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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02561962
Registration number
NCT02561962
Ethics application status
Date submitted
25/09/2015
Date registered
28/09/2015
Titles & IDs
Public title
A Phase 1 Study in Subjects With Relapsed or Refractory Multiple Myeloma
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Scientific title
A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects With Relapsed or Refractory Multiple Myeloma
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Secondary ID [1]
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20130314
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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:
Multiple Myeloma
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Condition category
Condition code
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 224
Experimental: Dose Exploration: AMG 224 Dose A - Participants were administered AMG 224 Dose A as an intravenous (IV) infusion once every 3 weeks (Q3W) on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose B - Participants were administered AMG 224 Dose B as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose C - Participants were administered AMG 224 Dose C as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose D - Participants were administered AMG 224 Dose D as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose E - Participants were administered AMG 224 Dose E as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose F - Participants were administered AMG 224 Dose F as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Exploration: AMG 224 Dose G - Participants were administered AMG 224 Dose G as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Expansion: AMG 224 Dose H + prior CD38 targeting antibody treatment - Participants who had prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the maximum tolerated dose \[MTD\] based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Experimental: Dose Expansion: AMG 224 Dose H + no prior CD38 targeting antibody treatment - Participants who had no prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the MTD based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
Treatment: Drugs: AMG 224
Administered as an IV infusion.
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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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Adverse events, including DLTs, were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT was considered as any of the below, if judged by the investigator to be possibly related to AMG 224:
Hematological:
* Grade 4 neutropenia lasting \> 7 days
* Grade 3 or 4 neutropenia with fever \> 38.5°C
* Grade 3 thrombocytopenia with = Grade 2 hemorrhage
* Grade 4 thrombocytopenia lasting \> 7 days
* Grade 3 anemia with symptoms or required intervention
* Grade 4 anemia
* Lymphopenia is not considered a DLT
Non-hematological:
* = Grade 3 nausea, vomiting or diarrhea persisting \> 3 days despite optimal medical support
* Grade 3 fatigue persisting \> 7 days
* = Grade 3 acute kidney injury lasting \> 3 days
* Elevation of aspartate aminotransferase or alanine aminotransferase \>3x to \>8x upper limit of normal (ULT) dependent on criteria
* Total bilirubin \> 3x ULN
Participants meeting the criteria for Hy's Law case were considered to have a DLT.
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Timepoint [1]
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Day 1 to Day 28
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Primary outcome [2]
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Number of Participants With a Treatment-emergent Adverse Event (TEAE)
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Assessment method [2]
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An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant.
TEAEs were any AE that occurred after receiving at least 1 dose of treatment.
Treatment-related TEAEs were those considered related to study treatment by the investigator.
Any clinically significant changes in ECGs, vital signs, physical examination with a neurologic assessment and clinical laboratory tests were recorded as TEAEs.
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Timepoint [2]
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Day 1 of Cycle 1 to up to the end of Cycle 4, where each cycle is 3 weeks; up to 12 weeks.
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Secondary outcome [1]
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Maximum Observed Concentration (Cmax) of AMG 224 Conjugated Antibody, Total Anti-B-cell Maturation Antigen (Anti-BCMA) Antibody, and Total Unconjugated DM1
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Assessment method [1]
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Cmax of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured. DM1 is a semi-synthetic derivative of the ansamycin antibiotic, maytansine conjugated to the non-cleavable linker 4-\[N-maleimidomethyl\] cyclohexane-1-carboxylate conjugated to lysine residues in the antibody (MCC).
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Timepoint [1]
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AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, end of infusion (EOI), 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)
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Secondary outcome [2]
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Minimum Observed Concentration (Cmin) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
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Assessment method [2]
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Cmin of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.
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Timepoint [2]
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AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)
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Secondary outcome [3]
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Area Under the Concentration-time Curve (AUC) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
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Assessment method [3]
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AUC from time zero to 3 weeks (AUC(3 weeks)) was determined for AMG 224 conjugated antibody and total anti-BCMA antibody, and AUC from time zero to 96 hours (AUC(0-96hr)) was determined for DM1.
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Timepoint [3]
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AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycle 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)
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Secondary outcome [4]
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Clearance (CL) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
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Assessment method [4]
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CL of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was determined.
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Timepoint [4]
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AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)
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Secondary outcome [5]
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Terminal Half-life (t1/2,z) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
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Assessment method [5]
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The t1/2,z of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.
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Timepoint [5]
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AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)
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Secondary outcome [6]
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Best Overall Response (BOR) According to International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
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Assessment method [6]
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BOR was the best observed post baseline disease response per IMWG-URC: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or = 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: = 50% reduction of serum M-protein and 24-h urinary M-protein by = 90% or to \< 200 mg/24-h. Minor Response (MR): 25-49% reduction of serum M-protein and 50-89% in 24-h urinary M-protein, exceeding 200 mg/24-h. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or Progressive Disease (PD). PD: = 25% increase in serum or urine M-component, development of new or increased size of existing bone lesions or soft tissue plasmacytomas, hypercalcemia attributed to the plasma cell proliferative disorder.
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Timepoint [6]
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Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
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Secondary outcome [7]
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Time To Progression (TTP) According to IMWG-URC
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Assessment method [7]
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TTP was the time from the first administration of AMG 224 to the first objective assessment of disease progression as per IMWG-URC or deaths or if applicable date of censoring. The median TTP was estimated using the Kaplan-Meier method
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Timepoint [7]
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Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
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Secondary outcome [8]
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Duration of Response (DOR) According to IMWG-URC
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Assessment method [8]
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DOR was defined as the time between the date of the first observation indicating an objective response as PR (or better) through to the subsequent date of disease progression as classified by the IMWG-URC for Multiple Myeloma or death or where applicable date of censoring. The median DOR was estimated using the Kaplan-Meier method.
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Timepoint [8]
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Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
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Secondary outcome [9]
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Number of Participants With Conversion to Minimal Residual Disease (MRD)-Negativity
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Assessment method [9]
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MRD negative was defined as a tumor load of less than 1 clonal cell in 10\^5 normal cells (as determined by flow cytometry).
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Timepoint [9]
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Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
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Secondary outcome [10]
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Number of Participants With Anti-AMG 224 Antibodies
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Assessment method [10]
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The number of participants who tested positive for pre-existing binding antibodies prior to exposure to AMG 224 and who tested positive for anti-AMG 224 binding antibodies after dosing with AMG 224 are presented. Participants with transient post-baseline results were binding antibody positive post-baseline with a negative or no result at baseline and a negative result at the participant's last timepoint tested.
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Timepoint [10]
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Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
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Eligibility
Key inclusion criteria
- Pathologically documented,multiple myeloma relapsed or refractory progressive disease after at least 3 lines of therapy for multiple myeloma.
Prior therapeutic treatment or regimens must include proteasome inhibitors (e.g. bortezomib) and immunomodulatory drugs (e.g. lenalidomide).
* Willing and able to undergo bone marrow aspirate per protocol (with or without bone marrow biopsy per institutional guidelines).
* Measurable disease per the International Myeloma Working Group (IMWG) response criteria
* Hematological function, as follows, without transfusion support:
* Absolute neutrophil count = 1.0 X 10^9/L,
* Platelet count = 75 X 10^9/L (in patients with < 50% of bone marrow nucleated cells were plasma cells) or = 50 X 10^9/L (in patients with = 50% of bone marrow nucleated cells were plasma cells) without transfusion or growth factor support
* Hemoglobin > 8 g/dL (> 80 g/L)
* Adequate renal and hepatic function
* Left ventricular ejection fraction (LVEF) > 50%
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Minimum age
18
Years
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Maximum age
No limit
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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
* Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study
* Autologous stem cell transplant less than 90 days prior to study day 1
* Multiple myeloma with IgM subtype
* POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome, Plasma cell leukemia, Waldenstrom's macroglobulinemia or Amyloidosis
* Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to study day
* Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II)
* A baseline ECG QTcF > 470 msec
* Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 28 days prior to study day 1
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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
Other
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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
Completed
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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
20/11/2015
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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
21/04/2022
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Sample size
Target
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Accrual to date
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Final
42
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Research Site - Prahran
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Recruitment postcode(s) [1]
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3181 - Prahran
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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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Country [2]
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United States of America
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State/province [2]
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Massachusetts
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Country [3]
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United States of America
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State/province [3]
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New York
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Country [4]
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United States of America
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State/province [4]
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Texas
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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
This is a first in human phase 1 multicenter open label study in subjects with relapsed or refractory multiple myeloma.
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Trial website
https://clinicaltrials.gov/study/NCT02561962
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Trial related presentations / publications
Lee HC, Raje NS, Landgren O, Upreti VV, Wang J, Avilion AA, Hu X, Rasmussen E, Ngarmchamnanrith G, Fujii H, Spencer A. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2021 Jan;35(1):255-258. doi: 10.1038/s41375-020-0834-9. Epub 2020 Apr 21. No abstract available.
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Public notes
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Contacts
Principal investigator
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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
Name
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Address
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Country
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Fax
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
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When will data be available (start and end dates)?
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.
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Available to whom?
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.
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Available for what types of analyses?
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How or where can data be obtained?
IPD available at link: https://www.amgen.com/datasharing
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/62/NCT02561962/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/62/NCT02561962/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT02561962