Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies
Condition: Multiple Myeloma; Acute Myeloid Leukemia; Non-Hodgkins Lymphoma; Myelodysplastic Syndrome; AML; MDS; NHL
MeSH terms: Leukemia; Leukemia, Myeloid; Multiple Myeloma; Leukemia, Myeloid, Acute; Preleukemia; Hematologic Neoplasms; Myelodysplastic Syndromes
Intervention: AMG 397; Dexamethasone; Azacitidine
Intervention description: AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.; Dexamethasone will be administered intravenously (IV) or orally on Days 1, 8, 15, and 22 of each 28-day cycle.; Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.
Intervention MeSH terms: Dexamethasone; Azacitidine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Multiple Myeloma; Acute Myeloid Leukemia; Myelodysplastic Syndrome; AML; MDS; MM; Myeloid Cell Leukemia 1 Inhibitor; MCL1 Inhibitor; MCL1

Summary:

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

Eligibility 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)