Clinical trial NCT02675452: AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Relapsed or Refractory Multiple Myeloma
Relapsed or Refractory Acute Myeloid Leukemia
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2016-02-05
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Multiple Myeloma (MM) Part 1a Incidence of dose-limiting toxicities (DLTs)
timeFrame: Up to 6 months
measure: MM Part 1a Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: MM Part 1a Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: MM Part 1a Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: MM Part 1a Incidence of clinically significant changes in electrocardiograms (ECGs)
timeFrame: Up to 6 months
measure: MM Part 1a Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: MM Part 1a Pharmacokinetic (PK) parameters for AMG 176: maximum observed concentration (Cmax)
timeFrame: 1 month on treatment
measure: MM Part 1a Pharmacokinetic parameters for AMG 176: area under the concentration-time curve (AUC)
timeFrame: 1 month on treatment
measure: MM Part 1a Pharmacokinetic parameters for AMG 176: clearance (CL)
timeFrame: 1 month on treatment
measure: MM Part 1a Pharmacokinetic parameters for AMG 176: half-life (t1/2)
timeFrame: 1 month on treatment
measure: MM Part 1b Incidence of DLTs
timeFrame: Up to 6 months
measure: MM Part 1b Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: MM Part 1b Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: MM Part 1b Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: MM Part 1b Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: MM Part 1b Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: MM Part 1b Pharmacokinetic parameters for AMG 176: Cmax
timeFrame: 1 month on treatment
measure: MM Part 1b Pharmacokinetic parameters for AMG 176: AUC
timeFrame: 1 month on treatment
measure: MM Part 1b Pharmacokinetic parameters for AMG 176: CL
timeFrame: 1 month on treatment
measure: MM Part 1b Pharmacokinetic parameters for AMG 176: t1/2
timeFrame: 1 month on treatment
measure: Acute Myeloid Leukemia (AML) Part 3a Incidence of DLTs
timeFrame: Up to 6 months
measure: AML Part 3a Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: AML Part 3a Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: AML Part 3a Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: AML Part 3a Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: AML Part 3a Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: AML Part 3a Pharmacokinetic parameters for AMG 176: Cmax
timeFrame: 1 month on treatment
measure: AML Part 3a Pharmacokinetic parameters for AMG 176: AUC
timeFrame: 1 month on treatment
measure: AML Part 3a Pharmacokinetic parameters for AMG 176: CL
timeFrame: 1 month on treatment
measure: AML Part 3a Pharmacokinetic parameters for AMG 176: t1/2
timeFrame: 1 month on treatment
measure: AML Part 3b Incidence of DLTs
timeFrame: Up to 6 months
measure: AML Part 3b Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: AML Part 3b Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: AML Part 3b Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: AML Part 3b Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: AML Part 3b Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: AML Part 3b Pharmacokinetic parameters for AMG 176: Cmax
timeFrame: 1 month on treatment
measure: AML Part 3b Pharmacokinetic parameters for AMG 176: AUC
timeFrame: 1 month on treatment
measure: AML Part 3b Pharmacokinetic parameters for AMG 176: CL
timeFrame: 1 month on treatment
measure: AML Part 3b Pharmacokinetic parameters for AMG 176: t1/2
timeFrame: 1 month on treatment
measure: AML Part 3c Incidence of DLTs
timeFrame: Up to 6 months
measure: AML Part 3c Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: AML Part 3c Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: AML Part 3c Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: AML Part 3c Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: AML Part 3c Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: AML Part 3c Pharmacokinetic parameters for AMG 176: Cmax
timeFrame: 1 month on treatment
measure: AML Part 3c Pharmacokinetic parameters for AMG 176: AUC
timeFrame: 1 month on treatment
measure: AML Part 3c Pharmacokinetic parameters for AMG 176: CL
timeFrame: 1 month on treatment
measure: AML Part 3c Pharmacokinetic parameters for AMG 176: t1/2
timeFrame: 1 month on treatment
measure: AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: Cmax
timeFrame: 3 weeks on treatment
measure: AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: AUC
timeFrame: 3 weeks on treatment
measure: AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: CL
timeFrame: 3 weeks on treatment
measure: AML Part 3d Pharmacokinetic parameters for AMG 176 and itraconazole: t1/2
timeFrame: 3 weeks on treatment
measure: AML Part 4 Incidence of DLTs
timeFrame: Up to 6 months
measure: AML Part 4 Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: AML Part 4 Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: AML Part 4 Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: AML Part 4 Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: AML Part 4 Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax
timeFrame: 1 month on treatment
measure: AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC
timeFrame: 1 month on treatment
measure: AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: CL
timeFrame: 1 month on treatment
measure: AML Part 4 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2
timeFrame: 1 month on treatment
measure: AML Part 5 Incidence of treatment-related adverse events
timeFrame: Up to 18 months
measure: AML Part 5 Incidence of treatment-emergent adverse events
timeFrame: Up to 18 months
measure: AML Part 5 Incidence of clinically significant changes in vital signs
timeFrame: Up to 6 months
measure: AML Part 5 Incidence of clinically significant changes in ECGs
timeFrame: Up to 6 months
measure: AML Part 5 Incidence of clinically significant changes in clinical laboratory tests
timeFrame: Up to 6 months
measure: AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: Cmax
timeFrame: 1 month on treatment
measure: AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: AUC
timeFrame: 1 month on treatment
measure: AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: CL
timeFrame: 1 month on treatment
measure: AML Part 5 Pharmacokinetic parameters for AMG 176 and azacitidine: t1/2
timeFrame: 1 month on treatment
Secondary outcomes:
measure: MM Part 1a Overall response (OR) according to International Myeloma Working Group uniform response criteria (IMWG-URC) for MM subjects
timeFrame: 6 months on treatment
measure: MM Part 1a Progression-free survival (PFS)
timeFrame: 6 months on treatment
measure: MM Part 1a Time to response
timeFrame: 6 months on treatment
measure: MM Part 1a Duration of response (DOR)
timeFrame: 6 months on treatment
measure: MM Part 1a BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts
timeFrame: 6 months on treatment
measure: MM Part 1b BAX and caspase 3 expression in circulating monocytes and/or circulating monocyte counts
timeFrame: 6 months on treatment
measure: MM Part 1b Overall response (OR) according to IMWG-URC for MM subjects
timeFrame: 6 months on treatment
measure: MM Part 1b Progression free survival (PFS)
timeFrame: 6 months on treatment
measure: MM Part 1b Time to response
timeFrame: 6 months on treatment
measure: MM Part 1b Duration of response (DOR)
timeFrame: 6 months on treatment
measure: AML Part 3a, 3b and 3c Overall response (OR) according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017)
timeFrame: 6 months on treatment
measure: AML Part 3a, 3b and 3c Event free survival (EFS)
timeFrame: 6 months on treatment
measure: AML Part 3a, 3b and 3c Time to response
timeFrame: 6 months on treatment
measure: AML Part 3a, 3b and 3c Duration of response (DOR)
timeFrame: 6 months on treatment
measure: AML Part 3d Incidence of treatment-emergent adverse events
timeFrame: 3 weeks on treatment
measure: AML Part 3d Incidence of clinically significant changes in vital signs
timeFrame: 3 weeks on treatment
measure: AML Part 3d Incidence of clinically significant changes in ECGs
timeFrame: 3 weeks on treatment
measure: AML Part 3d Incidence of clinically significant changes in clinical laboratory tests
timeFrame: 3 weeks on treatment
measure: AML Part 4 Overall response (OR) according to the 2017 ELN criteria in AML subjects
timeFrame: 6 months on treatment
measure: AML Part 4 Event free survival (EFS)
timeFrame: 6 months on treatment
measure: AML Part 4 Time to response
timeFrame: 6 months on treatment
measure: AML Part 4 Duration of response (DOR)
timeFrame: 6 months on treatment
measure: AML Part 5 OR according to the 2017 ELN criteria in AML subjects
timeFrame: 6 months on treatment
measure: AML Part 5 EFS
timeFrame: 6 months on treatment
measure: AML Part 5 Time to response
timeFrame: 6 months on treatment
measure: AML Part 5 DOR
timeFrame: 6 months on treatment
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Cancer Centre
state: Ontario
city: Aachen
country: Germany
facility: Universitaetsklinikum der Rheinisch-Westfaelischen Technischen Hochschule Aachen
city: Bonn
country: Germany
facility: Universitaetsklinikum Bonn
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Nagoya-shi
country: Japan
facility: National Hospital Organization Nagoya Medical Center
state: Aichi
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Fukuoka-shi
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
state: Fukuoka
city: Okayama-shi
country: Japan
facility: National Hospital Organization Okayama Medical Center
state: Okayama
city: Shinagawa-ku
country: Japan
facility: NTT Medical Center Tokyo
state: Tokyo
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: