AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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 Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- 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) [Up to 1.5 years]
As assessed according to the Uniform Response Criteria for Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).
Secondary Outcome Measures
- Part 1A and Part 1B: Overall Response [Up to 1.5 years]
As assessed according to the Uniform Response Criteria for MDS/MPN for R/R MDS/CMML participants.
- 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]
Eligibility Criteria
Criteria
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
- 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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Amgen
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 20200392