Back to resultsA Study of Itacitinib in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Participants With Myelofibrosis
Primary Purpose
MPN (Myeloproliferative Neoplasms)
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Itacitinib
Ruxolitinib
Sponsored by
About this trial
This is an interventional treatment trial for MPN (Myeloproliferative Neoplasms) focused on measuring Myelofibrosis, Janus kinase (JAK) inhibitor, itacitinib, ruxolitinib
Eligibility Criteria
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.
Sites / Locations
- Arizona Oncology Associates
- UC Irvine Medical Center
- Anschutz Cancer Pavilion - University Of Colorado
- Rocky Mountain Cancer Center
- Rocky Mountain Cancer Center
- Norwalk Hospital
- Parkview Research Center
- University of Michigan Cancer Center
- Providence Cancer Center
- Nebraska Cancer Specialist
- University Of New Mexico Cancer Center
- Duke University Medical Center
- Cleveland Clinic
- Willamette Valley Cancer Institute
- Consultants in Medical Oncology and Hematology, PC
- Texas Oncology - Round Rock Cancer Center
- Texas Oncology San Antonio
- Texas Oncology - Tyler
- University of Virginia
- Ordensklinikum Linz GmbH, Servicestelle für Studien
- Paracelsus Medical University Salzburg
- Hanusch Hospital
- VU Medical Center
- Maastricht University Medical Center
- Erasmus Medical Center
- UMC Utrecht Department of Hematology
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort A
Cohort B
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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).
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.
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).
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.
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 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 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).
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.
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).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03144687
Brief Title
A Study of Itacitinib in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Participants With Myelofibrosis
Official Title
An Open-Label Phase 2 Study of Itacitinib (INCB039110) in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Subjects With Myelofibrosis
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
January 26, 2018 (Actual)
Primary Completion Date
March 14, 2020 (Actual)
Study Completion Date
June 1, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Incyte Corporation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
MPN (Myeloproliferative Neoplasms)
Keywords
Myelofibrosis, Janus kinase (JAK) inhibitor, itacitinib, ruxolitinib
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort A
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort B
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Itacitinib
Other Intervention Name(s)
INCB039110
Intervention Description
Itacitinib self-administered orally once daily .
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
INCB018424, Jakafi, Jakavi
Intervention Description
Ruxolitinib self-administered orally at the stable dose of < 20 mg daily established before entering the study.
Primary Outcome Measure Information:
Title
Change in Spleen Volume at Week 24 Compared to Baseline
Description
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
Title
Percentage Change in Spleen Volume at Week 24 Compared to Baseline
Description
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
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
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)
Title
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
Description
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)
Title
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Description
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)
Title
Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
Description
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
Title
Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
Description
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
Title
Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
Description
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
Title
Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
Description
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
Title
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
Description
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
Title
Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary
Description
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
Title
Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF)
Description
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
Title
Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF
Description
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
Title
Patient Global Impression of Change (PGIC) Score at Each Visit
Description
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
Title
Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response
Description
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)
Title
Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib
Description
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
Title
Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib
Description
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
Title
Apparent Oral Dose Clearance (CL/F) of Itacitinib
Description
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
Title
Apparent Oral Dose Clearance (CL/F) of Ruxolitinib
Description
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
Title
Maximum Observed Plasma Concentration (Cmax) of Itacitinib
Description
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
Title
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
Description
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
Title
Time to Maximum Concentration (Tmax) of Itacitinib
Description
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
Title
Time to Maximum Concentration (Tmax) of Ruxolitinib
Description
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
Title
Concentration at the End of the Dosing Interval (Ctau) of Itacitinib
Description
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
Title
Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Langmuir
Organizational Affiliation
Incyte Corporation
Official's Role
Study Director
Facility Information:
Facility Name
Arizona Oncology Associates
City
Tempe
State/Province
Arizona
ZIP/Postal Code
85284
Country
United States
Facility Name
UC Irvine Medical Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Anschutz Cancer Pavilion - University Of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Rocky Mountain Cancer Center
City
Colorado Springs
State/Province
Colorado
ZIP/Postal Code
80907
Country
United States
Facility Name
Rocky Mountain Cancer Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Norwalk Hospital
City
Norwalk
State/Province
Connecticut
ZIP/Postal Code
06856
Country
United States
Facility Name
Parkview Research Center
City
Fort Wayne
State/Province
Indiana
ZIP/Postal Code
46845
Country
United States
Facility Name
University of Michigan Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Providence Cancer Center
City
Southfield
State/Province
Michigan
ZIP/Postal Code
48075
Country
United States
Facility Name
Nebraska Cancer Specialist
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68124
Country
United States
Facility Name
University Of New Mexico Cancer Center
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87102
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Willamette Valley Cancer Institute
City
Eugene
State/Province
Oregon
ZIP/Postal Code
97401
Country
United States
Facility Name
Consultants in Medical Oncology and Hematology, PC
City
Broomall
State/Province
Pennsylvania
ZIP/Postal Code
19008
Country
United States
Facility Name
Texas Oncology - Round Rock Cancer Center
City
Round Rock
State/Province
Texas
ZIP/Postal Code
78681
Country
United States
Facility Name
Texas Oncology San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78240
Country
United States
Facility Name
Texas Oncology - Tyler
City
Tyler
State/Province
Texas
ZIP/Postal Code
75702
Country
United States
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
Ordensklinikum Linz GmbH, Servicestelle für Studien
City
Linz
ZIP/Postal Code
4020
Country
Austria
Facility Name
Paracelsus Medical University Salzburg
City
Salzburg
ZIP/Postal Code
A-5020
Country
Austria
Facility Name
Hanusch Hospital
City
Wien
ZIP/Postal Code
1140
Country
Austria
Facility Name
VU Medical Center
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands
Facility Name
Maastricht University Medical Center
City
Maastricht
ZIP/Postal Code
6202
Country
Netherlands
Facility Name
Erasmus Medical Center
City
Rotterdam
ZIP/Postal Code
3015 AA
Country
Netherlands
Facility Name
UMC Utrecht Department of Hematology
City
Utrecht
ZIP/Postal Code
3584
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
A Study of Itacitinib in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Participants With Myelofibrosis
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