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

NCT ID: NCT03465540

Last Updated: 2023-04-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-17
• Study Completion Date: 2019-07-25

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 weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies

Conditions

Multiple Myeloma; Acute Myeloid Leukemia; Non-Hodgkins Lymphoma; Myelodysplastic Syndrome; AML; MDS; NHL

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1A: AMG 397 Dose Escalation

This arm includes subjects with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Part 1B: AMG 397 Dose Escalation

This arm includes subjects with acute myeloid leukemia (AML).

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Part 2A: AMG 397 Monotherapy

This arm includes subjects with AML or myelodysplastic syndrome (MDS).

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Part 2B: AMG 397 Monotherapy

This arm includes subjects with AML in Japan only.

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Part 2C: AMG 397 Monotherapy

This arm includes subjects with MM.

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Part 3A: AMG 397 + Azacitidine Combotherapy

This arm includes subjects MDS.

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Azacitidine

Intervention Type: DRUG

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

Part 3B: AMG 397+ Azacitidine Combotherapy

This arm includes subjects AML.

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Azacitidine

Intervention Type: DRUG

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

Part 3C: AMG 397+ Dexamethasone Combotherapy

This arm includes subjects MM.

Group Type: EXPERIMENTAL

AMG 397

Intervention Type: DRUG

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Dexamethasone

Intervention Type: DRUG

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

Interventions

AMG 397

AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.

Intervention Type: DRUG

Dexamethasone

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

Intervention Type: DRUG

Azacitidine

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

Intervention Type: DRUG

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
• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic Arizona

Phoenix, Arizona, United States

Mayo Clinic Florida

Jacksonville, Florida, United States

University of Kansas Cancer Center

Westwood, Kansas, United States

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University

St Louis, Missouri, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Froedtert and Med College Wisconsin

Milwaukee, Wisconsin, United States

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Institut Paoli Calmettes

Marseille, , France

Institut Gustave Roussy

Villejuif, , France

Alexandra Hospital

Athens, , Greece

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII

Bergamo, , Italy

Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi

Bologna, , Italy

Ogaki Municipal Hospital

Ogaki-shi, Gifu, Japan

Countries

United States; Australia; France; Greece; Italy; Japan

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.amgentrials.com

AmgenTrials clinical trials website

Other Identifiers

20170173

Identifier Type: -

Identifier Source: org_study_id