A Phase 1 Study in Subjects With Relapsed or Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02561962
• Other study ID #: 20130314
• Status: Completed
• Phase: Phase 1
• Start date: November 20, 2015
• Est. completion date: April 21, 2022

Study information

• Verified date: May 2023
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a first in human phase 1 multicenter open label study in subjects with relapsed or refractory multiple myeloma.

Description:

This is a first in human phase 1 multicenter open label study to evaluate the safety and tolerability of AMG 224 in subjects with relapsed or refractory multiple myeloma. The study will be conducted in 2 parts. Part 1 is the dose-exploration and part 2 is the dose-expansion. Study medication will be administered once every 3 weeks by intravenous (IV) infusion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: April 21, 2022
• Est. primary completion date: November 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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%

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• AMG 224
Administered as an IV infusion.

Locations

Country	Name	City	State
Australia	Research Site	Prahran	Victoria
United States	Research Site	Boston	Massachusetts
United States	Research Site	Houston	Texas
United States	Research Site	New York	New York
United States	Research Site	West Hollywood	California

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (1)

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. — View Citation

Outcome

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

External Links

•   AmgenTrials clinical trials website