INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders

Phase 2Active Not RecruitingNCT04455841

Incyte Corporation84 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Anemia Post-essential Thrombocythemia Myelofibrosis Post-polycythemia Vera Myelofibrosis

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants with MF who are transfusion-dependent or present with symptomatic anemia, defined as follows: 1. 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). 2. 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 1. * ECOG performance status score of the following: 1. 0 or 1 for the dose-escalation stages. 2. 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. * For TGA: * Participants previously treated with JAK inhibitors for at least 12 weeks. * Participants with intermediate-2 or high DIPSS MF according to IWG-MRT criteria. * For TGB: * 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. * For TGC: * 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.

Locations (34)

City of Hope National Medical Center

Duarte, California, United States

City of Hope Orange County

Irvine, California, United States

Usc Norris Comprehensive Cancer Center

Los Angeles, California, United States

Stanford Cancer Center

Palo Alto, California, United States

Prebys Cancer Center

San Diego, California, United States

Outcomes

Primary Outcomes

Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-emergent Serious Adverse Event (SAE)

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.

Time frame: up to approximately 4 years

Number of Participants With Any ≥Grade 3 TEAE and Any Treatment-emergent SAE

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.

Time frame: up to approximately 4 years

Number of Participants With Dose-limiting Toxicities (DLTs)

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.

Time frame: from Cycle 1 Day 1 to Cycle 1 Day 28

Maximum Tolerated Dose (MTD)

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.

Time frame: from Cycle 1 Day 1 to Cycle 1 Day 28

Recommended Dose for Expansion (RDE)

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

Time frame: from Cycle 1 Day 1 to Cycle 1 Day 28

Secondary Outcomes

Percentage of Participants With Anemia Response

Anemia response was defined as (a) a hemoglobin (Hgb) increase of 1.5 grams per deciliter (g/dL) relative to baseline for any "rolling" 12-week period (84 days with each assessment that met this requirement) during the first 24 weeks of treatment if transfusion independent (TI) at baseline; or (b) transfusion independence for any "rolling" 12-week period (absence of any red blood cell \[RBC\] transfusion over any 84-day period) during the first 24 weeks of treatment if transfusion dependent (TD) at baseline.

Time frame: up to Week 24

Duration of Anemia Response

Duration of anemia response was defined as (a) the interval from the first onset of anemia response to the earliest date of loss of anemia response that persisted for at least 4 weeks or death from any cause (for TI participants at baseline); or (b) the duration of the RBC-TI period for participants who achieved RBC-TI for at least 12 consecutive weeks during the first 24 weeks of treatment (for TD participants at baseline).

Time frame: up to 1530 days

Mean Change From Baseline in the Hgb Value Over 12-week Treatment Periods

Mean change from baseline was assessed as the largest increase from baseline in the mean Hgb values over any rolling 12-week treatment period during the first 24 weeks of treatment. Change from baseline was calculated as the post-baseline value minus the baseline value.

Time frame: Baseline; up to 24 weeks

Rate of Red Blood Cell (RBC) Transfusion From Week 24 Through Week 48

The rate of RBC transfusion was defined as the average number of RBC units per participant-month during the treatment period.

Time frame: from Week 24 through Week 48

Splenic Volume Response Rate at Week 24

Splenic volume response rate was defined as the percentage of participants achieving a ≥35% reduction in spleen volume at Week 24 relative to baseline as measured by magnetic resonance imaging or computed tomography scan.

Time frame: Week 24

Overall Response Rate (ORR)

ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) (including the morphologic effects of the combination of zilurgisertib with ruxolitinib on bone marrow) according to Tefferi et al (2013) definitions.

Time frame: Week 24

Progression-free Survival (PFS)

PFS was defined as the interval from the first dose of study treatment until the first documented progression or death according to Tefferi et al (2013) definitions.

Time frame: Week 24

Leukemia-free Survival (LFS)

LFS was defined as the interval from the first dose of study treatment until the first documented leukemia transformation or death from any cause.

Time frame: Week 24

Cmax of Zilurgisertib Alone

Cmax was defined as the maximum concentration of zilurgisertib.

Time frame: 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

tmax was defined as the time to the maximum concentration of zilurgisertib.

Time frame: 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

AUC0-t was defined as the area under the plasma concentration-time curve from time 0 to the last quantifiable measurable plasma concentration of zilurgisertib.

Time frame: 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

Percentage change was calculated as the (\[post-baseline value minus the baseline value\] / \[baseline value\]) \* 100.

Time frame: from Cycle 1 Day 15 to Cycle 7 Day 1

Change From Baseline in Ferritin

Change from Baseline (CFB) was calculated as the post-Baseline value minus the Baseline value.

Time frame: 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

Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Time frame: up to 1530 days