total |
|---|---|---|---|
| White/Caucasian | 13 | 8 | 21 |
| Other | 0 | 2 | 2 |
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