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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: AMG 224


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Exploration: AMG 224 Dose A<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose B<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose C<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose D<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose E<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose F<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Exploration: AMG 224 Dose G<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Expansion: AMG 224 Dose H + prior CD38 targeting antibody treatment<br>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<br>* Administered as an IV infusion.<br>|
| Experimental: Dose Expansion: AMG 224 Dose H + no prior CD38 targeting antibody treatment<br>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<br>* Administered as an IV infusion.<br>|

What is the study measuring?
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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 | Cmax of AMG 224 conjugated antibody, total anti-B-cell maturation antigen (anti-BCMA) antibody and 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: Cycles 1-4 (each cycle = 3 weeks): pre-dose and 0 to 336 hours post-dose; Cycles 5 onwards: pre-dose to 37 days post last dose. DM1: Cycles 1-2 only: pre-dose and 0 to 96 hours post-dose. | 
| Minimum Observed Concentration (Cmin) of AMG 224 | Cmin of AMG 224 conjugated antibody, total anti-BCMA antibody and DM1 was measured. | AMG 224: Cycles 1-4 (each cycle = 3 weeks): pre-dose and 0 to 336 hours post-dose; Cycles 5 onwards: pre-dose to 37 days post last dose. DM1: Cycles 1-2 only: pre-dose and 0 to 96 hours post-dose. | 
| Area Under the Concentration-time Curve (AUC) of AMG 224 | AUC of AMG 224 conjugated antibody, total anti-B-cell maturation antigen (anti-BCMA) antibody and DM1 was measured. | AMG 224: Cycles 1-4 (each cycle = 3 weeks): pre-dose and 0 to 336 hours post-dose; Cycles 5 onwards: pre-dose to 37 days post last dose. DM1: Cycles 1-2 only: pre-dose and 0 to 96 hours post-dose. | 
| Clearance (CL) of AMG 224 | CL of AMG 224 conjugated antibody, total anti-B-cell maturation antigen (anti-BCMA) antibody and DM1 was measured. | AMG 224: Cycles 1-4 (each cycle = 3 weeks): pre-dose and 0 to 336 hours post-dose; Cycles 5 onwards: pre-dose to 37 days post last dose. DM1: Cycles 1-2 only: pre-dose and 0 to 96 hours post-dose. | 
| Half-life (t1/2) of AMG 224 | t1/2 of AMG 224 conjugated antibody, total anti-B-cell maturation antigen (anti-BCMA) antibody and DM1 was measured. | AMG 224: Cycles 1-4 (each cycle = 3 weeks): pre-dose and 0 to 336 hours post-dose; Cycles 5 onwards: pre-dose to 37 days post last dose. DM1: Cycles 1-2 only: pre-dose and 0 to 96 hours post-dose. | 
| 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: Stringent Complete Response (sCR): Negative immunofixation on the serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in bone marrow (BM). Normal serum free light chain ratio and absence of clonal cells in BM Very Good Partial Response (PR[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-hour (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 above Progressive Disease (PD): ≥ 25% increase from lowest response value in serum. 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 (up to 37 days after the last dose), where each cycle is 3 weeks | 
| Time To Progression (TTP) According to International Myeloma Working Group Uniform Response Criteria (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. | Day 1 of Cycle 1 to up to the end of study (up to 37 days after the last dose), where each cycle is 3 weeks | 
| Duration of Response (DOR) According to International Myeloma Working Group Uniform Response Criteria (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 per the IMWG-URC for Multiple Myeloma or death or where applicable date of censoring. | Day 1 of Cycle 1 to up to the end of study (up to 37 days after the last dose), where each cycle is 3 weeks | 
| Percentage 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 105 normal cells (as determined by flow cytometry). The percentage of participants who converted to be MRD negative was calculated. | Day 1 of Cycle 1 to up to the end of study (up to 37 days after the last dose), where each cycle is 3 weeks | 
| Number of Participants With an Anti-AMG 224 Antibody Formation |  | Day 1 of Cycle 1 to up to the end of study (up to 37 days after the last dose), where each cycle is 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Relapsed Multiple Myeloma, Refractory Multiple Myeloma