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Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML

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 : Active, not recruiting
First Posted : March 14, 2018
Last Update Posted : March 20, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE March 8, 2018
First Posted Date  ICMJE March 14, 2018
Last Update Posted Date March 20, 2020
Actual Study Start Date  ICMJE August 17, 2018
Estimated Primary Completion Date October 16, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2019)
  • Subject incidence of dose limiting toxicity [ Time Frame: Up to 3 years ]
    Number of dose limiting toxicity
  • Incidence of treatment-emergent adverse events, treatment-related adverse events [ Time Frame: Up to 3 years ]
    Number of adverse events
  • Incidence of Clinically-significant changes in vital signs [ Time Frame: Up to 3 years ]
    Number of changes in vital signs
  • Incidence of Clinically significant changes in ECGs [ Time Frame: Up to 3 years ]
    Number of changes in ECGs
  • Incidence of clinically-significant changes in physical examinations [ Time Frame: Up to 3 years ]
    Number of changes in physical examinations
  • Incidence of Clinically significant changes in clinical laboratory tests [ Time Frame: Up to 3 years ]
    Number of changes in clinical laboratory tests
Original Primary Outcome Measures  ICMJE
 (submitted: March 8, 2018)
Subject incidence of dose limiting toxicity [ Time Frame: Up to 3 years ]
Number of dose limiting toxicity
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2019)
  • Objective response rate (ORR) [ Time Frame: Up to 3 years ]
    Objective response rate (ORR)
  • Duration of response [ Time Frame: Up to 3 years ]
    Duration of response
  • Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
    Progression-free survival (PFS)
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    Overall survival (OS)
  • AMG 397 PK parameter of maximum observed concentration [ Time Frame: Up to 3 years ]
    AMG 397 PK parameter of maximum observed concentration
  • PK parameter of time of maximum observed concentration (tmax) [ Time Frame: Up to 3 years ]
    PK parameter of time of maximum observed concentration (tmax)
  • PK parameter of area under the concentration time curve (AUC) [ Time Frame: Up to 3 years ]
    PK parameter of area under the concentration time curve (AUC)
  • PK parameter of clearance (CL) [ Time Frame: Up to 3 years ]
    PK parameter of clearance (CL)
  • PK parameter of half-life (t1/2) [ Time Frame: Up to 3 years ]
    PK parameter of half-life (t1/2)
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML
Official Title  ICMJE 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
Brief Summary Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.
Detailed Description This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once daily for 2 consecutive days followed by 5 days break at a weekly interval, as part of a 28-day treatment cycle in adult subjects with multiple myeloma, non-Hodgkin's lymphoma, and acute myeloid leukemia.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Multiple Myeloma
  • Non-Hodgkin's Lymphoma
  • Acute Myeloid Leukemia
  • AML
  • NHL
  • DLBCL
Intervention  ICMJE Drug: AMG 397
potent and selective inhibitor of protein-protein interactions between myeloid cell leukemia sequence 1 and pro-apoptotic members of the lymphoma/leukemia 2 family
Study Arms  ICMJE Experimental: AMG 397 Treatment
AMG 397 administered orally once daily for 2 consecutive days followed by 5 days break at a weekly interval, as part of a 28-day treatment cycle in adult subjects with selected RR hematological malignancies
Intervention: Drug: AMG 397
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 1, 2019)
24
Original Estimated Enrollment  ICMJE
 (submitted: March 8, 2018)
90
Estimated Study Completion Date  ICMJE October 16, 2022
Estimated Primary Completion Date October 16, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 MM, NHL, or AML and is intolerant to, or considered ineligible for available therapies known to provide clinical benefit.
  • MM subjects only: Measurable disease per the IMWG response criteria, as indicated by one or more of the following: 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
  • NHL subjects only: Radiographically measurable disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its largest dimension
  • AML subjects only: Pathologically confirmed diagnosis of AML as defined by the WHO Classification, More than 5% blasts in bone marrow
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
  • MM and NHL 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 &gt; 8 g/dL
    • Platelet count . 75 X 109/L Note: for MM subjects only: Platelet count . ≥ 50 X 109/L (in subjects where &lt; 50% of bone marrow nucleated cells were plasma cells) OR ≥ 30 X 109/L (in subjects where ≥50% of bone marrow nucleated cells were plasma cells) without transfusion or growth factor support are allowed into the study
  • 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 (TBIL) < 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 an ECHO or MUGA, No clinically significant ECG findings.
  • 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:

  • 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 prior to study day 1
  • Candidates for stem cell transplant should have failed or are not considered eligible for either allogeneic and autologous transplant
  • Myocardial infarction within 6 months of study day 1
  • 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 study day 1
  • Infection requiring intravenous anti-infective treatments within 1 week of study day 1
  • 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
  • Males and females of reproductive potential who are unwilling to practice an acceptable method(s) of effective birth control while on study through 3 months after receiving the last dose of study drug. Acceptable methods of effective birth control include sexual abstinence (males, females); vasectomy; bilateral tubal ligation/occlusion; or a condom with spermicide (men) in combination with barrier methods (diaphragm, cervical cap, or cervical sponge), hormonal birth control or IUD (females)
  • Females who are lactating/breastfeeding or who plan to breastfeed while on study through 3 months after receiving the last dose of study drug
  • Females with a positive pregnancy test or planning to become pregnant while on study through 3 months after receiving the last dose of study drug
  • Males who are unwilling to abstain from sperm donation while on study through 3 months after receiving the last dose of study drug
  • 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
  • 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 cytochrome P450 (CYP) 3A4 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
  • NHL subjects with the following criteria are excluded:

    • CNS lymphoma or evidence of uncontrolled CNS disease
    • Burkitt's lymphoma
    • Lymphoblastic lymphoma
  • AML subjects with any of the following criteria are excluded:

    • Circulating white blood cells &gt; 25,000 /μl. Hydroxyurea to control peripheral blood leukemic cell counts, within 24 hours of study day 1 is permitted.
    • Promyelocitic leukemia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   France,   Greece,   United States
Removed Location Countries Italy
 
Administrative Information
NCT Number  ICMJE NCT03465540
Other Study ID Numbers  ICMJE 20170173
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP