A Phase 1/2 Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Incyte Corporation
- Enrollment
- 84
- Locations
- 68
- Primary Endpoint
- Number of treatment-related adverse events
Study Overview
Brief Summary
This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as monotherapy or in combination with ruxolitinib in participants with MF who are transfusion-dependent or presenting with symptomatic anemia. This study will consist of 2 parts: dose escalation and expansion.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants with MF who are transfusion-dependent or present with symptomatic anemia, defined as follows:
- •Anemia: An Hgb value < 10 g/dL demonstrated during screening recorded on 3 separate occasions with at least 7 days between measurements (Note: RBC transfusion must be at least 2 weeks before the Hgb measurement during screening).
- •Transfusion-dependent: Participant has received at least 4 units of RBC transfusions during the 28 days immediately preceding Cycle 1 Day 1 OR has received an average of at least 4 units of RBC transfusions in the 8 weeks immediately preceding Cycle 1 Day 1, for an Hgb level of < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days before Cycle 1 Day
- •ECOG performance status score of the following:
- •0 or 1 for the dose-escalation stages.
- •0, 1, or 2 for the dose-expansion stage.
- •Life expectancy is greater than 6 months
- •Agreement to avoid pregnancy or fathering children.
- •Ineligible to receive or have not responded to available therapies for anemia such as ESAs.
- •Participants previously treated with JAK inhibitors for at least 12 weeks.
- •Participants with intermediate-2 or high DIPSS MF according to IWG-MRT criteria.
- •Participants must have been on a therapeutic and stable regimen of ruxolitinib for at least 12 consecutive weeks immediately preceding the first dose of study treatment.
- •Participants with intermediate-1, intermediate-2, or high DIPSS MF according to IWG-MRT criteria.
- •Participants must be JAK inhibitor treatment naive (no prior treatment with any JAK inhibitor) and have an indication for initiation of ruxolitinib treatment.
- •Participants with intermediate-1, intermediate-2, or high DIPSS MF according to IWG-MRT criteria.
Exclusion Criteria
- •Undergone any prior allogenic or autologous stem cell transplantation or a candidate for such transplantation.
- •Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody or hypomethylating agent to treat the participant's disease, with the exception of ruxolitinib for TGB only, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
- •Laboratory Values outside of protocol defined range at screening.
Arms & Interventions
Treatment Group A (TGA)
INCB000928 will be administered once daily (QD).
Intervention: INCB000928 (Drug)
Treatment Group C (TGC)
INCB000928 will be administered in combination with ruxolitinib.
Intervention: INCB000928 (Drug)
Treatment Group B (TGB)
INCB000928 will be administered in combination with ruxolitinib.
Intervention: INCB000928 (Drug)
Treatment Group B (TGB)
INCB000928 will be administered in combination with ruxolitinib.
Intervention: ruxolitinib (Drug)
Treatment Group C (TGC)
INCB000928 will be administered in combination with ruxolitinib.
Intervention: ruxolitinib (Drug)
Outcomes
Primary Outcomes
Number of treatment-related adverse events
Time Frame: Approximately up to 13 months
To determine the safety and tolerability of INCB000928 administered as monotherapy (TGA) or in combination with ruxolitinib (TGB and TGC).
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-emergent Serious Adverse Event (SAE)
Time Frame: up to approximately 4 years
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug/treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug.
Number of Participants With Any ≥Grade 3 TEAE and Any Treatment-emergent SAE
Time Frame: up to approximately 4 years
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
Number of Participants With Dose-limiting Toxicities (DLTs)
Time Frame: from Cycle 1 Day 1 to Cycle 1 Day 28
A DLT was defined as the occurrence of any protocol-defined toxicity occurring during the first treatment cycle, from Cycle 1 Day 1 up to and including Cycle 1 Day 28 (per regimen cycle schedule), except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. The DLT-Evaluable Population included all non-backfill participants eligible for dose escalation who met the criteria outlined in the Analysis Population field.
Maximum Tolerated Dose (MTD)
Time Frame: from Cycle 1 Day 1 to Cycle 1 Day 28
The MTD was defined as the dose at which the observed DLT rate was closest to the target DLT rate of 28% using an isotonical method that took the assumption of a monotonic dose-toxicity relationship into account. Per the protocol, the stopping rule was either (a) reaching a certain number of participants at one dose level under the early stopping rule or (b) reaching the pre-defined maximum sample size. Dose escalation was to be considered complete only when one of these conditions was met. After completion, the MTD was to be defined as the dose level closest to the target DLT rate. The MTD could not be concluded until the stopping rule was met.
Recommended Dose for Expansion (RDE)
Time Frame: from Cycle 1 Day 1 to Cycle 1 Day 28
The RDE was defined as a pharmacodynamically active dose. The RDE was determined in an independent fashion by evaluation of all available data (i.e., safety, pharmacokinetic, and pharmacodynamic data) from the respective dose-escalation stage of the study for further investigation in the expansion cohort, including safety (e.g., low-grade but chronic toxicities, dose reduction, dose interruption, or missed doses of zilurgisertib and/or ruxolitinib). The RDE(s) could not exceed the MTD in each treatment group
Secondary Outcomes
- Mean Change of Hemoglobin(Approximately up to 13 months)
- TGB and TGC only - Objective Response Rate(Approximately up to 13 months)
- TGB and TGC only - Leukemia Free Survival(Approximately upto 13 months)
- Tmax(Approximately up to 13 months)
- Iron Homeostasis(Approximately up to 13 months)
- AUC0-t(Approximately up to 13 months)
- Anemia Response(Approximately up to 13 months)
- TGB and TGC only -Splenic Volume(Approximately up to 13 months)
- TGB and TGC Only - Splenic Length(Approximately Up to 13 months)
- Hepcidin levels(Approximately up to 13 months)
- Erythropoesis(Approximately up to 13 months)
- Duration of Anemia Response(Approximately up to 13 months)
- Rate of RBC transfusion(Approximately up to 13 months)
- AUC(Approximately up to 13 months)
- TGB and TGC only - Progression Free Survival(Approximately up to 13 months)
- Percentage of Participants With Anemia Response(up to Week 24)
- Duration of Anemia Response(up to 1530 days)
- Mean Change From Baseline in the Hgb Value Over 12-week Treatment Periods(Baseline; up to 24 weeks)
- Rate of Red Blood Cell (RBC) Transfusion From Week 24 Through Week 48(from Week 24 through Week 48)
- Splenic Volume Response Rate at Week 24(Week 24)
- Spleen Length Response(Week 24)
- Overall Response Rate (ORR)(Week 24)
- Progression-free Survival (PFS)(Week 24)
- Leukemia-free Survival (LFS)(Week 24)
- Cmax of Zilurgisertib Alone(Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose)
- Tmax of Zilurgisertib(Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose)
- AUC0-t of Zilurgisertib(Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose)
- Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1(from Cycle 1 Day 15 to Cycle 7 Day 1)
- Change From Baseline in Ferritin(Baseline; Cycle 1 Day 8; Cycle 1 Day 15; Cycle 1 Day 22; Cycles 2, 3, 4, 5, 6, and 7 Day 1; Cycle 2 Day 15)
- Change From Baseline in Hemoglobin at the End of Treatment(up to 1530 days)