A Phase 1/2, Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy in Participants With Anemia Due to Myelodysplastic Syndromes or Multiple Myeloma
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Incyte Corporation
- Enrollment
- 22
- Locations
- 15
- Primary Endpoint
- Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
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 in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- 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
- •Agreement to avoid pregnancy or fathering children.
- •Participants who are transfusion-dependent or present with symptomatic anemia
- •For MDS participants:
- •Ineligible to receive or have not responded to available therapies for anemia such as ESAs or lenalidomide.
- •Not requiring cytoreductive therapy other than hydroxyurea.
- •BM and peripheral blood myeloblast count < 10%.
- •Histologically confirmed diagnosis of the MDS, CMML and unclassifiable MDS/MPN overlap syndromes.
- •For MM participants:
- •Histologically confirmed diagnosis of MM.
- •After failure of available standard treatments such as alkylating agents, glucocorticoids, immunomodulatory drugs (lenalidomide,pomalidomide, or thalidomide), proteasome inhibitors (bortezomib or carfilzomib), and daratumumab.
Exclusion Criteria
- •Any prior allogeneic stem cell transplantation or a candidate for such transplantation.
- •Any major surgery within 28 days before the first dose of study drug.
- •Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, or antibody or hypomethylating agent to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
- •Undergoing treatment with another investigational medication or having been treated with an investigational medication within 28 days before the first dose of study drug. -Undergoing treatment with ESAs, granulocyte colony-stimulating factor or granulocyte/macrophage colony-stimulating factor, romiplostin, or eltrombopag at any time within 28 days before the first dose of study drug.
- •Undergoing treatment with a strong or potent inhibitor or inducer of CYP3A4/5 within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug or expected to receive such treatment during the study.
- •History of clinically significant or uncontrolled cardiac disease.
- •History or presence of an abnormal ECG that, in the investigator's opinion, is clinically Meaningful.
- •Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
- •Diagnosis of chronic liver disease.
Arms & Interventions
INCB000928
INCB000928 will be administered in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.
Intervention: INCB000928 (Drug)
Outcomes
Primary Outcomes
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
Time Frame: up to 950 days
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE is an AE reported for the first time or the worsening of a pre-existing event after the first dose of study drug.
Number of Participants With Any ≥Grade 3 TEAE
Time Frame: up to 950 days
The severity of AEs was assessed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) Grades 1 through 5. The investigator made an assessment of intensity for each AE and SAE reported during the study and assigned it to one of the following categories. 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: up to Day 28
A DLT was defined as the occurrence of any protocol-defined toxicities occurring during the first study drug treatment cycle, from C1D1 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.
Maximum Tolerated Dose (MTD)
Time Frame: up to 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. Bayesian optimal interval (BOIN) design was used to determine the MTD for this study. 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: up to Day 28
RDE doses were defined as pharmacodynamically active. RDE doses were not to have exceeded the MTD defined in each treatment group.
Secondary Outcomes
- The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment(up to Week 24)
- Overall Response Rate (ORR) in MDS Participants(up to 920 days)
- Percentage of MDS Participants With an Event of Progression or Death(up to 920 days)
- Percentage of Participants With an Event of Leukemia or Death(up to 920 days)
- ORR in Multiple Myeloma (MM) Participants(up to 920 days)
- PFS in MM Participants(up to 920 days)
- Tmax of Zilurgisertib(Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose)
- AUClast of Zilurgisertib(Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose)
- Ctrough of Zilurgisertib(Day 15 of Cycle 1: pre-dose; 2, 4, 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; Cycles 2, 3, 4, 5, 6, and 7 Day 1)
- Change From Baseline in Hemoglobin at the End of Treatment(up to 950 days)
- Percentage of Participants With Anemia Response(up to Week 24)
- Duration of Anemia Response(up to 920 days)
- Percentage of Participants With RBC-transfusion Independence (TI)(up to Week 24)
- Duration of RBC-transfusion Independence (TI) Period for Participants Achieving RBC-TI for at Least 8 Consecutive Weeks During the First 24 Weeks of Treatment(up to 920 days)
- Cmax of Zilurgisertib(Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6 hours post-dose)
- Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24(from Week 12 through Week 24)