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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Higher Risk Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: AMG 176
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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: 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; 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A - AMG 176 Monotherapy (Dose Exploration)<br>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<br>* Administered as an intravenous (IV) infusion.<br>|
| Experimental: Part 1B - AMG 176 and Azacitidine Combination Therapy (Dose Exploration)<br>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<br>* Administered as an intravenous (IV) infusion.<br>Drug: Azacitidine<br>* Administered as an IV infusion or subcutaneous (SC) injection.<br>|
| Experimental: Part 2 - AMG 176 and Azacitidine Combination Therapy (Dose Expansion)<br>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<br>* Administered as an intravenous (IV) infusion.<br>Drug: Azacitidine<br>* Administered as an IV infusion or subcutaneous (SC) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A and 1B: Number of Participants Who Experience a Dose Limiting Toxicity (DLT) |  | Day 1 to Day 28 | 
| Part 1A and 1B: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) |  | Up to 1.5 years | 
| Part 2: Overall Response Rate (ORR) | As assessed according to the Uniform Response Criteria for Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN). | Up to 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A and Part 1B: Overall Response | As assessed according to the Uniform Response Criteria for MDS/MPN for R/R MDS/CMML participants. | Up to 1.5 years | 
| Part 1A, Part 1B and Part 2: Event-free Survival (EFS) |  | Up to 1.5 years | 
| Part 1A and Part 1B: Time to Response (TTR) |  | Up to 1.5 years | 
| Part 1A, Part 1B and Part 2: Duration of Response (DoR) |  | Up to 1.5 years | 
| Part 1A: Maximum Concentration (Cmax) of AMG 176 when Administered as Monotherapy |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1A: Area Under the Concentration-time Curve (AUC) of AMG 176 when Administered as Monotherapy |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1A: Clearance (CL) of AMG 176 when Administered as Monotherapy |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1A: Half-life (t1/2) of AMG 176 when Administered as Monotherapy |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1B and Part 2: Cmax of AMG 176 when Administered in Combination |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1B and Part 2: AUC of AMG 176 when Administered in Combination |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1B and Part 2: CL of AMG 176 when Administered in Combination |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1B and Part 2: T1/2 of AMG 176 when Administered in Combination |  | Cycle 1 (=23 days) Day 1 and Day 8: Pre-dose and 0.5, 3, 5, 7, 8, 12 (Day 8 only) and 24 hours post-dose. Day 15 and 22: Pre-dose and 0.5, 8 and 24 hours post-dose. Cycle 2-4 (=23 days) Day 1: Pre-dose and 0.5 and 24 hours post-dose | 
| Part 1B and Part 2: Cmax of Azacitidine when Administered in Combination |  | Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose. | 
| Part 1B and Part 2: AUC of Azacitidine when Administered in Combination |  | Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose. | 
| Part 1B and Part 2: CL of Azacitidine when Administered in Combination |  | Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose. | 
| Part 1B and Part 2: T1/2 of Azacitidine when Administered in Combination |  | Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose. | 
| Part 2: Time to Transformation to Acute Myeloid Leukemia (AML) |  | Up to 1.5 years | 
| Part 2: Overall Survival (OS) |  | Up to 1.5 years | 
| Part 2: Time to Next MDS Treatment (TTNT) |  | Up to 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Higher Risk Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Myelomonocytic Leukemia