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A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as Continuous Intravenous Infusion in Subjects With Myeloid Malignancies

A Phase 1 Study of AMG 330 in Subjects With Myeloid Malignancies

95

Sex: Group 1: 43 men (55.8%), 34 women (44.2%) Group 2: 4 men (66.7%), 2 women (33.3%) Group 3: 3 men (75.0%), 1 woman (25.0%) Group 4: 3 men (37.5%), 5 women (62.5%) Age, median (range): Group 1: 59.0 years (18 to 80 years) Group 2: 57.5 years (20 to 70 years) Group 3: 63.0 years (58 to 69 years) Group 4: 57.5 years (18 to 77 years) Race: Group 1: 58 subjects (75.3%) white, 12 subjects (15.6%) Asian, 3 subjects (3.9%) black, 2 subjects (2.6%) American Indian or Alaska Native, 1 subject each (1.3%) Native Hawaiian or other Pacific Islander and other Group 2: 3 subjects (50.0%) white, 2 subjects (33.3%) Asian, and 1 subject (16.7%) other Group 3: 3 subjects (75.0%) white, 1 subject (25.0%) Asian Group 4: 5 subjects (62.5%) white, 1 subject each (12.5%) Asian, black, and American Indian or Alaska Native. Ethnicity: Group 1: 66 subjects (85.7%) not Hispanic or Latino, 11 subjects (14.3%) Hispanic or Latino Group 2: 5 subjects (83.3%) not Hispanic or Latino, 1 subject (16.7%) Hispanic or Latino Group 3: 3 subjects (75.0%) not Hispanic or Latino, 1 subject (25.0%) Hispanic or Latino Group 4: 5 subjects (62.5%) not Hispanic or Latino, 3 subjects (37.5%) Hispanic or Latino.

Group 1: In group 1, 77 subjects were enrolled. All 77 subjects received AMG 330 and were included in the Safety Analysis Set. The reasons for study discontinuation were death (9 subjects [11.7%]), withdrawal of consent from study (8 subjects [10.4%]), and decision by sponsor (2 subjects [2.6%]). Group 2: In group 2, 6 subjects were enrolled. All 6 subjects received AMG 330 and were included in the Safety Analysis Set. Of the 6 subjects in group 2, 2 (33.3%) discontinued from the study because of withdrawal of consent from study. Group 3: In group 3, 4 subjects were enrolled. All 4 subjects received AMG 330 and were included in the Safety Analysis Set. Of the 4 subjects in group 3, 1 (25.0%) discontinued from the study because of death. Group 4: In group 4, 8 subjects were enrolled. All 8 subjects received AMG 330 and were included in the Safety Analysis Set. One (12.5%) subject discontinued from the study because of death.

Group 1: All 77 subjects (100%) had at least 1 treatment-emergent adverse event (hereafter referred to as adverse events). The adverse events by preferred term (PT) reported for > 25% of subjects were CRS (77.9%); febrile neutropenia (48.1%); diarrhea and rash (36.4% each); edema peripheral and hypophosphatemia (33.8% each); vomiting and hypomagnesemia (32.5% each); rash maculo-papular (31.2%); nausea (29.9%); hypotension and pruritus (28.6% each); pyrexia, decreased appetite, and hypokalemia (27.3% each). Grade 3 or higher adverse events were reported in 71 subjects (92.2%), while grade 4 or higher adverse events were reported in 41 subjects (53.2%). Fifty subjects (64.9%) had serious adverse events. The serious adverse event by PT reported for > 25% of subjects was CRS (27.3%). During DLT evaluation period, 1 subject (1.7%) reported a DLT in cohort 5 (30 ug/day cIV dose level). The subject incidence of treatment-emergent CRS was 60 subjects (77.9%). Group 2: All 6 subjects (100%) had at least 1 adverse event. The adverse events by PT reported for > 25% of subjects were CRS (100%); rash (66.7%); hypokalemia, hypophosphatemia, nausea, platelet count decreased, diarrhea (50.0% each); and anemia, neutrophil count decreased, white blood cell count decreased, abdominal pain, hiccups, hypoalbuminemia, hypocalcemia, hypomagnesemia, edema peripheral, pruritus, vomiting, and febrile neutropenia (33.3% each). Grade 3 or higher adverse events were reported in 5 subjects (83.3%) while grade 4 or higher adverse events were reported in 3 subjects (50.0%). One subject (16.7%) had serious adverse events. The serious adverse events by PT were abdominal pain, bacteremia, febrile neutropenia, and rash. During DLT evaluation period, 1 subject (20.0%) reported a DLT in cohort 2 (AMG 330 30/240/840 ug/day cIV dose level). Treatment-emergent CRS was reported for 6 subjects (100.0%). Group 3: All 4 subjects (100%) had at least 1 adverse event. The adverse events by PT reported for >= 50% of subjects were CRS, decreased appetite, febrile neutropenia, hypocalcemia, edema peripheral, pruritus, and rash maculo-papular (100.0% each); anemia, back pain, blood fibrinogen decreased, diarrhea, fatigue, hypokalemia, hypomagnesemia, hypophosphatemia, lymphocyte count decreased, nausea, vomiting, white blood cell count decreased (75.0% each); and anxiety, arthralgia, atelectasis, blood creatinine increased, bone pain, dizziness, dysgeusia, fluid retention, hypoalbuminemia, hypoxia, lung infiltration, neuropathy peripheral, oropharyngeal pain, pain in extremity, platelet count decreased, pleural effusion, stomatitis, and transfusion reaction (50.0% each). All 4 subjects (100.0%) had grade 4 or higher adverse events (100.0%). One subject (25.0%) had a serious adverse event. The serious adverse events by PT were Fournier's gangrene, hemolytic anemia, intestinal ischemia, pulmonary edema, and septic shock. No DLTs were reported. Treatment-emergent CRS was reported for 4 subjects (100.0%). Group 4: All 8 subjects (100%) had at least 1 adverse event. The adverse events by PT reported for > 25% of subjects were CRS (100%); pruritus (75.0%); nausea and vomiting (62.5% each); ALT increased, hypomagnesemia, hypotension, edema peripheral (50.0% each); hypokalemia, rash maculo-papular, rash, AST increased, dizziness, fatigue, rash erythematous, headache, blood fibrinogen decreased, decreased appetite, face edema, and fluid retention (37.5% each). Grade 3 or higher adverse events were reported in 7 subjects (87.5%) while grade 4 or higher adverse events were reported in 4 subjects (50.0%). Four subjects (50.0%) had serious adverse events. The serious adverse events by PT were bacteremia, CRS, fall, gastrointestinal hemorrhage, pneumonia, transfusion reaction, acute respiratory failure, cardiac failure congestive, lactic acidosis, optic neuritis, optic neuropathy, and septic shock (1 subject each [12.5%]). No DLTs were reported. Treatment-emergent CRS was reported for 8 subjects (100.0%).

1. Primary Outcome Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) Group 1: During DLT evaluation period, 1 subject (1.7%) reported a grade 4 DLT of CRS in cohort 5 (30 ug/day cIV dose level). This event was considered as related to AMG 330 by the investigator. Group 2: During DLT evaluation period, 1 subject (20.0%) reported a DLT of neutrophil count decreased in cohort 2 (AMG 330 30/240/840 ug/day cIV dose level). This event was considered as related to AMG 330 by the investigator. Group 3: No DLTs were reported. Group 4: No DLTs were reported. 2. Secondary Outcome Number of Participants Who Experienced an Incident of Anti-AMG 330 Antibody Formation Blood samples were collected at time points outlined in the schedule of assessments for the measurement of anti-AMG 330 binding antibodies from subjects who received AMG 330. Ninety-four subjects (groups 1 to 4) were tested for the presence of anti-AMG 330 antibodies during the study. Of the 83 subjects with postbaseline results, 7 subjects (8.4%) developed anti-AMG 330 antibodies after administration of AMG 330, including 3 from group 1 (3/70; 4.3%; 1 from cohorts 3, 7, 12 each), 1 from group 2 (1/3; 33.3%; from cohort 2), 2 from group 3 (2/3; 66.7%; both from cohort 1), and 1 from group 4 (1/7; 14.3%). The antibody response for all of the 7 anti-AMG 330 antibody-positive subjects was not 'transient', with antibody-positive results lasting until the last on-study assessment.

- Among subjects in groups 1 to 4, 8.4% (7 of 83) of subjects developed anti-AMG 330 binding antibodies. - In group 1, the overall response rate (CR/CRi/CRh*/MLFS) was 10.4% (95% CI: 4.6, 19.4). In group 2, the overall response rate (CRMRD-/CRiMRD-) was 16.7% (95% CI: 0.4, 64.1). In group 3, the overall response rate (CR/partial remission/marrow CR) was 25.0% (95% CI: 0.6, 80.6). In group 4, all 6 subjects who were evaluated for best overall response had treatment failure.

Yes

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

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210044

Contact Local

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Contact Local

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

Complete

Aug. 31, 2015

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Informed consent provided
2. 18 years or older
3. Relapsed/refractory AML: AML as defined by the WHO Classification persisting or recurring following one or more treatment courses except promyelocytic leukemia (APML)

1. Active extramedullary AML in testes or central nervous system (CNS)
2. Known hypersensitivity to immunoglobulins or to any other component of the IP formulation (eg, sucrose, captisol, potassium, polysorbate 80, citrate, lysine)
3. Prior malignancy (other than in situ cancer) unless treated with curative intent and without evidence of disease for more than 1 years before screening

Both

Relapsed/Refractory AML, Minimal Residual Disease Positive AML, Myelodysplastic Syndrome

Experimental: Group 1: Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Experimental: Group 2: Minimal Residual Disease Positive (MRD+) AML
Experimental: Group 3: Myelodysplastic syndrome (MDS)
Experimental: Group 4: R/R AML with alternative pretreatment
Experimental: Group 5: R/R AML with alternative dose schedule

0.5 ug/day - 1.6 mg/day cIV infusion administered in cycles from 14 to 28 days.

1. Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) [Time Frame: Day 1 to Day 14]
A participant was not DLT-evaluable if they dropped out before completion of the DLT window (14 days) for reasons other than an adverse event related to study drug or the participant had not received investigational product (IP) treatment for at least 14 days at the target dose for a 3- or 4-week cycle or at least 7 days at a target dose for a 2- week cycle. Furthermore, following drug interruptions, if a participant was unable to complete 2 repeat cycles for reasons other than DLT, the participant was not DLT evaluable.
2. Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) [Time Frame: Day 1 until 30 days after last dose. Median duration of treatment was: Group 1 - 29.0 days; Group 2 - 29.0 days; Group 3 - 49.50 days; Group 4 - 23.50 days]
The severity of TEAEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. The general guideline for assessment ranged from Grade 1 to 5, with higher grades indicating a worse outcome, and included: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 = death.

1. Number of Participants Who Experienced an Incident of Anti-AMG 330 Antibody Formation [Time Frame: Baseline until the end of study, up to approximately 6 months]
Number of participants with a binding anti-body positive result at any timepoint post-baseline who had a negative or no result at baseline.
2. Response Rate in Participants With R/R AML [Time Frame: From first dose of IP (Day 1) until the end of study, up to approximately 6months]
Response for participants with R/R AML was defi ned as the percentage of participants with complete response (CR)/complete remission with incomplete count recovery (CRi)/morphologic leukemia-free state (MLFS) [per modified international working group (IWG) criteria] or complete remission with partial hematologic recovery (CRh).
3. Response Rate in Participants With MRD-positive AML [Time Frame: From first dose of IP (Day 1) until the end of study, up to approximately 6 months]
Response for participants with MRD-positive AML was defined as the percentage of participants with a conversion from MRD+ status with 0.1% threshold to CRMDR- or CRiMD-.
4. Response Rate in Participants With MDS [Time Frame: From first dose of IP (Day 1) until the end of study, up to approximately 6 months]
Response for participants with MDS was defined as the percentage of participants with CR or marrow complete remission per IWG.
5. Duration of Response [Time Frame: From fi rst dose of IP (Day 1) until the end of study, up to approximately 6 months]
Duration of response was defi ned as the interval from the date of the fi rst disease assessment indicating an overall response to the first documented relapse, disease progression, or death due to any cause, whichever occurs first.
6. Time to Response [Time Frame: From fi rst dose of IP (Day 1) until the end of study, up to approximately 6 months]
Time to response was defi ned as the interval from the first administration of AMG 330 to the fi rst documentation of response.
7. Event-free Survival [Time Frame: From fi rst dose of IP (Day 1) until the end of study, up to approximately 6 months]
Event-free survival was defined as the interval from fi rst administration of AMG 330 to the earliest of date of treatment failure, relapse for responders, or death due to any cause.
8. Overall Survival [Time Frame: Baseline until the end of study, up to approximately 6 months]
Overall survival was defi ned as the time from enrollment until death due to any cause.
9. 14 Day Infusion Duration: Terminal Half Life (t1/2 z) of AMG 330 [Time Frame: 14 day infusion duration: Pre-dose to 48 hours from the start of infusion, and days 4, 8, 11, 15, 16 and 22 of Cycle 1 for Group 1 and days 8, 15 and 16 for Group 4 (each cycle was 28 days)]
10. 28 Day Infusion Duration: t1/2 z of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 8, 15, 22, 29, and 30of Cycle 1 (each cycle was 36 days)]
11. 14 Day Infusion Duration: Steady State Serum Concentration After End of Infusion (Css) of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 4, 8, 11, 15, 16 and 22 of Cycle 1 for Group 1 and days 8, 15 and 16 for Group 4 (each cycle was 28days)]
12. 28 Day Infusion Duration: Css After End of Infusion of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 8,15, 22, 29, and 30 of Cycle 1 (each cycle was 36 days)]
13. 14 Day Infusion Duration: Volume of Distribution at Steady State (Vz) of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 4, 8, 11, 15, 16 and 22 of Cycle 1 for Group 1 and days 8, 15 and 16 for Group 4 (each cycle was 28 days)]
14. 28 Day Infusion Duration: Vz of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 8, 15, 22, 29, and 30 ofCycle 1 (each cycle was 36 day)]
15. 14 Day Infusion Duration: Clearance at Steady State (CL) for AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 4, 8, 11, 15, 16 and 22 of Cycle 1 for Group 1 and days 8, 15 and 16 for Group 4 (each cycle was 28 days)]
16. 28 Day Infusion Duration: CL of AMG 330 [Time Frame: Pre-dose to 48 hours from the start of infusion, and days 8, 15, 22, 29, and 30 of Cycle 1 (each cycle was 36 days)]

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July. 28, 2018

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