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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
Date last updated
1/02/2024

Titles & IDs
Public title
A Phase 1 Study in Subjects With Relapsed or Refractory Multiple Myeloma
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
Secondary ID [1] 0 0
20130314
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Day 1 to Day 28
Primary outcome [2] 0 0
Number of Participants With a Treatment-emergent Adverse Event (TEAE)
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
Day 1 of Cycle 1 to up to the end of Cycle 4, where each cycle is 3 weeks; up to 12 weeks.
Secondary outcome [1] 0 0
Maximum Observed Concentration (Cmax) of AMG 224 Conjugated Antibody, Total Anti-B-cell Maturation Antigen (Anti-BCMA) Antibody, and Total Unconjugated DM1
Assessment method [1] 0 0
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).
Timepoint [1] 0 0
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)
Secondary outcome [2] 0 0
Minimum Observed Concentration (Cmin) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
Assessment method [2] 0 0
Cmin of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.
Timepoint [2] 0 0
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)
Secondary outcome [3] 0 0
Area Under the Concentration-time Curve (AUC) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
Assessment method [3] 0 0
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.
Timepoint [3] 0 0
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)
Secondary outcome [4] 0 0
Clearance (CL) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
Assessment method [4] 0 0
CL of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was determined.
Timepoint [4] 0 0
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)
Secondary outcome [5] 0 0
Terminal Half-life (t1/2,z) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1
Assessment method [5] 0 0
The t1/2,z of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Best Overall Response (BOR) According to International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
Assessment method [6] 0 0
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.
Timepoint [6] 0 0
Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
Secondary outcome [7] 0 0
Time To Progression (TTP) According to IMWG-URC
Assessment method [7] 0 0
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
Timepoint [7] 0 0
Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
Secondary outcome [8] 0 0
Duration of Response (DOR) According to IMWG-URC
Assessment method [8] 0 0
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.
Timepoint [8] 0 0
Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
Secondary outcome [9] 0 0
Number of Participants With Conversion to Minimal Residual Disease (MRD)-Negativity
Assessment method [9] 0 0
MRD negative was defined as a tumor load of less than 1 clonal cell in 10\^5 normal cells (as determined by flow cytometry).
Timepoint [9] 0 0
Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years
Secondary outcome [10] 0 0
Number of Participants With Anti-AMG 224 Antibodies
Assessment method [10] 0 0
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.
Timepoint [10] 0 0
Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

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%
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/11/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/04/2022
Sample size
Target
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Research Site - Prahran
Recruitment postcode(s) [1] 0 0
3181 - Prahran
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Amgen
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02561962