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

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

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: AMG 224

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Research Site
• United States
  • California
    • West Hollywood, California, United States, 90069
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.
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.	Drug: AMG 224; Administered as an IV infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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)
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

General 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2015
• Primary Completion (Actual): November 30, 2018
• Study Completion (Actual): April 21, 2022

Study Registration Dates

• First Submitted: September 25, 2015
• First Submitted That Met QC Criteria: September 25, 2015
• First Posted (Estimated): September 28, 2015

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: May 18, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Refractory Multiple Myeloma; Relapsed Multiple Myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: 20130314

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR