Clinical trial NCT05209152: AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia
Official title: A Phase 1 Study of AMG 176 as Monotherapy and in Combination With Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Higher Risk Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Keywords: Higher Risk Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Myelomonocytic Leukemia
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2022-01-26
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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

  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

Primary outcomes:
measure: Part 1A and 1B: Number of Participants Who Experience a Dose Limiting Toxicity (DLT)
timeFrame: Day 1 to Day 28
measure: Part 1A and 1B: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
timeFrame: Up to 1.5 years
measure: Part 2: Overall Response Rate (ORR)
timeFrame: Up to 1.5 years
Secondary outcomes:
measure: Part 1A and Part 1B: Overall Response
timeFrame: Up to 1.5 years
measure: Part 1A, Part 1B and Part 2: Event-free Survival (EFS)
timeFrame: Up to 1.5 years
measure: Part 1A and Part 1B: Time to Response (TTR)
timeFrame: Up to 1.5 years
measure: Part 1A, Part 1B and Part 2: Duration of Response (DoR)
timeFrame: Up to 1.5 years
measure: Part 1A: Maximum Concentration (Cmax) of AMG 176 when Administered as Monotherapy
timeFrame: 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
measure: Part 1A: Area Under the Concentration-time Curve (AUC) of AMG 176 when Administered as Monotherapy
timeFrame: 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
measure: Part 1A: Clearance (CL) of AMG 176 when Administered as Monotherapy
timeFrame: 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
measure: Part 1A: Half-life (t1/2) of AMG 176 when Administered as Monotherapy
timeFrame: 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
measure: Part 1B and Part 2: Cmax of AMG 176 when Administered in Combination
timeFrame: 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
measure: Part 1B and Part 2: AUC of AMG 176 when Administered in Combination
timeFrame: 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
measure: Part 1B and Part 2: CL of AMG 176 when Administered in Combination
timeFrame: 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
measure: Part 1B and Part 2: T1/2 of AMG 176 when Administered in Combination
timeFrame: 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
measure: Part 1B and Part 2: Cmax of Azacitidine when Administered in Combination
timeFrame: Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose.
measure: Part 1B and Part 2: AUC of Azacitidine when Administered in Combination
timeFrame: Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose.
measure: Part 1B and Part 2: CL of Azacitidine when Administered in Combination
timeFrame: Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose.
measure: Part 1B and Part 2: T1/2 of Azacitidine when Administered in Combination
timeFrame: Cycle 1 (=23 days) Day 1: Pre-dose, 5 mins post-dose, 30 mins post-dose, 1, 2, 4, and 8 hours post-dose.
measure: Part 2: Time to Transformation to Acute Myeloid Leukemia (AML)
timeFrame: Up to 1.5 years
measure: Part 2: Overall Survival (OS)
timeFrame: Up to 1.5 years
measure: Part 2: Time to Next MDS Treatment (TTNT)
timeFrame: Up to 1.5 years
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: