AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia

A Phase 1 Study of AMG 176 as Monotherapy and in Combination With Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia

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).

Study Overview

• Status: Terminated
• Conditions: Chronic Myelomonocytic Leukemia; Higher Risk Myelodysplastic Syndrome
• Intervention / Treatment: Drug: AMG 176; Drug: Azacitidine

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A - AMG 176 Monotherapy (Dose Exploration); Two dose levels of AMG 176 will be tested in Part 1A to find the optimal biological dose/minimum safe biologically effective dose (OBD/MSBED).	Drug: AMG 176; Administered as an intravenous (IV) infusion.
Experimental: Part 1B - AMG 176 and Azacitidine Combination Therapy (Dose Exploration); After the OBD is found in Part 1A, two dose levels of AMG 176 in combination with azacitidine will be tested in Part 1B to find the OBD/MSBED.	Drug: AMG 176; Administered as an intravenous (IV) infusion.; Drug: Azacitidine; Administered as an IV infusion or subcutaneous (SC) injection.
Experimental: Part 2 - AMG 176 and Azacitidine Combination Therapy (Dose Expansion); After the completion of Part 1, the Part 2 dose expansion phase will begin at the OBD/MSBED identified in Part 1. Venetoclax-naïve and venetoclax-exposed R/R HR-MDS participants after HMA failure will be enrolled along with participants with newly diagnosed HR-MDS/CMML.	Drug: AMG 176; Administered as an intravenous (IV) infusion.; Drug: Azacitidine; Administered as an IV infusion or subcutaneous (SC) injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1 to day 28 of cycle 1 (each cycle was 28 days)
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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
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.	Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
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.	Cycle 1 to disease progression or end of study, whichever occurred earlier (cycle length = 28 days). Median time on study was 4.1 months
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	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.	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
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.	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
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.	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
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.	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
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.	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

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2022
• Primary Completion (Actual): December 19, 2023
• Study Completion (Actual): December 19, 2023

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 26, 2022

Study Record Updates

• Last Update Posted (Actual): July 14, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Higher Risk Myelodysplastic Syndrome; Myelomonocytic Leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Precancerous Conditions; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Syndrome; Leukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Preleukemia; Myelodysplastic Syndromes; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Azacitidine
• Other Study ID Numbers: 20200392

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No