Anemia, Multiple Myeloma, Myelodysplastic Syndromes
Conditions
Keywords
Myelodysplastic Syndromes, Multiple Myeloma, Anemia, LIMBER
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.
Interventions
DRUGINCB000928
INCB000928 will be administered once daily.
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 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 | 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) | 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) | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| Overall Response Rate (ORR) in MDS Participants | up to 920 days | 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. |
| Percentage of MDS Participants With an Event of Progression or Death | up to 920 days | 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. |
| Percentage of Participants With an Event of Leukemia or Death | up to 920 days | 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. |
| ORR in Multiple Myeloma (MM) Participants | up to 920 days | ORR was defined as the percentage of participants with stringent CR, CR, very good PR, and PR. |
| PFS in MM Participants | up to 920 days | PFS was defined as the interval from the first dose of study drug until the first documented progression or death. |
| Percentage of Participants With Anemia Response | up to Week 24 | 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. |
| Tmax of Zilurgisertib | Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose | tmax was defined as the time to the maximum observed concentration of zilurgisertib. |
| AUClast of Zilurgisertib | Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose | AUClast was defined as the area under the plasma concentration-time curve from time 0 to the last quantifiable measurable plasma concentration of zilurgisertib. |
| Ctrough of Zilurgisertib | Day 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose | Ctrough was defined as the lowest concentration of zilurgisertib. |
| Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | 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. |
| 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 (CFB) was calculated as the post-Baseline value minus the Baseline value. |
| Change From Baseline in Hemoglobin at the End of Treatment | up to 950 days | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Cmax of Zilurgisertib | Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6 hours post-dose | Cmax was defined as the maximum concentration of zilurgisertib. |
| Duration of Anemia Response | up to 920 days | 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. |
| Percentage of Participants With RBC-transfusion Independence (TI) | up to Week 24 | 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. |
| 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 | 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. |
| Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 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. |
Countries
France, Italy, United States
Participant flow
Pre-assignment details
This study was conducted at 8 study centers in the United States, France, and Italy.
Participants by arm
| Arm | Count |
|---|---|
| Zilurgisertib 50 mg QD Participants with myelodysplastic syndromes (MDS) or multiple myeloma (MM) who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 50 milligrams (mg) once daily (QD) administered as a monotherapy for up to 6 months. | 4 |
| Zilurgisertib 100 mg QD Participants with MDS or MM who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 100 mg QD administered as a monotherapy for up to 6 months. | 5 |
| Zilurgisertib 200 mg QD Participants with MDS or MM who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 200 mg QD administered as a monotherapy for up to 6 months. | 4 |
| Zilurgisertib 400 mg QD Participants with MDS or MM who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 400 mg QD administered as a monotherapy for up to 6 months. | 5 |
| Zilurgisertib 600 mg QD Participants with MDS or MM who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 600 mg QD administered as a monotherapy for up to 6 months. | 3 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Participant Started New Therapy; Did Not Return to Clinic | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 3 | 2 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Zilurgisertib 50 mg QD | Zilurgisertib 100 mg QD | Zilurgisertib 200 mg QD | Zilurgisertib 400 mg QD | Zilurgisertib 600 mg QD | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 4.5 | 74.6 years STANDARD_DEVIATION 3.78 | 78.5 years STANDARD_DEVIATION 6.19 | 74.8 years STANDARD_DEVIATION 4.87 | 75.7 years STANDARD_DEVIATION 6.66 | 74.4 years STANDARD_DEVIATION 5.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants | 3 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 1 / 5 | 0 / 4 | 1 / 5 | 0 / 3 | 3 / 21 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 4 / 4 | 5 / 5 | 2 / 3 | 20 / 21 |
| serious Total, serious adverse events | 2 / 4 | 1 / 5 | 2 / 4 | 2 / 5 | 0 / 3 | 7 / 21 |
Outcome results
Primary
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.
Time frame: up to Day 28
Population: Full Analysis Set-MDS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Maximum Tolerated Dose (MTD) | NA milligrams |
Primary
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
Population: Full Analysis Set-MDS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zilurgisertib 50 mg QD | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
| Zilurgisertib 100 mg QD | Number of Participants With Any ≥Grade 3 TEAE | 3 Participants |
| Zilurgisertib 200 mg QD | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
| Zilurgisertib 400 mg QD | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
| Zilurgisertib 600 mg QD | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
Primary
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
Population: Full Analysis Set-MDS: all participants with myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndromes who received at least 1 dose of zilurgisertib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zilurgisertib 50 mg QD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 4 Participants |
| Zilurgisertib 100 mg QD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 5 Participants |
| Zilurgisertib 200 mg QD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 4 Participants |
| Zilurgisertib 400 mg QD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 5 Participants |
| Zilurgisertib 600 mg QD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 2 Participants |
Primary
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
Population: DLT Evaluable Population: all participants in the FAS Population who met the following criteria: observed for at least the first treatment cycle (i.e., 28 days); received ≥75% of doses of study treatment at the level assigned to that cohort (i.e., 21 days of treatment) or had a DLT during the first study treatment cycle; did not receive any strong or potent CYP3A4/5 inhibitor or inducer during the first study drug treatment cycle (DLT assessment period); was not part of a backfill cohort
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zilurgisertib 50 mg QD | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Zilurgisertib 100 mg QD | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Zilurgisertib 200 mg QD | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Zilurgisertib 400 mg QD | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Zilurgisertib 600 mg QD | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
Primary
Recommended Dose for Expansion (RDE)
RDE doses were defined as pharmacodynamically active. RDE doses were not to have exceeded the MTD defined in each treatment group.
Time frame: up to Day 28
Population: Full Analysis Set-MDS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Recommended Dose for Expansion (RDE) | NA milligrams |
Secondary
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
Population: PK Evaluable Population. Only participants with available data were analyzed. One participant who was supposed to receive 100 mg actually received 25 mg from Day 1 to Day 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zilurgisertib 50 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | 343 nanomolar x hour | — |
| Zilurgisertib 100 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | 749 nanomolar x hour | Standard Deviation 312 |
| Zilurgisertib 100 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 15 | 1890 nanomolar x hour | Standard Deviation 749 |
| Zilurgisertib 200 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | 1070 nanomolar x hour | Standard Deviation 471 |
| Zilurgisertib 200 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 15 | 3090 nanomolar x hour | Standard Deviation 1620 |
| Zilurgisertib 400 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | 2540 nanomolar x hour | Standard Deviation 1150 |
| Zilurgisertib 400 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 15 | 6850 nanomolar x hour | Standard Deviation 3050 |
| Zilurgisertib 600 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | 8050 nanomolar x hour | Standard Deviation 2680 |
| Zilurgisertib 600 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 15 | 12300 nanomolar x hour | Standard Deviation 26100 |
| Zilurgisertib 600 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 15 | NA nanomolar x hour | — |
| Zilurgisertib 600 mg QD | AUClast of Zilurgisertib | Cycle 1 Day 1 | NA nanomolar x hour | — |
Secondary
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
Population: Full Analysis Set-MDS. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 3 Day 1 | 307.58 nanograms per milliliter | Standard Deviation 709.602 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 15 | 292.00 nanograms per milliliter | Standard Deviation 161.22 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 6 Day 1 | 297.67 nanograms per milliliter | Standard Deviation 614.18 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 2 Day 1 | 101.65 nanograms per milliliter | Standard Deviation 245.814 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 5 Day 1 | 349.00 nanograms per milliliter | Standard Deviation 680.559 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 8 | 47.67 nanograms per milliliter | Standard Deviation 43.501 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 7 Day 1 | 365.50 nanograms per milliliter | Standard Deviation 658.316 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | Baseline | 1022.35 nanograms per milliliter | Standard Deviation 634.096 |
| Zilurgisertib 50 mg QD | Change From Baseline in Ferritin | CFB at Cycle 4 Day 1 | 409.83 nanograms per milliliter | Standard Deviation 689.052 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 4 Day 1 | -21.15 nanograms per milliliter | Standard Deviation 48.295 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | Baseline | 930.18 nanograms per milliliter | Standard Deviation 697.078 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 8 | -65.24 nanograms per milliliter | Standard Deviation 57.388 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 15 | 17.30 nanograms per milliliter | Standard Deviation 31.109 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 2 Day 1 | 70.03 nanograms per milliliter | Standard Deviation 76.619 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 3 Day 1 | -6.70 nanograms per milliliter | Standard Deviation 46.054 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 5 Day 1 | 172.00 nanograms per milliliter | — |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 6 Day 1 | 488.50 nanograms per milliliter | Standard Deviation 152.028 |
| Zilurgisertib 100 mg QD | Change From Baseline in Ferritin | CFB at Cycle 7 Day 1 | 971.00 nanograms per milliliter | — |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 4 Day 1 | 875.00 nanograms per milliliter | Standard Deviation 649.85 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | Baseline | 2092.25 nanograms per milliliter | Standard Deviation 1220.166 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 7 Day 1 | 315.33 nanograms per milliliter | Standard Deviation 222.172 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 5 Day 1 | 574.00 nanograms per milliliter | Standard Deviation 394.335 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 3 Day 1 | 532.00 nanograms per milliliter | Standard Deviation 833.804 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 2 Day 1 | 154.50 nanograms per milliliter | Standard Deviation 453.658 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 6 Day 1 | 347.33 nanograms per milliliter | Standard Deviation 362.417 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 15 | 67.50 nanograms per milliliter | Standard Deviation 140.95 |
| Zilurgisertib 200 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 8 | 203.25 nanograms per milliliter | Standard Deviation 523.789 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 2 Day 1 | -92.87 nanograms per milliliter | Standard Deviation 364.312 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 3 Day 1 | 353.77 nanograms per milliliter | Standard Deviation 314.682 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 8 | -98.83 nanograms per milliliter | Standard Deviation 567.584 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 4 Day 1 | 619.00 nanograms per milliliter | Standard Deviation 275.281 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 7 Day 1 | 507.35 nanograms per milliliter | Standard Deviation 64.559 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 5 Day 1 | 516.10 nanograms per milliliter | Standard Deviation 502.323 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | Baseline | 2034.42 nanograms per milliliter | Standard Deviation 1329.794 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 15 | -109.77 nanograms per milliliter | Standard Deviation 98.223 |
| Zilurgisertib 400 mg QD | Change From Baseline in Ferritin | CFB at Cycle 6 Day 1 | 442.15 nanograms per milliliter | Standard Deviation 264.246 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 4 Day 1 | -153.50 nanograms per milliliter | Standard Deviation 82.731 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 3 Day 1 | -383.00 nanograms per milliliter | Standard Deviation 536.324 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 2 Day 1 | 135.00 nanograms per milliliter | Standard Deviation 200.818 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | Baseline | 1469.00 nanograms per milliliter | Standard Deviation 1191.873 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 15 | -96.00 nanograms per milliliter | Standard Deviation 56.569 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 5 Day 1 | -106.50 nanograms per milliliter | Standard Deviation 211.425 |
| Zilurgisertib 600 mg QD | Change From Baseline in Ferritin | CFB at Cycle 1 Day 8 | -110.00 nanograms per milliliter | Standard Deviation 24.042 |
Secondary
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
Population: Full Analysis Set-MDS. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zilurgisertib 50 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Baseline | 77.7750 grams per liter | Standard Deviation 5.83688 |
| Zilurgisertib 50 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Change from Baseline at end of treatment | -1.7500 grams per liter | Standard Deviation 4.59619 |
| Zilurgisertib 100 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Baseline | 75.7200 grams per liter | Standard Deviation 4.00899 |
| Zilurgisertib 100 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Change from Baseline at end of treatment | 10.1333 grams per liter | Standard Deviation 12.87685 |
| Zilurgisertib 200 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Baseline | 74.9354 grams per liter | Standard Deviation 5.9833 |
| Zilurgisertib 200 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Change from Baseline at end of treatment | 4.0182 grams per liter | Standard Deviation 7.61104 |
| Zilurgisertib 400 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Change from Baseline at end of treatment | 16.9556 grams per liter | Standard Deviation 12.34055 |
| Zilurgisertib 400 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Baseline | 74.6767 grams per liter | Standard Deviation 7.94708 |
| Zilurgisertib 600 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Baseline | 79.4139 grams per liter | Standard Deviation 4.14997 |
| Zilurgisertib 600 mg QD | Change From Baseline in Hemoglobin at the End of Treatment | Change from Baseline at end of treatment | 69.6667 grams per liter | Standard Deviation 10.40833 |
Secondary
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
Population: Pharmacokinetic (PK) Evaluable Population: all participants who received at least 1 dose of zilurgisertib and provided at least 1 postdose plasma sample (1 PK measurement). Only participants with available data were analyzed. One participant who was supposed to receive 100 mg actually received 25 mg from Day 1 to Day 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zilurgisertib 50 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | 79.9 nanomolar | — |
| Zilurgisertib 100 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 15 | 350 nanomolar | Standard Deviation 131 |
| Zilurgisertib 100 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | 181 nanomolar | Standard Deviation 80.4 |
| Zilurgisertib 200 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | 249 nanomolar | Standard Deviation 100 |
| Zilurgisertib 200 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 15 | 636 nanomolar | Standard Deviation 330 |
| Zilurgisertib 400 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | 569 nanomolar | Standard Deviation 291 |
| Zilurgisertib 400 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 15 | 1360 nanomolar | Standard Deviation 613 |
| Zilurgisertib 600 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 15 | 2620 nanomolar | Standard Deviation 4620 |
| Zilurgisertib 600 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | 1950 nanomolar | Standard Deviation 652 |
| Zilurgisertib 600 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 1 | NA nanomolar | — |
| Zilurgisertib 600 mg QD | Cmax of Zilurgisertib | Cycle 1 Day 15 | NA nanomolar | — |
Secondary
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
Population: PK Evaluable Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zilurgisertib 50 mg QD | Ctrough of Zilurgisertib | 214 nanomolar | Standard Deviation 91.8 |
| Zilurgisertib 100 mg QD | Ctrough of Zilurgisertib | 304 nanomolar | Standard Deviation 175 |
| Zilurgisertib 200 mg QD | Ctrough of Zilurgisertib | 619 nanomolar | Standard Deviation 241 |
| Zilurgisertib 400 mg QD | Ctrough of Zilurgisertib | 981 nanomolar | Standard Deviation 3130 |
| Zilurgisertib 600 mg QD | Ctrough of Zilurgisertib | NA nanomolar | — |
Secondary
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
Population: Full Analysis Set-MDS. Participants must have been on treatment for ≥8 consecutive weeks and have discontinued treatment before Week 8. Only participants who were transfusion independent at baseline and had a response were analyzed.
Secondary
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
Population: Full Analysis Set-MDS. Only participants who were transfusion dependent at Baseline and achieved transfusion independence were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zilurgisertib 100 mg QD | 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 | 60 days |
Secondary
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
Population: Full Analysis Set. No participants with MM were enrolled.
Secondary
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
Population: Full Analysis Set-MDS only. Participants with MDS/MPN overlap syndromes were excluded from analysis. The 95% confidence interval was calculated using exact binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Overall Response Rate (ORR) in MDS Participants | 0.0 percentage of participants |
| Zilurgisertib 100 mg QD | Overall Response Rate (ORR) in MDS Participants | 0.0 percentage of participants |
| Zilurgisertib 200 mg QD | Overall Response Rate (ORR) in MDS Participants | 0.0 percentage of participants |
| Zilurgisertib 400 mg QD | Overall Response Rate (ORR) in MDS Participants | 0.0 percentage of participants |
| Zilurgisertib 600 mg QD | Overall Response Rate (ORR) in MDS Participants | 0.0 percentage of participants |
Secondary
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
Population: Pharmacodynamic (PD) Evaluable Population: all participants who received at least 1 dose of zilurgisertib and provided at least 1 plasma/serum sample (1 PD measurement)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zilurgisertib 50 mg QD | Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | -24.53 percent change | Standard Deviation 41.69 |
| Zilurgisertib 100 mg QD | Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | -16.25 percent change | Standard Deviation 47.06 |
| Zilurgisertib 200 mg QD | Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | -11.25 percent change | Standard Deviation 39.97 |
| Zilurgisertib 400 mg QD | Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | -59.02 percent change | Standard Deviation 32.35 |
| Zilurgisertib 600 mg QD | Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | -63.79 percent change | Standard Deviation 44.23 |
Secondary
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
Population: Full Analysis Set-MDS only. Participants with MDS/MPN overlap syndromes were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Percentage of MDS Participants With an Event of Progression or Death | 25.0 percentage of participants |
| Zilurgisertib 100 mg QD | Percentage of MDS Participants With an Event of Progression or Death | 0.0 percentage of participants |
| Zilurgisertib 200 mg QD | Percentage of MDS Participants With an Event of Progression or Death | 0.0 percentage of participants |
| Zilurgisertib 400 mg QD | Percentage of MDS Participants With an Event of Progression or Death | 20.0 percentage of participants |
| Zilurgisertib 600 mg QD | Percentage of MDS Participants With an Event of Progression or Death | 0.0 percentage of participants |
Secondary
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
Population: Full Analysis Set-MDS. Participants must have been on treatment for ≥8 consecutive weeks or discontinued treatment before Week 8. Only participants who were transfusion independent at baseline were analyzed. The 95% confidence interval was calculated using exact binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Percentage of Participants With Anemia Response | 0.0 percentage of participants |
| Zilurgisertib 100 mg QD | Percentage of Participants With Anemia Response | 0.0 percentage of participants |
| Zilurgisertib 200 mg QD | Percentage of Participants With Anemia Response | 0.0 percentage of participants |
| Zilurgisertib 400 mg QD | Percentage of Participants With Anemia Response | 0.0 percentage of participants |
| Zilurgisertib 600 mg QD | Percentage of Participants With Anemia Response | 0.0 percentage of participants |
Secondary
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
Population: Full Analysis Set-MDS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Percentage of Participants With an Event of Leukemia or Death | 25.0 percentage of participants |
| Zilurgisertib 100 mg QD | Percentage of Participants With an Event of Leukemia or Death | 20.0 percentage of participants |
| Zilurgisertib 200 mg QD | Percentage of Participants With an Event of Leukemia or Death | 0.0 percentage of participants |
| Zilurgisertib 400 mg QD | Percentage of Participants With an Event of Leukemia or Death | 20.0 percentage of participants |
| Zilurgisertib 600 mg QD | Percentage of Participants With an Event of Leukemia or Death | 0.0 percentage of participants |
Secondary
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
Population: Full Analysis Set-MDS. Only participants who were transfusion dependent at Baseline were analyzed. The 95% confidence interval was calculated using exact binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zilurgisertib 50 mg QD | Percentage of Participants With RBC-transfusion Independence (TI) | 0.0 percentage of participants |
| Zilurgisertib 100 mg QD | Percentage of Participants With RBC-transfusion Independence (TI) | 100.0 percentage of participants |
| Zilurgisertib 200 mg QD | Percentage of Participants With RBC-transfusion Independence (TI) | 0.0 percentage of participants |
| Zilurgisertib 400 mg QD | Percentage of Participants With RBC-transfusion Independence (TI) | 0.0 percentage of participants |
| Zilurgisertib 600 mg QD | Percentage of Participants With RBC-transfusion Independence (TI) | 0.0 percentage of participants |
Secondary
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
Population: Full Analysis Set. No participants with MM were enrolled.
Secondary
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
Population: Full Analysis Set-MDS. Only participants who were on treatment for at least 78 days were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zilurgisertib 50 mg QD | Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 2.53 RBC units per participant-month | Standard Deviation 1.955 |
| Zilurgisertib 100 mg QD | Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 1.34 RBC units per participant-month | Standard Deviation 0.948 |
| Zilurgisertib 200 mg QD | Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 3.01 RBC units per participant-month | Standard Deviation 2.955 |
| Zilurgisertib 400 mg QD | Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 2.71 RBC units per participant-month | Standard Deviation 2.232 |
| Zilurgisertib 600 mg QD | Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24 | 1.19 RBC units per participant-month | Standard Deviation 2.067 |
Secondary
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
Population: Full Analysis Set-MDS. Participants were included in the mean change from baseline in hemoglobin value analysis if the participant was in the FAS and met both of the following criteria: a. was on treatment for more than 8 weeks; b. had ≥1 valid post-baseline Hgb assessment(s).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zilurgisertib 50 mg QD | The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment | 2.19 grams per liter | Standard Deviation 2.782 |
| Zilurgisertib 100 mg QD | The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment | 9.73 grams per liter | Standard Deviation 2.842 |
| Zilurgisertib 200 mg QD | The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment | 2.51 grams per liter | Standard Deviation 3.681 |
| Zilurgisertib 400 mg QD | The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment | 4.92 grams per liter | Standard Deviation 10.24 |
| Zilurgisertib 600 mg QD | The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment | 6.59 grams per liter | Standard Deviation 4.229 |
Secondary
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
Population: PK Evaluable Population. Only participants with available data were analyzed. One participant who was supposed to receive 100 mg actually received 25 mg from Day 1 to Day 16.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zilurgisertib 50 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | 2.0 hours |
| Zilurgisertib 100 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | 2.0 hours |
| Zilurgisertib 100 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 15 | 2.0 hours |
| Zilurgisertib 200 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | 2.0 hours |
| Zilurgisertib 200 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 15 | 2.0 hours |
| Zilurgisertib 400 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | 3.0 hours |
| Zilurgisertib 400 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 15 | 3.0 hours |
| Zilurgisertib 600 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | 2.0 hours |
| Zilurgisertib 600 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 15 | 2.0 hours |
| Zilurgisertib 600 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 15 | NA hours |
| Zilurgisertib 600 mg QD | Tmax of Zilurgisertib | Cycle 1 Day 1 | NA hours |