A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid Leukemia
AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia
Tagashira Shuzo
Amgen K.K.
Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo
+81-80-7217-8592
clinicaltrials_japan@amgen.com
Local Contact
Amgen K.K.
Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo
+81-80-7217-8592
clinicaltrials_japan@amgen.com
completed
June. 13, 2016
175
Interventional
Phase 1, First-in-Human, Multicenter, Non-Randomized, Open-label, Parallel Assignment, Dose-escalation study
treatment purpose
1
1. Age >= 18 years old
2. (Multiple myeloma [MM] participants) Pathologically documented, multiple myeloma relapsed or refractory disease after at least 2 lines of therapy
3. (MM participants only) Measurable disease per the International Myeloma Working Group response criteria
4. (Acute myeloid leukemia [AML] participants) AML as defined by the World Health Organization Classification persisting or recurring following one or more treatment courses; and for participants in Japan, determined by the investigator to be not eligible for approved anticancer drug therapy in Japan; EXCEPT acute promyelocytic leukemia.
5. (AML participants only) More than 5% blasts in bone marrow and Circulating white blood cells < 25,000/ul.
6. Must be willing and able to undergo a core bone marrow biopsy (MM participants only) and bone marrow aspirate (MM and AML participants) at screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of <= 2.
8. (MM participants only) Satisfactory hematological function without transfusion or growth factor support
9. Life expectancy of > 3 months, in the opinion of the investigator
10. Adequate hepatic function
11. Adequate cardiac function
12. Adequate renal function
13. Female participants of childbearing potential must have a negative serum or urine pregnancy test
Other Inclusion Criteria May Apply.
1. Previously received an allogeneic stem cell transplant within 6 months OR having received immunosuppressive therapy within the last three months OR having signs or symptoms of acute or chronic graft-versus-host disease
2. Autologous stem cell transplant less than 90 days prior to study day 1
3. (MM participants only) MM with Immunoglobulin M subtype
4. (MM participants only) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes syndrome
5. (MM participants only) Existing plasma cell leukemia
6. (MM participants only) Waldenstrom's macroglobulinemia
7. (MM participants only) Amyloidosis
8. Infection requiring intravenous anti-infective treatments within 1 week of study enrollment (day 1)
9. Myocardial infarction within 6 months of enrollment, symptomatic congestive heart failure (New York Heart Association > class II)
10. History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 Months prior to enrollment
11. Currently receiving treatment in another investigational device or drug study. Other investigational procedures while participating in this study will be allowed if approved by Amgen medical monitor
12. Participants with elevated cardiac troponin above the manufacturer's 99th percentile upper reference limit for ADVIA Centaur XP assay at screening performed by the central laboratory
13. Participants with evidence of recent cardiac injury at screening based on creatine kinase-muscle/brain, N-terminal prohormone of brain natriuretic peptide, and electrocardiogram
Other exclusion Criteria May Apply.
14. (AML Part 3d only) History of QT prolongation, torsades de pointes, ventricular tachycardia and cardiac arrest
15. History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed upon with medical monitor.
18age old over
75age old under
Both
Relapsed or Refractory Multiple Myeloma
Relapsed or Refractory Acute Myeloid Leukemia
investigational material(s)
Generic name etc : AMG 176
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material :
- AMG 176 - Part 1a - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion for two-consecutive days (QD2) followed by a 5 days break.
- AMG 176 - Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
- AMG 176 - Part 3a - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion once a day, for two-consecutive days (QD2) followed by a 5 daybreak.
- AMG 176 - Part 3b - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
- AMG 176 - Part 3c - Participants in Japan only with acute myeloid leukemia (AML) administered AMG 176as an intravenous (IV) infusion, once a week (QW) followed by 6 days break.
- AMG 176 - Part 3d - Participants in the United States with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW), for 3 weeks, in combination with itraconazole.
- AMG 176 - Part 4 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, either once a week (QW) followed by 6 days break, or once a day, fortwo-consecutive days (QD2), in combination with azacytidine.
- AMG 176 - Part 5 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion at the maximum tolerated combination dose from Part 4, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.
safety
pharmacokinetics
other
1. Multiple Myeloma (MM) Part 1a Incidence of Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 6 months ]
2. MM Part 1a Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
3. MM Part 1a Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
4. MM Part 1a Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
5. MM Part 1a Incidence of clinically significant changes in electrocardiograms (ECGs) [ Time Frame: Up to 6 months ]
6. MM Part 1a Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
7. MM Part 1a Pharmacokinetic (PK) parameters for AMG 176: maximum observed concentration (Cmax) [ Time Frame: 1 month on treatment ]
8. MM Part 1a Pharmacokinetic parameters for AMG 176: area under the concentration-time curve (AUC) [ Time Frame: 1 month on treatment ]
9. MM Part 1a Pharmacokinetic parameters for AMG 176: clearance (CL) [ Time Frame: 1 month on treatment ]
10. MM Part 1a Pharmacokinetic parameters for AMG 176: half-life (t1/2) [ Time Frame: 1 month on treatment ]
11. MM Part 1b Incidence of DLTs [ Time Frame: Up to 6 months ]
12. MM Part 1b Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
13. MM Part 1b Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
14. MM Part 1b Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
15. MM Part 1b Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
16. MM Part 1b Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
17. MM Part 1b Pharmacokinetic parameters for AMG 176: Cmax [ Time Frame: 1 month on treatment ]
18. MM Part 1b Pharmacokinetic parameters for AMG 176: AUC [ Time Frame: 1 month on treatment ]
19. MM Part 1b Pharmacokinetic parameters for AMG 176: CL [ Time Frame: 1 month on treatment ]
20. MM Part 1b Pharmacokinetic parameters for AMG 176: t1/2 [ Time Frame: 1 month on treatment ]
21. Acute Myeloid Leukemia (AML) Part 3a Incidence of DLTs [ Time Frame: Up to 6 months ]
22. AML Part 3a Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
23. AML Part 3a Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
24. AML Part 3a Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
25. AML Part 3a Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
26. AML Part 3a Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
27. AML Part 3a Pharmacokinetic parameters for AMG 176: Cmax [ Time Frame: 1 month on treatment ]
28. AML Part 3a Pharmacokinetic parameters for AMG 176: AUC [ Time Frame: 1 month on treatment ]
29. AML Part 3a Pharmacokinetic parameters for AMG 176: CL [ Time Frame: 1 month on treatment ]
30. AML Part 3a Pharmacokinetic parameters for AMG 176: t1/2 [ Time Frame: 1 month on treatment ]
31. AML Part 3b Incidence of DLTs [ Time Frame: Up to 6 months ]
32. AML Part 3b Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
33. AML Part 3b Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
34. AML Part 3b Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
35. AML Part 3b Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
36. AML Part 3b Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
37. AML Part 3b Pharmacokinetic parameters for AMG 176: Cmax [ Time Frame: 1 month on treatment ]
38. AML Part 3b Pharmacokinetic parameters for AMG 176: AUC [ Time Frame: 1 month on treatment ]
39. AML Part 3b Pharmacokinetic parameters for AMG 176: CL [ Time Frame: 1 month on treatment ]
40. AML Part 3b Pharmacokinetic parameters for AMG 176: t1/2 [ Time Frame: 1 month on treatment ]
41. AML Part 3c Incidence of DLTs [ Time Frame: Up to 6 months ]
42. AML Part 3c Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
43. AML Part 3c Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
44. AML Part 3c Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
45. AML Part 3c Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
46. AML Part 3c Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
47. AML Part 3c Pharmacokinetic parameters for AMG 176: Cmax [ Time Frame: 1 month on treatment ]
48. AML Part 3c Pharmacokinetic parameters for AMG 176: AUC [ Time Frame: 1 month on treatment ]
49. AML Part 3c Pharmacokinetic parameters for AMG 176: CL [ Time Frame: 1 month on treatment ]
50. AML Part 3c Pharmacokinetic parameters for AMG 176: t1/2 [ Time Frame: 1 month on treatment ]
51. AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: Cmax [ Time Frame: 3 weeks on treatment ]
52. AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: AUC [ Time Frame: 3 weeks on treatment ]
53. AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: CL [ Time Frame: 3 weeks on treatment ]
54. AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: t1/2 [ Time Frame: 3 weeks on treatment ]
55. AML Part 4 Incidence of DLTs [ Time Frame: Up to 6 months ]
56. AML Part 4 Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
57. AML Part 4 Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
58. AML Part 4 Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
59. AML Part 4 Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
60. AML Part 4 Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
61. AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax [ Time Frame: 1 month on treatment ]
62. AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC [ Time Frame: 1 month on treatment ]
63. AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: CL [ Time Frame: 1 month on treatment ]
64. AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2 [ Time Frame: 1 month on treatment ]
65. AML Part 5 Incidence of treatment-related adverse events [ Time Frame: Up to 18 months ]
66. AML Part 5 Incidence of treatment-emergent adverse events [ Time Frame: Up to 18 months ]
67. AML Part 5 Incidence of clinically significant changes in vital signs [ Time Frame: Up to 6 months ]
68. AML Part 5 Incidence of clinically significant changes in ECGs [ Time Frame: Up to 6 months ]
69. AML Part 5 Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: Up to 6 months ]
70. AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax [ Time Frame: 1 month on treatment ]
71. AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC [ Time Frame: 1 month on treatment ]
72. AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: CL [ Time Frame: 1 month on treatment ]
73. AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2 [ Time Frame: 1 month on treatment ]
efficacy
pharmacodynamics
1. MM Part 1a Overall response (OR) according to International Myeloma Working Group uniform response criteria (IMWG-URC) for MM subjects [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM
2. MM Part 1a progression-free survival (PFS) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM
3. MM Part 1a time to response [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM
4. MM Part 1a duration of response (DOR) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM
5. MM Part 1a BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts [ Time Frame: 6 months on treatment ]
Demonstrate inactivation of myeloid cell leukemia sequence 1 (MCL1) by the increase of active Bcl 2 associated X protein (BAX) and caspase 3 in circulating monocytes and/or the decrease of circulating monocytes in AMG 176 QD2 treated subjects
6. MM Part 1b BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts [ Time Frame: 6 months on treatment ]
Demonstrate inactivation of MCL1 by the increase of active BAX and caspase 3 in circulating monocytes and /or the decrease of circulating monocytes in AMG 176 QW treated subjects
7. MM Part 1b Overall response (OR) according to IMWG-URC for MM subjects [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM
8. MM Part 1b Progression free survival (PFS) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM
9. MM Part 1b Time to response [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM
10. MM Part 1b Duration of response (DOR) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM
11. AML Part 3a, 3b and 3c Overall response (OR) according to the 2017 European Leukemia Net (ELN) criteria (Dohner et al, 2017) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML
12. AML Part 3a, 3b and 3c Event free survival (EFS) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML
13. AML Part 3a, 3b and 3c Time to response [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML
14. AML Part 3a, 3b and 3c Duration of response (DOR) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML
15. AML Part 3d Incidence of treatment-emergent adverse events [ Time Frame: 3 weeks on treatment ]
Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML
16. AML Part 3d Incidence of clinically significant changes in vital signs [ Time Frame: 3 weeks on treatment ]
Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML
17. AML Part 3d Incidence of clinically significant changes in ECGs [ Time Frame: 3 weeks on treatment ]
Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML
18. AML Part 3d Incidence of clinically significant changes in clinical laboratory tests [ Time Frame: 3 weeks on treatment ]
Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML
19. AML Part 4 Overall response (OR) according to the 2017 ELN criteria in AML subjects [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
20. AML Part 4 Event free survival (EFS) [ Time Frame: 6 months on treatment ]
valuate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
21. AML Part 4 time to response [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
22. AML Part 4 Duration of response (DOR) [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
23. AML Part 5 OR according to the 2017 ELN criteria in AML subjects [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
24. AML Part 5 EFS [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
25. AML Part 5 Time to response [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
26. AML Part 5 DOR [ Time Frame: 6 months on treatment ]
Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML
Amgen K.K.
National Hospital Organization Kyushu Cancer Center institutional review board
