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

NCT02675452 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 201501612015-004777-32
• Study Type: interventional
• Target: 141
• Locations: 5 countries
• Sites: 24

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.

Conditions

Relapsed or Refractory Multiple Myeloma; Relapsed or Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (8)

• Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)

  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.

  Days 1 to 28 of cycle 1 (4 weeks)

• Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)

  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).

  Day 1 cycle 1 to 30 days after the last dose of AMG 176; median treatment duration was 1.2 months

• Maximum Observed Concentration (Cmax) of AMG 176

  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.

  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

• 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])

  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.

  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

• 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])

  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.

  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

• AUC From Time 0 to 168 Hours (AUC0-168) of AMG 176 (Parts 1B, 3 [Cohort 4], 3B, 3C, and 3D)

  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.

  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

• Clearance (CL) of AMG 176

  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.

  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

• Terminal Half-life (t1/2) of AMG 176

  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.

  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

Secondary Outcomes (2)

• 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

• 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

Study Arms (8)

AMG 176 - Part 1a

EXPERIMENTAL

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.

Drug: AMG 176

AMG 176 - Part 1b

EXPERIMENTAL

Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.

Drug: AMG 176

AMG 176 - Part 3a

EXPERIMENTAL

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.

Drug: AMG 176

AMG 176 - Part 3b

EXPERIMENTAL

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.

Drug: AMG 176

AMG 176 - Part 3c

EXPERIMENTAL

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.

Drug: AMG 176

AMG 176 - Part 3d

EXPERIMENTAL

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.

Drug: AMG 176; Drug: Itraconazole

AMG 176 - Part 4

EXPERIMENTAL

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.

Drug: AMG 176; Drug: Azacitidine

AMG 176 - Part 5

EXPERIMENTAL

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.

Drug: AMG 176; Drug: Azacitidine

Interventions

AMG 176 DRUG

Study Drug

Also known as: Study Investigational Product (IP)

AMG 176 - Part 1a; AMG 176 - Part 1b; AMG 176 - Part 3a; AMG 176 - Part 3b; AMG 176 - Part 3c; AMG 176 - Part 3d; AMG 176 - Part 4; AMG 176 - Part 5

Azacitidine DRUG

Non-investigational product

AMG 176 - Part 4; AMG 176 - Part 5

Itraconazole DRUG

Non-investigational product

AMG 176 - Part 3d

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For participants in Japan only: if a participant is younger than 20 years at the time of signing the informed consent form, informed consent must be obtained from both the participant and his/her legal representative
• (Multiple myeloma \[MM\] participants) Pathologically documented, multiple myeloma relapsed or refractory disease after at least 2 lines of therapy
• (MM participants only) Measurable disease per the International Myeloma Working Group response criteria
• (Acute myeloid leukemia \[AML\] participants) AML as defined by the World Health Organization Classification persisting or recurring following one or more treatment courses, and for participants in Japan, determined by the investigator to be not eligible for approved anticancer drug therapy in Japan; EXCEPT acute promyelocytic leukemia.
• (AML participants only) More than 5% blasts in bone marrow and Circulating white blood cells \< 25,000/ul.
• Must be willing and able to undergo a core bone marrow biopsy (MM participants only) and bone marrow aspirate (MM and AML participants) at screening.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2,
• (MM partiicpants only) Satisfactory hematological function without transfusion or growth factor support
• Life expectancy of \> 3 months, in the opinion of the investigator
• Adequate hepatic function
• Adequate cardiac function
• Adequate renal function
• Female participants of childbearing potential must have a negative serum or urine pregnancy test

You may not qualify if:

• Previously received an allogeneic stem cell transplant within 6 months OR having received immunosuppressive therapy within the last three months OR having signs or symptoms of acute or chronic graft-versus-host disease
• Autologous stem cell transplant less than 90 days prior to study day 1
• (MM participants only) MM with Immunoglobulin M subtype
• (MM participants only) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes syndrome
• (MM participants only) Existing plasma cell leukemia
• (MM participants only) Waldenstrom's macroglobulinemia
• (MM participants only) Amyloidosis
• Infection requiring intravenous anti-infective treatments within 1 week of study enrollment (day 1)
• Myocardial infarction within 6 months of enrollment, symptomatic congestive heart failure (New York Heart Association \> class II)
• History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months prior to enrollment
• Currently receiving treatment in another investigational device or drug study. Other investigational procedures while participating in this study will be allowed if approved by Amgen medical monitor
• Participants with elevated cardiac troponin above the manufacturer's 99th percentile upper reference limit for ADVIA Centaur XP assay at screening performed by the central laboratory
• Participants with evidence of recent cardiac injury at screening based on creatine kinase-muscle/brain, N-terminal prohormone of brain natriuretic peptide, and electrocardiogram
• (AML Part 3d only) History of QT prolongation, torsades de pointes, ventricular tachycardia and cardiac arrest
• History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed upon with medical monitor.

Sponsors & Collaborators

• Amgen: lead

Study Sites (24)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

University of California Davis Medical Center

Sacramento, California, 95817, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Northside Hospital

Atlanta, Georgia, 30342, United States

Location

University of Chicago Hospital

Chicago, Illinois, 60637, United States

Location

University Medical Center New Orleans

New Orleans, Louisiana, 70112, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

Location

The Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

The Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 2T9, Canada

Location

University Health Network-Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Universitaetsklinikum der Rheinisch-Westfaelischen Technischen Hochschule Aachen

Aachen, 52074, Germany

Location

Universitaetsklinikum Bonn

Bonn, 53127, Germany

Location

Universitaetsklinikum Ulm

Ulm, 89081, Germany

Location

Universitaetsklinikum Wuerzburg

Würzburg, 97080, Germany

Location

National Hospital Organization Nagoya Medical Center

Nagoya, Aichi-ken, 460-0001, Japan

Location

National Cancer Center Hospital East

Kashiwa-shi, Chiba, 277-8577, Japan

Location

National Hospital Organization Kyushu Cancer Center

Fukuoka, Fukuoka, 811-1395, Japan

Location

National Hospital Organization Okayama Medical Center

Okayama, Okayama-ken, 701-1192, Japan

Location

NTT Medical Center Tokyo

Shinagawa-ku, Tokyo, 141-8625, Japan

Location

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Recurrence; Multiple Myeloma; Leukemia, Myeloid, Acute

Interventions

tapotoclax; Azacitidine; Itraconazole

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Leukemia

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Triazoles; Azoles; Piperazines

Limitations and Caveats

The study was conducted in multiple parts and Part 5 did not enroll any participants due to early termination of the study.

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2015
• First Posted: February 5, 2016
• Study Start: June 13, 2016
• Primary Completion: May 27, 2024
• Study Completion: May 27, 2024
• Last Updated: July 9, 2025
• Results First Posted: July 9, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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 (or other new use) 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.
• 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, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. 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 link below.

Locations

CA (2); AU (3); DE (4); JP (5); US (10)