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Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03465540
Recruitment Status : Terminated (Strategic decision given our current development of AMG 176 (a similar MCL-1 inhibitor) that is in clinic, and not because of safety concerns)
First Posted : March 14, 2018
Last Update Posted : March 18, 2021
Sponsor:
Information provided by (Responsible Party):
Amgen

Brief Summary:
Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Acute Myeloid Leukemia Non-Hodgkins Lymphoma Myelodysplastic Syndrome AML MDS NHL Drug: AMG 397 Drug: Dexamethasone Drug: Azacitidine Phase 1

Detailed Description:
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies
Actual Study Start Date : August 17, 2018
Actual Primary Completion Date : August 29, 2019
Actual Study Completion Date : August 29, 2019


Arm Intervention/treatment
Experimental: Part 1A: AMG 397 Dose Escalation
This arm includes subjects with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Experimental: Part 1B: AMG 397 Dose Escalation
This arm includes subjects with acute myeloid leukemia (AML).
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Experimental: Part 2A: AMG 397 Monotherapy
This arm includes subjects with AML or myelodysplastic syndrome (MDS).
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Experimental: Part 2B: AMG 397 Monotherapy
This arm includes subjects with AML in Japan only.
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Experimental: Part 2C: AMG 397 Monotherapy
This arm includes subjects with MM.
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Experimental: Part 3A: AMG 397 + Azacitidine Combotherapy
This arm includes subjects MDS.
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Drug: Azacitidine
Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.

Experimental: Part 3B: AMG 397+ Azacitidine Combotherapy
This arm includes subjects AML.
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Drug: Azacitidine
Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.

Experimental: Part 3C: AMG 397+ Dexamethasone Combotherapy
This arm includes subjects MM.
Drug: AMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Drug: Dexamethasone
Dexamethasone will be administered intravenously (IV) or orally on Days 1, 8, 15, and 22 of each 28-day cycle.




Primary Outcome Measures :
  1. Part 1A: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  2. Part 1A: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  3. Part 1A: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  4. Part 1A: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  5. Part 1A: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  6. Part 1A: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  7. Part 1A: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  8. Part 1B: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  9. Part 1B: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  10. Part 1B: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  11. Part 1B: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  12. Part 1B: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  13. Part 1B: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  14. Part 1B: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  15. Part 2A: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  16. Part 2A: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  17. Part 2A: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  18. Part 2A: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  19. Part 2A: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  20. Part 2A: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  21. Part 2A: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  22. Part 2B: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  23. Part 2B: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  24. Part 2B: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  25. Part 2B: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  26. Part 2B: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  27. Part 2B: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  28. Part 2B: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  29. Part 2B: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  30. Part 2B: Area Under the Concentration-time Curve (AUC) for AMG 397 [ Time Frame: Up to 6 months ]
  31. Part 2B: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  32. Part 2B: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  33. Part 2C: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  34. Part 2C: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  35. Part 2C: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  36. Part 2C: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  37. Part 2C: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  38. Part 2C: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  39. Part 2C: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  40. Part 3A: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  41. Part 3A: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  42. Part 3A: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  43. Part 3A: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  44. Part 3A: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  45. Part 3A: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  46. Part 3A: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  47. Part 3B: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  48. Part 3B: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  49. Part 3B: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  50. Part 3B: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  51. Part 3B: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  52. Part 3B: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  53. Part 3B: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]
  54. Part 3C: Subject Incidence of Dose-Limiting Toxicity [ Time Frame: 28 days ]
  55. Part 3C: Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 19 months ]
  56. Part 3C: Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 19 months ]
  57. Part 3C: Incidence of Clinically Significant Changes in Vital Signs [ Time Frame: Up to 8 months ]
  58. Part 3C: Incidence of Clinically Significant Changes in Physical Examinations [ Time Frame: Up to 8 months ]
  59. Part 3C: Incidence of Clinically Significant Changes in Electrocardiograms (ECGs) [ Time Frame: Up to 8 months ]
  60. Part 3C: Incidence of Clinically Significant Changes in Clinical Laboratory Tests [ Time Frame: Up to 8 months ]

Secondary Outcome Measures :
  1. Part 1A: Objective Response Rate (ORR) for Multiple Myeloma (MM) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).

  2. Part 1A: Objective Response Rate (ORR) for Non-Hodgkin's Lymphoma (HNL) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Lugano Classification.

  3. Part 1A: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  4. Part 1A: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  5. Part 1A: Time to Response [ Time Frame: Up to 19 months ]
  6. Part 1A: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  7. Part 1A: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  8. Part 1A: Time of Maximum Observed Concentration (Tmax) of AMG 397 [ Time Frame: Up to 6 months ]
  9. Part 1A: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  10. Part 1A: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  11. Part 1A: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  12. Part 1B: Objective Response Rate (ORR) for Acute Myeloid Leukemia (AML) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  13. Part 1B: Objective Response Rate (ORR) for Myelodysplastic Syndrome (MDS) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  14. Part 1B: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  15. Part 1B: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  16. Part 1B: Time to Response [ Time Frame: Up to 19 months ]
  17. Part 1B: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  18. Part 1B: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  19. Part 1B: Time of Maximum Observed Concentration (Tmax) of AMG 397 [ Time Frame: Up to 6 months ]
  20. Part 1B: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  21. Part 1B: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  22. Part 1B: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  23. Part 2A: Objective Response Rate (ORR) for Myelodysplastic Syndrome (MDS) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  24. Part 2A: Objective Response Rate (ORR) for Acute Myeloid Leukemia (AML) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  25. Part 2A: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  26. Part 2A: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  27. Part 2A: Time to Response [ Time Frame: Up to 19 months ]
  28. Part 2A: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  29. Part 2A: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  30. Part 2A: Time of Maximum Observed Concentration (Tmax) of AMG 397 [ Time Frame: Up to 6 months ]
  31. Part 2A: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  32. Part 2A: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  33. Part 2A: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  34. Part 2B: Objective Response Rate (ORR) for Acute Myeloid Leukemia (AML) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  35. Part 2B: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  36. Part 2B: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  37. Part 2B: Time to Response [ Time Frame: Up to 19 months ]
  38. Part 2B: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  39. Part 2B: Time of Maximum Observed Concentration (Tmax) of AMG 397 [ Time Frame: Up to 6 months ]
  40. Part 2C: Objective Response Rate (ORR) for Multiple Myeloma (MM) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).

  41. Part 2C: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  42. Part 2C: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  43. Part 2C: Time to Response [ Time Frame: Up to 19 months ]
  44. Part 2C: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  45. Part 2C: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  46. Part 2C: Time of Maximum Observed Concentration (Tmax) of AMG 397 [ Time Frame: Up to 6 months ]
  47. Part 2C: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  48. Part 2C: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  49. Part 2C: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  50. Part 3A: Objective Response Rate (ORR) for Myelodysplastic Syndrome (MDS) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per Revised International Working Group (IWG).

  51. Part 3A: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  52. Part 3A: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  53. Part 3A: Time to Response [ Time Frame: Up to 19 months ]
  54. Part 3A: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  55. Part 3A: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  56. Part 3A: Maximum Observed Concentration (Cmax) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  57. Part 3A: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  58. Part 3A: Area Under the Concentration Time Curve (AUC) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  59. Part 3A: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  60. Part 3A: Clearance (CL) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  61. Part 3A: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  62. Part 3A: Half-life (t1/2) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  63. Part 3B: Objective Response Rate (ORR) for Acute Myeloid Leukemia (AML) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per 2017 European LeukemiaNet (ELN) criteria.

  64. Part 3B: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  65. Part 3B: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  66. Part 3B: Time to Response [ Time Frame: Up to 19 months ]
  67. Part 3B: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  68. Part 3B: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  69. Part 3B: Maximum Observed Concentration (Cmax) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  70. Part 3B: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  71. Part 3B: Area Under the Concentration Time Curve (AUC) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  72. Part 3B: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  73. Part 3B: Clearance (CL) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  74. Part 3B: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  75. Part 3B: Half-life (t1/2) of Azacitidine [ Time Frame: Pre-dose to 8 hours after infusion ]
  76. Part 3C: Objective Response Rate (ORR) for Multiple Myeloma (MM) Subjects [ Time Frame: Up to 19 months ]
    Response criteria per International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).

  77. Part 3C: Progression-free survival (PFS) [ Time Frame: Up to 19 months ]
  78. Part 3C: Overall Survival (OS) [ Time Frame: Up to 19 months ]
  79. Part 3C: Time to Response [ Time Frame: Up to 19 months ]
  80. Part 3C: Duration of Response (DoR) [ Time Frame: Up to 19 months ]
  81. Part 3C: Maximum Observed Concentration (Cmax) of AMG 397 [ Time Frame: Up to 6 months ]
  82. Part 3C: Maximum Observed Concentration (Cmax) of Dexamethasone [ Time Frame: Pre-dose to 48 hours after infusion ]
  83. Part 3C: Area Under the Concentration Time Curve (AUC) of AMG 397 [ Time Frame: Up to 6 months ]
  84. Part 3C: Area Under the Concentration Time Curve (AUC) of Dexamethasone [ Time Frame: Pre-dose to 48 hours after infusion ]
  85. Part 3C: Clearance (CL) of AMG 397 [ Time Frame: Up to 6 months ]
  86. Part 3C: Clearance (CL) of Dexamethasone [ Time Frame: Pre-dose to 48 hours after infusion ]
  87. Part 3C: Half-life (t1/2) of AMG 397 [ Time Frame: Up to 6 months ]
  88. Part 3C: Half-life (t1/2) of Dexamethasone [ Time Frame: Pre-dose to 48 hours after infusion ]


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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject has provided informed consent prior to initiation of any study-specific activities/procedures
  • Age ≥ 18 years old
  • Pathologically-documented, definitively-diagnosed relapsed or refractory multiple myeloma (MM), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) and is intolerant to, or considered ineligible for available therapies known to provide clinical benefit
  • MM subjects only: Measurable disease per the International Myeloma Working Group (IMWG) response criteria (assessed within 21 days prior to enrollment), as indicated by one or more of the following: cytogenic risk factor: 1q21 amplification/gain, serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours. For Subjects who do not meet 1 of the 2 prior criteria: Serum Free Light Chain (sFLC) ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65) as per the IMWG response criteria
  • MM subjects only: Hematological function, as follows without transfusion or growth factor support within 2 weeks prior to study day 1: absolute neutrophil count ≥ 1.0 X 109/L, hemoglobin > 8 g/dL and platelet count ≥ 75 X 109/L
  • AML subjects only: Pathologically confirmed diagnosis of AML as defined by the World Health Organisation (WHO) Classification, more than 5% blasts in bone marrow and persisting or recurring following one or more treatment courses
  • MDS subjects only: pathologically confirmed diagnosis of MDS as defined by the WHO Classification, intermediate and high risk MDS and intolerant or refractory to HMA treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
  • Life expectancy of > 3 months, based on the opinion of the investigator
  • Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption.
  • Hepatic function, as follows:

    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
    • total bilirubin (TBL) < 1.5 X ULN (except subjects with Gilbert's syndrome)
  • Cardiac function, as follows:

    • Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion as determined by echocardiogram or multigated acquisition (MUGA) scan
    • no ECG findings representing a recent cardiac injury within 6 months before enrollment
  • Renal function as follows:

    • Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault [(140 - Age) × Mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female

Exclusion Criteria:

Disease Related

  • Previously received an allogeneic stem cell transplant within 6 months of study day 1 OR having signs or symptoms of acute or chronic graft-versus-host disease
  • Autologous stem cell transplant < 90 days before enrollment
  • Candidates for stem cell transplant should have failed or are not considered eligible for either allogeneic and autologous transplant

Other Medical Conditions

  • History of other malignancy except:

    • Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductal carcinoma in situ without evidence of disease
    • Prostatic intraepithelial neoplasia without evidence of prostate cancer
    • Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
  • Myocardial infarction within 6 months before 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 before enrollment
  • Uncontrollable active infection requiring intravenous anti-infective treatments within 1 week before enrollment
  • Known positive results for human immunodeficiency virus (HIV)
  • Active hepatitis B and C based on the following results: Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic, hepatitis B or recent acute hepatitis B), Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C
  • Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1, or to levels dictated in the eligibility criteria with the exception of grade 2peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 4 weeks prior to study day 1 may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor)
  • Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent or procedures) within 14 days of day 1
  • Prior systemic radiation therapy must have been completed at least 28 days before study day 1. Prior focal radiotherapy completed at 14 days before study day 1
  • Females of reproductive potential who are unwilling to practice acceptable methods of highly effective contraception while on study through 8 months after receiving the last dose of study drug. Males who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with or without spermicide while on study through 5 months after receiving the last dose of study drug if sexually active with a female of childbearing potential
  • Females who are lactating/breastfeeding or who plan to breastfeed while on study through 8 months after receiving the last dose of study drug
  • Females with a positive pregnancy test or planning to become pregnant while on study through 8 months after receiving the last dose of study drug
  • Males who are unwilling to abstain from sperm donation while on study through 8 months after receiving the last dose of study drug
  • History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
  • Use of any over-the-counter or prescription medications within 14 days or 5 half-lives (whichever is longer), prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
  • Use of herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within 14 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
  • Use of any known inhibitors of P-gp within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
  • Use of known CYP3A4 sensitive substrates, (with a narrow therapeutic window), within 14 days or 5 half-lives (whichever is longer) of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
  • Use of known P-gp substrates (with a narrow therapeutic window) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
  • Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, long term follow-up) to the best of the subject and investigator's knowledge
  • Known sensitivity to any of the products or component to be administered during dosing
  • MM subjects with any of the following criteria are excluded:

    • Multiple myeloma with IgM subtype
    • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
    • Existing plasma cell leukemia
    • Waldenstrom's macroglobulinemia
    • Amyloidosis
  • AML subjects with the following criteria are excluded:

    • Circulating white blood cells > 25,000/μl. Hydroxyurea to control peripheral blood leukemic cell counts, within 24 hours of study day 1 is permitted
    • Promyelocytic leukemia
  • AML/MDS subjects fit for intensive salvage therapy
  • Subjects 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 (Covance)
  • Subjects 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 ECG assessments at screening
  • Subjects with MDS that are eligible for hematopoietic stem cell transplant (HSCT)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03465540


Locations
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United States, Alabama
Research Site
Birmingham, Alabama, United States, 35249
United States, Arizona
Research Site
Phoenix, Arizona, United States, 85054
United States, Florida
Research Site
Jacksonville, Florida, United States, 32224
United States, Kansas
Research Site
Fairway, Kansas, United States, 66205
United States, Maryland
Research Site
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02215
United States, Minnesota
Research Site
Rochester, Minnesota, United States, 55905
United States, Missouri
Research Site
Saint Louis, Missouri, United States, 63110
United States, New York
Research Site
Buffalo, New York, United States, 14263
Research Site
New York, New York, United States, 10065
United States, Texas
Research Site
Houston, Texas, United States, 77030-4009
United States, Wisconsin
Research Site
Milwaukee, Wisconsin, United States, 53226
Australia, New South Wales
Research Site
Camperdown, New South Wales, Australia, 02050
Australia, Queensland
Research Site
Woolloongabba, Queensland, Australia, 4102
Australia, Victoria
Research Site
Melbourne, Victoria, Australia, 3004
France
Research Site
Marseille Cedex 09, France, 13272
Research Site
Villejuif, France, 94805
Greece
Research Site
Athens, Greece, 11528
Italy
Research Site
Bergamo, Italy, 24127
Research Site
Bologna, Italy, 40138
Japan
Research Site
Ogaki-shi, Gifu, Japan, 503-8502
Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
Additional Information:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT03465540    
Other Study ID Numbers: 20170173
First Posted: March 14, 2018    Key Record Dates
Last Update Posted: March 18, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amgen:
Multiple Myeloma
Acute Myeloid Leukemia
Myelodysplastic Syndrome
AML
MDS
MM
Myeloid Cell Leukemia 1 Inhibitor
MCL1 Inhibitor
MCL1
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Multiple Myeloma
Preleukemia
Hematologic Neoplasms
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Precancerous Conditions
Neoplasms by Site
Dexamethasone
Azacitidine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs