Chronic Myelomonocytic Leukemia, Higher Risk Myelodysplastic Syndrome
Conditions
Keywords
Higher Risk Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Myelomonocytic Leukemia
Brief summary
The main objective is to assess the safety, tolerability, and efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of azacitidine for the treatment of Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia (HR-MDS/CMML).
Detailed description
This study is a Phase 1 clinical trial designed to assess the safety, tolerability, and efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of azacitidine for the treatment of HR-MDS/CMML. Participants will be treated with intravenous (IV) AMG 176 and IV or subcutaneous (SC) azacitidine.
Interventions
DRUGAMG 176
Administered as an intravenous (IV) infusion.
DRUGAzacitidine
Administered as an IV infusion or subcutaneous (SC) injection.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age \>= 18 years of age * For Part 1, participants have R/R MDS post-HMA failure, defined as prior receipt of 4 cycles of HMA therapy (including but not limited to decitabine, azacitidine, investigational HMAs such as SGI-110, and oral HMAs such as oral decitabine and cedazuridine \[ASTX727\] and oral azacitidine \[CC-486\]) with failure to attain a response or progression of disease or relapse at any time after prior response to HMA therapy a. Note: participants with HR-CMML (CMML-1 or 2 by World Health Organization \[WHO\]) are eligible. Hydroxyurea administration will be allowed on the study to lower the white cell count to \<= 10 000/μL prior to the initiation of therapy * For Part 2, participants will be divided into 2 cohorts: 1. HMA Failure Cohort: participants with R/R MDS post-HMA failure. Participants who have previously received venetoclax are eligible and will be stratified accordingly in the HMA failure cohort; 2. Newly Diagnosed Cohort: Participants with treatment-naïve newly diagnosed HR-MDS (revised International Prognostic Scoring System \[IPSS-R\] score \>3.5) are eligible for enrollment only after all prior cohorts have been completed. Hydroxyurea administration will be allowed on the study to lower the white cell count to \<= 10 000/μL prior to the initiation of therapy. Participants with HR-CMML (CMML-1 or 2 by WHO) are eligible
Exclusion criteria
* Participants with newly diagnosed MDS with Revised International Prognostic Scoring System (IPSS-R) lower-risk category (IPSS-R score \< 3.5) * Participants with CMML-0 by WHO * History of other malignancy within the past 2 years prior to enrollment (with some exceptions as listed in full list of criteria) * Excluded prior and/or concomitant therapies as listed in the full list of criteria * Participants who are fit and deemed eligible by the investigator for intensive salvage therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | Day 1 to day 28 of cycle 1 (each cycle was 28 days) | DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and included the below if considered by the investigator to be related to AMG 176: Grade 3 or higher non-hematological or a Grade 4 hematologic adverse event (AE) during the DLT observation period in Part 1. CTCAE Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 results in death. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 cycle 1 to 30 days after the last dose of AMG 176 or end of study, whichever occurred earlier (cycle length = 28 days). Median treatment duration was 2.7 months | An AE was defined as any untoward medical occurrence in a clinical trial participants. TEAEs were any AE that started on or after receiving the first dose of investigational product and up to 28 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered possibly related to study treatment by the investigator. Any clinically significant changes in electrocardiograms, vital signs, and clinical laboratory tests were recorded as TEAEs. A serious TEAE resulted in death, was immediately life threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response According to the Uniform Response Criteria for MDS/MPN | Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months | A responder was assessed as having CR or PR. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline. |
| Event-free Survival | Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months | — |
| Maximum Plasma Concentration (Cmax) of AMG 176 | Cycle 1: pre-dose, end of infusion (EOI), 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4 | AMG 176 plasma concentrations with values below the limit of quantification were set to zero. Pharmacokinetic (PK) parameters were determined from the time concentration profile using noncompartmental analysis. |
| Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN) | Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months | A responder was assessed as having complete remission (CR) or partial remission (PR). Non-responders had stable disease, progressive disease or were not evaluable. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline. Progression: ≥ 50% reduction from maximum response levels in granulocytes or platelets, and/or reduction in hemoglobin by ≥ 1.5 g/dL in the absence of another explanation; transfusion dependence. |
| Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176 | Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4 | AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis. |
| Terminal Half-life of AMG 176 | Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4 | AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis. |
| Clearance (CL) of AMG 176 | Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4 | AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis. |
| Time to Cmax (Tmax) of AMG 176 | Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4 | AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis. |
| Time to a Response According to the Uniform Response Criteria for MDS/MPN | Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months | A responder was assessed as having CR or PR. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline. |
Countries
United States
Participant flow
Recruitment details
A total of 7 participants with higher risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia were enrolled at a single study center in the United States from November 2022 and the last participant's last visit was in December 2023.
Pre-assignment details
The study was planned to be conducted in 3 parts and was discontinued early after the completion of Part 1A (dose exploration). Part 1B (dose escalation/de-escalation) and Part 3 (dose expansion) were not conducted and did not enroll any participants. Dose level 1 is a low dose and Dose level 2 is a high dose.
Participants by arm
| Arm | Count |
|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Participants received IV AMG 176 at dose level 1 once a week in 28-day cycles. Treatment was planned until disease progression or unacceptable toxicity. | 4 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 Participants received IV AMG 176 at dose level 1 on cycle 1 day 1 and then dose level 2 from cycle 1 day 8 and once a week thereafter (each cycle = 28 days). Treatment was planned until disease progression or unacceptable toxicity. | 3 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Sponsor decision | 1 | 2 |
Baseline characteristics
| Characteristic | Part 1A Dose Exploration: AMG 176 Dose Level 1 | Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 1 / 3 |
| other Total, other adverse events | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 3 / 4 | 2 / 3 |
Outcome results
Primary
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and included the below if considered by the investigator to be related to AMG 176: Grade 3 or higher non-hematological or a Grade 4 hematologic adverse event (AE) during the DLT observation period in Part 1. CTCAE Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 results in death.
Time frame: Day 1 to day 28 of cycle 1 (each cycle was 28 days)
Population: DLT-evaluable participants were those who experienced a DLT during the DLT evaluation period or if they received 75% of the planned doses of AMG 176 and completed the DLT evaluation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a clinical trial participants. TEAEs were any AE that started on or after receiving the first dose of investigational product and up to 28 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered possibly related to study treatment by the investigator. Any clinically significant changes in electrocardiograms, vital signs, and clinical laboratory tests were recorded as TEAEs. A serious TEAE resulted in death, was immediately life threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
Time frame: Day 1 cycle 1 to 30 days after the last dose of AMG 176 or end of study, whichever occurred earlier (cycle length = 28 days). Median treatment duration was 2.7 months
Population: The full analysis set included all enrolled participants who received at least 1 dose of AMG 176.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 4 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any serious TEAE | 3 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any serious TEAE | 2 Participants |
Secondary
Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176
AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Time frame: Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4
Population: The PK analysis set included all participants who received at least 1 dose of AMG 176 and had at least 1 PK sample collected. Participants with data available at each time point are included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176 | Cycle 1 day 1 | 198000 hour*ng/mL | Standard Deviation 148000 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176 | Cycle 1 day 8 | 167000 hour*ng/mL | Standard Deviation 146000 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176 | Cycle 1 day 1 | 75900 hour*ng/mL | Standard Deviation 32000 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Area Under the Plasma Concentration Time Curve From 0 to 168 Hours (AUC168hr) of AMG 176 | Cycle 1 day 8 | 179000 hour*ng/mL | Standard Deviation 85600 |
Secondary
Clearance (CL) of AMG 176
AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Time frame: Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4
Population: The PK analysis set included all participants who received at least 1 dose of AMG 176 and had at least 1 PK sample collected. Participants with data available at each time point are included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Clearance (CL) of AMG 176 | Cycle 1 day 1 | 1300 mL/hour/m^2 | Standard Deviation 1400 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Clearance (CL) of AMG 176 | Cycle 1 day 8 | 1150 mL/hour/m^2 | Standard Deviation 788 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Clearance (CL) of AMG 176 | Cycle 1 day 1 | 1890 mL/hour/m^2 | Standard Deviation 1070 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Clearance (CL) of AMG 176 | Cycle 1 day 8 | 1540 mL/hour/m^2 | Standard Deviation 595 |
Secondary
Duration of Response According to the Uniform Response Criteria for MDS/MPN
A responder was assessed as having CR or PR. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline.
Time frame: Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
Population: The full analysis set included all enrolled participants who received at least 1 dose of AMG 176. No participants were responders.
Secondary
Event-free Survival
Time frame: Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
Population: As pre-specified in Section 10 of the statistical analysis plan, EFS was not analyzed.
Secondary
Maximum Plasma Concentration (Cmax) of AMG 176
AMG 176 plasma concentrations with values below the limit of quantification were set to zero. Pharmacokinetic (PK) parameters were determined from the time concentration profile using noncompartmental analysis.
Time frame: Cycle 1: pre-dose, end of infusion (EOI), 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4
Population: The PK analysis set included all participants who received at least 1 dose of AMG 176 and had at least 1 PK sample collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Maximum Plasma Concentration (Cmax) of AMG 176 | Cycle 1 day 1 | 18600 ng/mL | Standard Deviation 16600 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Maximum Plasma Concentration (Cmax) of AMG 176 | Cycle 1 day 8 | 19500 ng/mL | Standard Deviation 6600 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Maximum Plasma Concentration (Cmax) of AMG 176 | Cycle 1 day 1 | 5650 ng/mL | Standard Deviation 1790 |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Maximum Plasma Concentration (Cmax) of AMG 176 | Cycle 1 day 8 | 14900 ng/mL | Standard Deviation 5060 |
Secondary
Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN)
A responder was assessed as having complete remission (CR) or partial remission (PR). Non-responders had stable disease, progressive disease or were not evaluable. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline. Progression: ≥ 50% reduction from maximum response levels in granulocytes or platelets, and/or reduction in hemoglobin by ≥ 1.5 g/dL in the absence of another explanation; transfusion dependence.
Time frame: Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
Population: The full analysis set included all enrolled participants who received at least 1 dose of AMG 176.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN) | Responders | 0 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN) | Non-responders | 4 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN) | Responders | 0 Participants |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Number of Participants With a Response According to the Uniform Response Criteria for MDS/Myeloproliferative Neoplasm (MPN) | Non-responders | 3 Participants |
Secondary
Terminal Half-life of AMG 176
AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Time frame: Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4
Population: The PK analysis set included all participants who received at least 1 dose of AMG 176 and had at least 1 PK sample collected. Participants with data available at each time point are included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Terminal Half-life of AMG 176 | Cycle 1 day 1 | 27.0 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Terminal Half-life of AMG 176 | Cycle 1 day 8 | 19.7 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Terminal Half-life of AMG 176 | Cycle 1 day 1 | 19.2 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Terminal Half-life of AMG 176 | Cycle 1 day 8 | 21.1 hours |
Secondary
Time to a Response According to the Uniform Response Criteria for MDS/MPN
A responder was assessed as having CR or PR. CR: ≤ 5% myeloblasts with normal maturation of all cell lines and return to normal cellularity; osteomyelofibrosis was absent or equal to mild reticulin fibrosis; resolution of extramedullary disease present before therapy. PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50% but \>5% of cellularity except in cases of MDS/MPN with ≤ 5% blasts at baseline.
Time frame: Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
Population: The full analysis set included all enrolled participants who received at least 1 dose of AMG 176. No participants were responders.
Secondary
Time to Cmax (Tmax) of AMG 176
AMG 176 plasma concentrations with values below the limit of quantification were set to zero. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Time frame: Cycle 1: pre-dose, EOI, 3, 5, 7, 8, 24 hours post-infusion in weeks 1 and 2; pre-dose, EOI, 8 and 24 hours post-infusion in cycle 1 weeks 3 and 4
Population: The PK analysis set included all participants who received at least 1 dose of AMG 176 and had at least 1 PK sample collected.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Time to Cmax (Tmax) of AMG 176 | Cycle 1 day 1 | 2.4 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 | Time to Cmax (Tmax) of AMG 176 | Cycle 1 day 8 | 2.5 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Time to Cmax (Tmax) of AMG 176 | Cycle 1 day 1 | 2.5 hours |
| Part 1A Dose Exploration: AMG 176 Dose Level 1 Then Dose Level 2 | Time to Cmax (Tmax) of AMG 176 | Cycle 1 day 8 | 3.0 hours |