An Open-Label Phase 2 Study of Itacitinib (INCB039110) in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Subjects With Myelofibrosis
Overview
- Phase
- Phase 2
- Intervention
- Itacitinib
- Conditions
- MPN (Myeloproliferative Neoplasms)
- Sponsor
- Incyte Corporation
- Enrollment
- 23
- Locations
- 25
- Primary Endpoint
- Change in Spleen Volume at Week 24 Compared to Baseline
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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).
Investigators
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
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.
Arms & Interventions
Cohort A
Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of 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.
Intervention: Itacitinib
Cohort A
Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of 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.
Intervention: Ruxolitinib
Cohort B
Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment are met.
Intervention: Itacitinib
Outcomes
Primary Outcomes
Change in Spleen Volume at Week 24 Compared to Baseline
Time Frame: Baseline and Week 24
Spleen volume was measured using magnetic resonance imaging (MRI) or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Percentage Change in Spleen Volume at Week 24 Compared to Baseline
Time Frame: Baseline and Week 24
Spleen volume was measured using MRI or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume.
Secondary Outcomes
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(up to approximately 40 months (3.3 years))
- Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters(up to approximately 40 months (3.3 years))
- Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)(Baseline through Week 12)
- Number of Participants With Clinically Significant Changes From Baseline in Vital Signs(up to approximately 40 months (3.3 years))
- Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation(Baseline through Weeks 12 and 24)
- Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation(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)(Baseline through Week 12 and Week 24)
- Number of Participants With Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response(up to approximately 40 months (3.3 years))
- Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)(Baseline through Week 12)
- Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Time to Maximum Concentration (Tmax) of Itacitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Time to Maximum Concentration (Tmax) of Ruxolitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary(Baseline through Weeks 12 and 24)
- Patient Global Impression of Change (PGIC) Score at Each Visit(Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 168)
- Apparent Oral Dose Clearance (CL/F) of Itacitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Maximum Observed Plasma Concentration (Cmax) of Itacitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MFSAF v2.0 Symptom Diary(Baseline through Weeks 12 and 24)
- Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF(Baseline through Week 12 and Week 24)
- Apparent Oral Dose Clearance (CL/F) of Ruxolitinib(0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4)
- Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib(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(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(0 (pre-dose), 1, 2, 5 and 8 hours post-dose Week 2 and Week 4)