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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02675452
Registration number
NCT02675452
Ethics application status
Date submitted
22/12/2015
Date registered
5/02/2016
Date last updated
9/07/2025
Titles & IDs
Public title
AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia
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Scientific title
A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid Leukemia
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Secondary ID [1]
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2015-004777-32
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Secondary ID [2]
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20150161
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Relapsed or Refractory Multiple Myeloma
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Relapsed or Refractory Acute Myeloid Leukemia
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Cancer
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Other cancer types
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - AMG 176
Treatment: Drugs - Azacitidine
Treatment: Drugs - Itraconazole
Experimental: AMG 176 - Part 1a - 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.
Experimental: AMG 176 - Part 1b - Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
Experimental: AMG 176 - Part 3a - 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.
Experimental: AMG 176 - Part 3b - 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.
Experimental: AMG 176 - Part 3c - 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.
Experimental: AMG 176 - Part 3d - 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.
Experimental: AMG 176 - Part 4 - 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.
Experimental: AMG 176 - Part 5 - 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.
Treatment: Drugs: AMG 176
Study Drug
Treatment: Drugs: Azacitidine
Non-investigational product
Treatment: Drugs: Itraconazole
Non-investigational product
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
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Assessment method [1]
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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.
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Timepoint [1]
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Days 1 to 28 of cycle 1 (4 weeks)
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Primary outcome [2]
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Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
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Assessment method [2]
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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).
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Timepoint [2]
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Day 1 cycle 1 to 30 days after the last dose of AMG 176; median treatment duration was 1.2 months
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Primary outcome [3]
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Maximum Observed Concentration (Cmax) of AMG 176
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Assessment method [3]
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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.
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Timepoint [3]
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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
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Primary outcome [4]
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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])
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Assessment method [4]
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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.
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Timepoint [4]
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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
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Primary outcome [5]
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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])
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Assessment method [5]
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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.
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Timepoint [5]
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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
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Primary outcome [6]
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AUC From Time 0 to 168 Hours (AUC0-168) of AMG 176 (Parts 1B, 3 [Cohort 4], 3B, 3C, and 3D)
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Assessment method [6]
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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.
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Timepoint [6]
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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
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Primary outcome [7]
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Clearance (CL) of AMG 176
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Assessment method [7]
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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.
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Timepoint [7]
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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
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Primary outcome [8]
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Terminal Half-life (t1/2) of AMG 176
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Assessment method [8]
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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.
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Timepoint [8]
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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
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Secondary outcome [1]
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Best Overall Response According to Revised International Working Group Uniform Response Criteria (IMWG-URC) for MM Participants (Parts 1A and 1B)
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Assessment method [1]
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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.
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Timepoint [1]
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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
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Secondary outcome [2]
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Best Overall Response According to the 2017 European LeukemiaNet (ELN) Criteria in AML Participants (Parts 3A, 3B, 3C, 3D, and 4)
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Eligibility
Key inclusion criteria
INCLUSION CRITERIA:
* 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
* Other inclusion criteria may apply
EXCLUSION CRITERIA:
* 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
* Other exclusion criteria may apply
* (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.
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Minimum age
18
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Maximum age
85
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Stopped early
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
13/06/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
27/05/2024
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Sample size
Target
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Accrual to date
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Final
141
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Royal North Shore Hospital - St Leonards
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Recruitment hospital [2]
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The Alfred Hospital - Melbourne
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Recruitment hospital [3]
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The Royal Melbourne Hospital - Parkville
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Recruitment postcode(s) [1]
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2065 - St Leonards
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Recruitment postcode(s) [2]
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3004 - Melbourne
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Recruitment postcode(s) [3]
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3050 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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State/province [2]
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Colorado
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United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Louisiana
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United States of America
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Massachusetts
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United States of America
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New Jersey
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United States of America
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Texas
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United States of America
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Utah
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Canada
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Alberta
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Canada
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Ontario
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Germany
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Aachen
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Germany
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State/province [13]
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Bonn
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Germany
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State/province [14]
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Ulm
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Country [15]
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Germany
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State/province [15]
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Wuerzburg
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Country [16]
0
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Japan
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State/province [16]
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Aichi
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Country [17]
0
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Japan
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State/province [17]
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Chiba
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Country [18]
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Japan
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State/province [18]
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Fukuoka
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Country [19]
0
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Japan
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State/province [19]
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Okayama
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Country [20]
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Japan
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State/province [20]
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Tokyo
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Amgen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT02675452
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Country
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Phone
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Fax
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Email
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Contact person for public queries
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Address
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/52/NCT02675452/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/52/NCT02675452/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02675452
Download to PDF