Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

All Drugs and Chemicals

Antibodies

Immunoglobulins

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.

Participants were administered AMG 224 Dose B as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Participants were administered AMG 224 Dose C as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Participants were administered AMG 224 Dose D as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Participants were administered AMG 224 Dose E as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Participants were administered AMG 224 Dose F as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Participants were administered AMG 224 Dose G as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

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.

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.

AMG 224

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

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.

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

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

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.

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.

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).

Cmin of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.

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.

CL of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was determined.

The t1/2,z of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.

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.

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

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.

MRD negative was defined as a tumor load of less than 1 clonal cell in 10\^5 normal cells (as determined by flow cytometry).

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.

Amgen

Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.

Participants were administered AMG 224 Dose A as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Dose Exploration: AMG 224 Dose A

Dose Exploration: AMG 224 Dose B

Dose Exploration: AMG 224 Dose C

Participants were administered AMG 224 Dose D as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks

Dose Exploration: AMG 224 Dose D

Dose Exploration: AMG 224 Dose E

Dose Exploration: AMG 224 Dose F

Participants were administered AMG 224 Dose G as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks

Dose Exploration: AMG 224 Dose G

Participants who had prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the maximum tolerated dose \[MTD\] identified based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Dose Expansion: AMG 224 Dose H + Prior CD38 Targeting Antibody Treatment

Participants who had no prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the MTD identified based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Dose Expansion: AMG 224 Dose H + no Prior CD38 Targeting Antibody Treatment

Participants were administered AMG 224 Dose G as an intravenous (IV) infusion once every 3 weeks (Q3W) on Day 1 of each cycle, where each cycle is 3 weeks.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Safety analysis set: all participants that are enrolled and received at least 1 dose of AMG 224.

Study Director

DLT analysis set: all participants who are DLT evaluable. A participant was not DLT-evaluable if the participant discontinued treatment for any reason other than a DLT prior to completing the first 28 days of AMG 224 treatment or did not receive 2 doses of AMG 224 during the 28-day DLT window.

Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)

TEAE

Treatment-related TEAE

Number of Participants With a Treatment-emergent Adverse Event (TEAE)

AMG 224 Conjugated Antibody after Cycle 1

AMG 224 Conjugated Antibody after Cycle 2

Total Anti-BCMA Antibody after Cycle 1

Total Anti-BCMA Antibody after Cycle 2

DM1 after Cycle 1

DM1 after Cycle 2

All participants in Dose Expansion who had prior treatment or no prior treatment with a CD38-targeting antibody were administered the MTD of AMG 224 identified in the dose escalation as 3 mg/kg. AMG 224 was administered as an intravenous (IV) infusion once every 3 weeks (Q3W) on Day 1 of each cycle, where each cycle is 3 weeks.

Dose Expansion: AMG 224 3 mg/kg

The pharmacokinetic (PK) parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated.

Maximum Observed Concentration (Cmax) of AMG 224 Conjugated Antibody, Total Anti-B-cell Maturation Antigen (Anti-BCMA) Antibody, and Total Unconjugated DM1

The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated.

Minimum Observed Concentration (Cmin) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1

AUC(3weeks): AMG 224 Conjugated Antibody after Cycle 1

AUC(3weeks): AMG 224 Conjugated Antibody after Cycle 2

AUC(3weeks): Total Anti-BCMA Antibody after Cycle 1

AUC(3weeks): Total Anti-BCMA Antibody after Cycle 2

AUC(0-96hr): DM1 after Cycle 1

AUC(0-96hr): DM1 after Cycle 2

The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated. All participants included in the overall number of participants analyzed contributed data to this endpoint.

Area Under the Concentration-time Curve (AUC) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1

Clearance (CL) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1

Terminal Half-life (t1/2,z) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1

VGPR

Progressive disease

Unevaluable

Safety analysis set included all participants who received at least 1 dose of AMG 224.

Best Overall Response (BOR) According to International Myeloma Working Group Uniform Response Criteria (IMWG-URC)

The safety analysis set included all participants who received at least 1 dose of AMG 224.

Spots Global Cancer Trial Database for A Phase 1 Study in Subjects With Relapsed or Refractory Multiple Myeloma

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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