Description:
At least one dose level of AMG 176 will achieve acceptable safety and tolerability in
subjects with relapsed or refractory multiple myeloma and subjects with relapsed or
refractory acute myeloid leukemia
Title
- Brief Title: AMG 176 First in Human Trial in Subjects With Relapsed or Refractory Multiple Myeloma and Subjects 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
Clinical Trial IDs
- ORG STUDY ID:
20150161
- SECONDARY ID:
2015-004777-32
- NCT ID:
NCT02675452
Conditions
- Relapsed or Refractory Multiple Myeloma
- Relapsed or Refractory Acute Myeloid Leukemia
Interventions
Drug | Synonyms | Arms |
---|
AMG 176 | Study Investigational Product (IP) | AMG 176 - Part 1a |
Azacitidine | | AMG 176 - Part 4 |
Itraconazole | | AMG 176 - Part 3d |
Purpose
At least one dose level of AMG 176 will achieve acceptable safety and tolerability in
subjects with relapsed or refractory multiple myeloma and subjects 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 subjects with relapsed or refractory
multiple myeloma and subjects with relapsed or refractory acute myeloid leukemia The study
will be conducted in four parts.
Trial Arms
Name | Type | Description | Interventions |
---|
AMG 176 - Part 1a | Experimental | 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. | |
AMG 176 - Part 1b | Experimental | 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 | Experimental | 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. | |
AMG 176 - Part 3b | Experimental | 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 | Experimental | 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. | |
AMG 176 - Part 3d | Experimental | 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 | Experimental | Part 4 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break, in combination with azacitidine. | |
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 subjects) Pathologically documented, multiple myeloma relapsed or
refractory disease after at least 2 lines of therapy
- (MM subjects only) Measurable disease per the IMWG response criteria
- (Acute myeloid leukemia subjects) AML as defined by the World Health Organization
(WHO) 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 subjects only) More than 5% blasts in bone marrow and Circulating white blood
cells (WBCs) < 25,000/ul.
- Must be willing and able to undergo a core bone marrow biopsy (MM subjects only) and
bone marrow aspirate (MM and AML subjects) at screening.
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2,
- (MM subjects 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 subjects 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 subjects only) Multiple myeloma with IgM subtype
- (MM subjects only) POEMS syndrome
- (MM subjects only) Existing plasma cell leukemia
- (MM subjects only) Waldenstrom's macroglobulinemia
- (MM subjects only) Amyloidosis
- (Acute myeloid leukemia Part 4 only) Presence of advanced malignant hepatic tumors
with baseline albumin < 3 g/dL
- 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 (CK-MB), N-terminal prohormone of brain natriuretic peptide
(NT-pro-BNP), and electrocardiogram (ECG)
- Other exclusion criteria may apply
- (Acute myeloid leukemia Part 3d only) History of QT prolongation, torsades de pointes,
ventricular tachycardia and cardiac arrest
Maximum Eligible Age: | 85 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Multiple Myeloma (MM) Part 1a Incidence of dose-limiting toxicities (DLTs) |
Time Frame: | Up to 6 months |
Safety Issue: | |
Description: | 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) |
Secondary Outcome Measures
Measure: | MM Part 1a BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | 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 |
Measure: | 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 |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1a Progression-free survival (PFS) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1a Time to response |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1a Duration of response (DOR) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QD2 when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1b BAX and caspase 3 expression in circulating monocytes and /or circulating monocyte counts |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | 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 |
Measure: | MM Part 1b Overall response (OR) according to IMWG-URC for MM subjects |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1b Progression free survival (PFS) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1b Time to response |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM |
Measure: | MM Part 1b Duration of response (DOR) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 QW when given as monotherapy in relapsed or refractory MM |
Measure: | AML Part 3a, 3b and 3c Overall response (OR) according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML |
Measure: | AML Part 3a, 3b and 3c Event free survival (EFS) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML |
Measure: | AML Part 3a, 3b and 3c Time to response |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML |
Measure: | AML Part 3a, 3b and 3c Duration of response (DOR) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given as monotherapy in relapsed or refractory AML |
Measure: | AML Part 3d Incidence of treatment-emergent adverse events |
Time Frame: | 3 weeks on treatment |
Safety Issue: | |
Description: | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML |
Measure: | AML Part 3d Incidence of clinically significant changes in vital signs |
Time Frame: | 3 weeks on treatment |
Safety Issue: | |
Description: | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML |
Measure: | AML Part 3d Incidence of clinically significant changes in ECGs |
Time Frame: | 3 weeks on treatment |
Safety Issue: | |
Description: | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML |
Measure: | AML Part 3d Incidence of clinically significant changes in clinical laboratory tests |
Time Frame: | 3 weeks on treatment |
Safety Issue: | |
Description: | Evaluate the safety and tolerability of AMG 176 when given alone and in combination with itraconazole in subjects with AML |
Measure: | AML Part 4 Overall response (OR) according to the 2017 ELN criteria in AML subjects |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML |
Measure: | AML Part 4 Event free survival (EFS) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML |
Measure: | AML Part 4 Time to response |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML |
Measure: | AML Part 4 Duration of response (DOR) |
Time Frame: | 6 months on treatment |
Safety Issue: | |
Description: | Evaluate preliminary efficacy of AMG 176 when given in combination with azacitidine in relapsed or refractory AML |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Amgen |
Last Updated
June 3, 2021