To Assess the Safety and Tolerability of INCB000928 in Participants With Myelodysplastic Syndromes or Multiple Myeloma

Phase 2TerminatedNCT04582539

Incyte Corporation22 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 in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Myelodysplastic Syndromes Multiple Myeloma Anemia

Interventions

INCB000928DRUG

INCB000928 will be administered once daily.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (15)

Stanford Cancer Center

Palo Alto, California, United States

University of Miami

Miami, Florida, United States

Outcomes

Primary Outcomes

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

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.

Time frame: up to 950 days

Number of Participants With Any ≥Grade 3 TEAE

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.

Time frame: up to 950 days

Number of Participants With Dose-limiting Toxicities (DLTs)

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.

Time frame: up to 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. 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Percentage of Participants With Anemia Response

Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline. Transfusion-independent participants at baseline were those that did not receive ≥4 units of red blood cell (RBC) transfusions during the 28 days immediately preceding Cycle 1 Day 1 or did not receive ≥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.

Time frame: up to Week 24

Duration of Anemia Response

Duration of anemia response was defined as 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. Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline. Transfusion-independent participants at baseline were those that did not receive ≥4 units of red blood cell (RBC) transfusions during the 28 days immediately preceding Cycle 1 Day 1 or did not receive ≥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.

Time frame: up to 920 days

Percentage of Participants With RBC-transfusion Independence (TI)

Participants with RBC-transfusion independence were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.

Time frame: 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

Participants with RBC-TI were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.

Time frame: up to 920 days

Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24

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 12 through Week 24

The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment

Baseline Hgb was measured up to 8 weeks prior to the first dose administration of zilurgisertib. The baseline Hgb was defined as the average of all eligible Hgb assessments. The Hgb assessment(s) within the window from the date received RBC transfusion+1 day to the date received RBC transfusion+14 days that didn't trigger another transfusion were excluded.

Time frame: up to Week 24

Overall Response Rate (ORR) in MDS Participants

ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). For MDS, CR: bone marrow with ≤5% myeloblasts with normal maturation of all cell lines; HgB ≥11 g/dl, neutrophils ≥1.0x10\^9/Liter (L), platelets ≥100x10\^9/L, and no blasts in the peripheral blood. For MDS, PR: all CR criteria, but bone marrow blasts decreased by ≥50% over pretreatment but still \>5%; cellularity and morphology not relevant. For MDS/MPN overlap syndromes, CR: bone marrow with ≤5% myeloblasts; no osteomyelofibrosis or ≤Grade 1 fibrosis; white blood cells ≤10X10\^9 cells/L, HgB ≥11 g/dL, platelets ≥100x10\^9/L/≤450x10\^9/L, neutrophils ≥1.0x10\^9/L, no blasts, neutrophil precursors reduced to ≤2%, monocytes ≤1x10\^9/L in peripheral blood; complete resolution of medullary disease. For MDS/MPN overlap syndromes, PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50%, but remaining \>5% of cellularity.

Time frame: up to 920 days

Percentage of MDS Participants With an Event of Progression or Death

Participants with MDS/MPN overlap syndromes were excluded from analysis. Data have been reported as the percentage of participants with an event of progression or death rather than median PFS (the interval from the first dose of study drug until the first documented progression or death) because 2 participants had an event of PFS or death. It was pre-specified in the SAP that the number of MDS participants with documented progression or death was to be summarized.

Time frame: up to 920 days

Percentage of Participants With an Event of Leukemia or Death

Data have been reported as the percentage of participants with an event of leukemia or death rather than LFS (the interval from the first dose of study drug until the first documented leukemia transformation or death from any cause) because 3 participants had an event of leukemia or death. It was pre-specified in the SAP that the number of participants with leukemia transformation or death was to be summarized.

Time frame: up to 920 days

ORR in Multiple Myeloma (MM) Participants

ORR was defined as the percentage of participants with stringent CR, CR, very good PR, and PR.

Time frame: up to 920 days

PFS in MM Participants

PFS was defined as the interval from the first dose of study drug until the first documented progression or death.

Time frame: up to 920 days

Cmax of Zilurgisertib

Cmax was defined as the maximum concentration of zilurgisertib.

Time frame: Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6 hours post-dose

Tmax of Zilurgisertib

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

Time frame: Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose

AUClast of Zilurgisertib

AUClast 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: Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose

Ctrough of Zilurgisertib

Ctrough was defined as the lowest concentration of zilurgisertib.

Time frame: 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

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; Cycles 2, 3, 4, 5, 6, and 7 Day 1

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 950 days