AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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At least one dose level of AMG 176 will achieve acceptable safety and tolerability in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia

Detailed Description
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This is a Phase 1, first-in-human, multicenter; non-randomized, open-label and dose-exploration study of AMG 176 administered IV in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia The study will be conducted in five parts.

Official Title
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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

Conditions
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Relapsed or Refractory Multiple Myeloma, Relapsed or Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: AMG 176
* Drug: Azacitidine
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: For participants in Japan only: if a participant is younger than 20 years at the time of signing the informed consent form, informed consent must be obtained from both the participant and his/her legal representative (Multiple myeloma [MM] participants) Pathologically documented, multiple myeloma relapsed or refractory disease after at least 2 lines of therapy (MM participants only) Measurable disease per the International Myeloma Working Group response criteria (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. (AML participants only) More than 5% blasts in bone marrow and Circulating white blood cells < 25,000/ul. 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. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, (MM partiicpants only) Satisfactory hematological function without transfusion or growth factor support Life expectancy of > 3 months, in the opinion of the investigator Adequate hepatic function Adequate cardiac function Adequate renal function Female participants of childbearing potential must have a negative serum or urine pregnancy test Other inclusion criteria may apply EXCLUSION CRITERIA: 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 Autologous stem cell transplant less than 90 days prior to study day 1 (MM participants only) MM with Immunoglobulin M subtype (MM participants only) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes syndrome (MM participants only) Existing plasma cell leukemia (MM participants only) Waldenstrom's macroglobulinemia (MM participants only) Amyloidosis Infection requiring intravenous anti-infective treatments within 1 week of study enrollment (day 1) Myocardial infarction within 6 months of enrollment, symptomatic congestive heart failure (New York Heart Association > class II) History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months prior to enrollment 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 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 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 (AML Part 3d only) History of QT prolongation, torsades de pointes, ventricular tachycardia and cardiac arrest History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed upon with medical monitor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 176 - Part 1a<br>Part 1a - Participants with muliple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion for two-consecutive days (QD2) followed by a 5 days break. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);|
| Experimental: AMG 176 - Part 1b<br>Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);|
| Experimental: AMG 176 - Part 3a<br>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 day break. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);|
| Experimental: AMG 176 - Part 3b<br>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. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);|
| Experimental: AMG 176 - Part 3c<br>Part 3c - Participants in Japan only with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);|
| Experimental: AMG 176 - Part 3d<br>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. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);Drug: Itraconazole<br>* Non-investigational product<br>|
| Experimental: AMG 176 - Part 4<br>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, for two-consecutive days (QD2), in combination with azacitidine. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);Drug: Azacitidine<br>* Non-investigational product<br>|
| Experimental: AMG 176 - Part 5<br>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. | Drug: AMG 176<br>* Study Drug<br>* Other names: Study Investigational Product (IP);Drug: Azacitidine<br>* Non-investigational product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Multiple Myeloma (MM) Part 1a Incidence of dose-limiting toxicities (DLTs) | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the maximum tolerated dose (MTD) for two-consecutive days per week dosing schedule (QD2) | Up to 6 months | 
| MM Part 1a Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for QD2 | Up to 18 months | 
| MM Part 1a Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for QD2 | Up to 18 months | 
| MM Part 1a Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for QD2 | Up to 6 months | 
| MM Part 1a Incidence of clinically significant changes in electrocardiograms (ECGs) | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for QD2 | Up to 6 months | 
| MM Part 1a Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for QD2 | Up to 6 months | 
| MM Part 1a Pharmacokinetic (PK) parameters for AMG 176: maximum observed concentration (Cmax) | Evaluate the pharmacokinetics (PK) of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| MM Part 1a Pharmacokinetic parameters for AMG 176: area under the concentration-time curve (AUC) | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| MM Part 1a Pharmacokinetic parameters for AMG 176: clearance (CL) | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| MM Part 1a Pharmacokinetic parameters for AMG 176: half-life (t1/2) | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| MM Part 1b Incidence of DLTs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a once weekly (QW) dosing schedule | Up to 6 months | 
| MM Part 1b Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a QW dosing schedule | Up to 18 months | 
| MM Part 1b Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a QW dosing schedule | Up to 18 months | 
| MM Part 1b Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a QW dosing schedule | Up to 6 months | 
| MM Part 1b Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a QW dosing schedule | Up to 6 months | 
| MM Part 1b Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory MM and determine the MTD for a QW dosing schedule | Up to 6 months | 
| MM Part 1b Pharmacokinetic parameters for AMG 176: Cmax | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| MM Part 1b Pharmacokinetic parameters for AMG 176: AUC | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| MM Part 1b Pharmacokinetic parameters for AMG 176: CL | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| MM Part 1b Pharmacokinetic parameters for AMG 176: t1/2 | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| Acute Myeloid Leukemia (AML) Part 3a Incidence of DLTs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3a Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 3a Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 3a Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3a Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3a Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 monotherapy in subjects with relapsed or refractory AML and determine the MTD for QD2 dosing as a monotherapy in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3a Pharmacokinetic parameters for AMG 176: Cmax | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| AML Part 3a Pharmacokinetic parameters for AMG 176: AUC | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| AML Part 3a Pharmacokinetic parameters for AMG 176: CL | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| AML Part 3a Pharmacokinetic parameters for AMG 176: t1/2 | Evaluate the PK of AMG 176 when administered as monotherapy QD2 | 1 month on treatment | 
| AML Part 3b Incidence of DLTs | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3b Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 3b Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 3b Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3b Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3b Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 monotherapy (QW) in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 3b Pharmacokinetic parameters for AMG 176: Cmax | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| AML Part 3b Pharmacokinetic parameters for AMG 176: AUC | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| AML Part 3b Pharmacokinetic parameters for AMG 176: CL | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| AML Part 3b Pharmacokinetic parameters for AMG 176: t1/2 | Evaluate the PK of AMG 176 when administered as monotherapy QW | 1 month on treatment | 
| AML Part 3c Incidence of DLTs | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 6 months | 
| AML Part 3c Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 18 months | 
| AML Part 3c Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 18 months | 
| AML Part 3c Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 6 months | 
| AML Part 3c Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 6 months | 
| AML Part 3c Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 QW monotherapy in participants in Japan with relapsed or refractory AML | Up to 6 months | 
| AML Part 3c Pharmacokinetic parameters for AMG 176: Cmax | Evaluate the PK of AMG 176 when administered as monotherapy (QW) in Japan | 1 month on treatment | 
| AML Part 3c Pharmacokinetic parameters for AMG 176: AUC | Evaluate the PK of AMG 176 when administered as monotherapy (QW) in Japan | 1 month on treatment | 
| AML Part 3c Pharmacokinetic parameters for AMG 176: CL | Evaluate the PK of AMG 176 when administered as monotherapy (QW) in Japan | 1 month on treatment | 
| AML Part 3c Pharmacokinetic parameters for AMG 176: t1/2 | Evaluate the PK of AMG 176 when administered as monotherapy (QW) in Japan | 1 month on treatment | 
| AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: Cmax | Evaluate the PK of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: AUC | Evaluate the PK of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: CL | Evaluate the PK of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: t1/2 | Evaluate the PK of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 4 Incidence of DLTs | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the maximum tolerated combination dose (MTCD) of AMG 176 in combination with azacitidine | Up to 6 months | 
| AML Part 4 Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the MTCD of AMG 176 in combination with azacitidine | Up to 18 months | 
| AML Part 4 Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the MTCD of AMG 176 in combination with azacitidine | Up to 18 months | 
| AML Part 4 Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the MTCD of AMG 176 in combination with azacitidine | Up to 6 months | 
| AML Part 4 Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the MTCD of AMG 176 in combination with azacitidine | Up to 6 months | 
| AML Part 4 Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML and determine the MTCD of AMG 176 in combination with azacitidine | Up to 6 months | 
| AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: CL | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2 | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 5 Incidence of treatment-related adverse events | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 5 Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML | Up to 18 months | 
| AML Part 5 Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 5 Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 5 Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 in combination with azacitidine in subjects with relapsed or refractory AML | Up to 6 months | 
| AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: CL | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 
| AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2 | Evaluate the PK of AMG 176 and azacitidine when administered in combination | 1 month on treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MM Part 1a Overall response (OR) according to International Myeloma Working Group uniform response criteria (IMWG-URC) for MM subjects | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1a Progression-free survival (PFS) | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1a Time to response | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1a Duration of response (DOR) | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1a BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts | 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 months on treatment | 
| MM Part 1b BAX and caspase 3 expression in circulating monocytes and/or circulating monocyte counts | 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 | 6 months on treatment | 
| MM Part 1b Overall response (OR) according to IMWG-URC for MM subjects | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1b Progression free survival (PFS) | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1b Time to response | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| MM Part 1b Duration of response (DOR) | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM | 6 months on treatment | 
| AML Part 3a, 3b and 3c Overall response (OR) according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017) | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML | 6 months on treatment | 
| AML Part 3a, 3b and 3c Event free survival (EFS) | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML | 6 months on treatment | 
| AML Part 3a, 3b and 3c Time to response | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML | 6 months on treatment | 
| AML Part 3a, 3b and 3c Duration of response (DOR) | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML | 6 months on treatment | 
| AML Part 3d Incidence of treatment-emergent adverse events | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Incidence of clinically significant changes in vital signs | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Incidence of clinically significant changes in ECGs | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 3d Incidence of clinically significant changes in clinical laboratory tests | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML | 3 weeks on treatment | 
| AML Part 4 Overall response (OR) according to the 2017 ELN criteria in AML subjects | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 4 Event free survival (EFS) | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 4 Time to response | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 4 Duration of response (DOR) | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 5 OR according to the 2017 ELN criteria in AML subjects | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 5 EFS | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 5 Time to response | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment | 
| AML Part 5 DOR | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML | 6 months on treatment |