A Study of Itacitinib in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Participants With Myelofibrosis

MPN (Myeloproliferative Neoplasms) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03144687
• Other study ID #: INCB 39110-209
• Secondary ID: 2017-005109-11
• Status: Completed
• Phase: Phase 2
• Start date: January 26, 2018
• Est. completion date: June 1, 2021

Study information

• Verified date: May 2022
• Source: Incyte Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: June 1, 2021
• Est. primary completion date: March 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• MPN (Myeloproliferative Neoplasms)
• Myeloproliferative Disorders
• Primary Myelofibrosis

Intervention

Drug:
• Itacitinib
Itacitinib self-administered orally once daily .
• Ruxolitinib
Ruxolitinib self-administered orally at the stable dose of < 20 mg daily established before entering the study.

Locations

Country	Name	City	State
Austria	Ordensklinikum Linz GmbH, Servicestelle für Studien	Linz
Austria	Paracelsus Medical University Salzburg	Salzburg
Austria	Hanusch Hospital	Wien
Netherlands	VU Medical Center	Amsterdam
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Erasmus Medical Center	Rotterdam
Netherlands	UMC Utrecht Department of Hematology	Utrecht
United States	University Of New Mexico Cancer Center	Albuquerque	New Mexico
United States	University of Michigan Cancer Center	Ann Arbor	Michigan
United States	Anschutz Cancer Pavilion - University Of Colorado	Aurora	Colorado
United States	Consultants in Medical Oncology and Hematology, PC	Broomall	Pennsylvania
United States	University of Virginia	Charlottesville	Virginia
United States	Cleveland Clinic	Cleveland	Ohio
United States	Rocky Mountain Cancer Center	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Center	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Willamette Valley Cancer Institute	Eugene	Oregon
United States	Parkview Research Center	Fort Wayne	Indiana
United States	Norwalk Hospital	Norwalk	Connecticut
United States	Nebraska Cancer Specialist	Omaha	Nebraska
United States	UC Irvine Medical Center	Orange	California
United States	Texas Oncology - Round Rock Cancer Center	Round Rock	Texas
United States	Texas Oncology San Antonio	San Antonio	Texas
United States	Providence Cancer Center	Southfield	Michigan
United States	Arizona Oncology Associates	Tempe	Arizona
United States	Texas Oncology - Tyler	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Incyte Corporation

Countries where clinical trial is conducted

United States,  Austria,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline and Week 24
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.	Baseline and Week 24
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.	up to approximately 40 months (3.3 years)
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.	up to approximately 40 months (3.3 years)
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.	up to approximately 40 months (3.3 years)
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.	Baseline through Week 12
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.	Baseline through Week 12
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.	Baseline through Weeks 12 and 24
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.	Baseline through Weeks 12 and 24
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.	Baseline through Weeks 12 and 24
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.	Baseline through Weeks 12 and 24
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.	Baseline through Week 12 and Week 24
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%.	Baseline through Week 12 and Week 24
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.	Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 168
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.	up to approximately 40 months (3.3 years)
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.	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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).	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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.	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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).	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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.	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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).	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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.	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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).	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
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.	0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 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).	0 (pre-dose), 1, 2, 5 and 8 hours post-dose Week 2 and Week 4