AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia

Phase 1

Terminated

Conditions: Relapsed or Refractory Multiple Myeloma
Relapsed or Refractory Acute Myeloid Leukemia

Interventions: Drug: AMG 176
Drug: Itraconazole
Drug: Azacitidine

Registration Number: NCT02675452

Lead Sponsor: Amgen

Brief Summary: The main objectives are to evaluate the safety and tolerability of AMG 176 monotherapy in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia.

Detailed Description: This is a Phase 1, first-in-human, multicenter; non-randomized, open-label and dose-exploration study of AMG 176 administered IV in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia The study will be conducted in five parts.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 141

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AMG 176 - Part 1a	AMG 176	Part 1a - Participants with muliple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion for two-consecutive days (QD2) followed by a 5 days break.
AMG 176 - Part 1b	AMG 176	Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
AMG 176 - Part 3b	AMG 176	Part 3b - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
AMG 176 - Part 3d	Itraconazole	Part 3d - Participants in the United States with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW), for 3 weeks, in combination with itraconazole.
AMG 176 - Part 4	Azacitidine	Part 4 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.
AMG 176 - Part 3a	AMG 176	Part 3a - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion once a day, for two-consecutive days (QD2) followed by a 5 day break.
AMG 176 - Part 3c	AMG 176	Part 3c - Participants in Japan only with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
AMG 176 - Part 3d	AMG 176	Part 3d - Participants in the United States with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW), for 3 weeks, in combination with itraconazole.
AMG 176 - Part 4	AMG 176	Part 4 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.
AMG 176 - Part 5	AMG 176	Part 5 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion at the maximum tolerated combination dose from Part 4, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.
AMG 176 - Part 5	Azacitidine	Part 5 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion at the maximum tolerated combination dose from Part 4, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)	Days 1 to 28 of cycle 1 (4 weeks)	A DLT was assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0, and considered by the investigators to be related to AMG 176. A DLT was defined as a grade 3 or higher non-hematological or a grade 4 hematologic adverse event (AE) that occurred during the DLT observation period. CTCAE is graded from grade 1 to 5, with higher grades indicating a worse outcome, and included; grade 1 = mild, grade 2= moderate, grade 3 = severe, grade 4 = life-threatening, and grade 5 = death.
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)	Day 1 cycle 1 to 30 days after the last dose of AMG 176; median treatment duration was 1.2 months	An AE was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was an AE that started on or after the first dose of investigational product (AMG 176) up to 30 days after the end of investigational product. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests were reported as TEAEs. A treatment-related AE was any TEAE that per investigator review had a reasonable possibility of being caused by the investigational product (AMG 176).
Maximum Observed Concentration (Cmax) of AMG 176	Parts 1B, 3B, 3C, 3A (cohort 4) Cycle 1: day 1 pre, end of infusion (EOI), 1, 2, 3, 5, 7 hrs EOI, day 8 pre, EOI; Part 3D also days 9, 15 pre and EOI; Parts 1A, 3 (except cohort 4), 4: also day 2 pre, EOI, 1, 2, 3, 5, 7 hrs EOI, day 9 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of pharmacokinetic (PK) parameters. Concentrations below the lower limit of quantification (LLOQ) of 5.00 ng/mL were set to zero before data analysis.
Area Under the Concentration-time Curve (AUC) From Time 0 to 24 Hours (AUC0-24) of AMG 176 (Parts 1A, 3A [Cohorts 1, 2, and 3], and 4 [Cohorts 5A and 5B])	Parts 1A, 3A and, 4: Cycle 1 day 1 pre, EOI, 1, 2, 3, 5, and 7 hrs EOI, cycle 1 day 8 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.
AUC From Time 0 to 144 Hours (AUC0-144) of AMG 176 (Parts 1A, 3A [Cohorts 1, 2, and 3], and 4 [Cohorts 5A and 5B])	Parts 1A, 3A, and 4: Cycle 1 day 2 pre, EOI, 1, 2, 3, 5, and 7 hrs EOI, cycle 1 day 9 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.
AUC From Time 0 to 168 Hours (AUC0-168) of AMG 176 (Parts 1B, 3 [Cohort 4], 3B, 3C, and 3D)	Parts 1B, 3B, 3C, and 3 (cohort 4): Cycle 1 day 1 pre, EOI, 1, 2, 3, 5, and 7 hrs EOI, cycle 1 day 8 pre, EOI; Part 3d also cycle 1 day 15 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.
Clearance (CL) of AMG 176	Parts 1B, 3B, 3C, 3A (cohort 4) Cycle 1: day 1 pre, EOI, 1, 2, 3, 5, 7 hrs EOI, day 8 pre, EOI; Part 3D also days 9, 15 pre and EOI; Parts 1A, 3 (except cohort 4), 4: also day 2 pre, EOI, 1, 2, 3, 5, 7 hrs EOI, day 9 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis. Clearance was calculated as Dose/ AUC0-144 for Parts 1A, 3A, and 4; and as Dose/AUC0-168 for Parts 1B, 3 (Cohort 4 only) 3B, 3C, and 3D.
Terminal Half-life (t1/2) of AMG 176	Parts 1B, 3B, 3C, 3A (cohort 4) Cycle 1: day 1 pre, EOI, 1, 2, 3, 5, 7 hrs EOI, day 8 pre, EOI; Part 3D also days 9, 15 pre and EOI; Parts 1A, 3 (except cohort 4), 4: also day 2 pre, EOI, 1, 2, 3, 5, 7 hrs EOI, day 9 pre and EOI	Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response According to Revised International Working Group Uniform Response Criteria (IMWG-URC) for MM Participants (Parts 1A and 1B)	Day 1 cycle 1 to end of study; median duration from start of study treatment to end of study for all participants was 2.2 months	A response consisted of any of the following, assessed according to the IMWG-URC: stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minor response (MR), stable disease (SD), or progressive disease (PD) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hrs). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hrs urinary M-protein by ≥ 90% or to \< 200 mg/24-hours; MR: 25-49% reduction in serum M-protein and 50-89% reduction in 24-hr urinary M-protein (\>200 mg/24-hrs); SD: not meeting criteria for CR, VGPR, PR, or PD; PD: ≥ 25% increase in serum or urine M-component, BM plasma cell percentages.
Best Overall Response According to the 2017 European LeukemiaNet (ELN) Criteria in AML Participants (Parts 3A, 3B, 3C, 3D, and 4)	Day 1 cycle 1 to end of study; median duration from start of study treatment to end of study for all participants was 2.2 months	A response was of any of the following, per the ELN criteria: Complete remission (CR) without minimal residual disease (CRMRD-), CR, CR with incomplete hematology recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), SD, PD. CRMRD-: CR with negativity for genetic marker by quantitative reverse transcription (RT-qPCR) or multicolor flow cytometry (MFC); CR: BM blasts \<5% bone marrow, no circulating blasts/ extramedullary disease, ANC \> 1.0 x 10\^9/L, platelets ≥ 100 x 10\^9/L; CRi: CR except for neutropenia (\< 1.0 x 10\^9/L) or thrombocytopenia (\< 100 x 10\^9/L); MLFS: BM blasts \< 5% no blasts with auer rods/extramedullary disease, no hematologic recovery; PR: hematological criteria of CR; decrease BM blast to 5-25%; decrease of BM blast percentage by ≤ 50%; SD: absence of CRMRD-, CR, CRi, PR, MLFS and criteria for PD not met; PD: evidence of increase in BM blast percentage and/or increase of absolute blast count.

Trial Locations

Locations (24): City of Hope National Medical Center
🇺🇸
Duarte, California, United States
University of California Davis Medical Center
🇺🇸
Sacramento, California, United States
University of Colorado
🇺🇸
Aurora, Colorado, United States
Northside Hospital
🇺🇸
Atlanta, Georgia, United States
University of Chicago Hospital
🇺🇸
Chicago, Illinois, United States
University Medical Center New Orleans
🇺🇸
New Orleans, Louisiana, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Utah Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
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City of Hope National Medical Center
🇺🇸Duarte, California, United States