Phase I first-in-human study Evaluating the Safety, Tolerability Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as Continuous Intravenous Infusion in Subjects with Relapsed/Refractory Acute Myeloid Leukemia
The goal of this clinical research study is to learn about the safety of giving AMG 330 to patients with acute myeloid leukemia (AML) that is relapsed (has come back) or refractory (has not responded to treatment). Researchers want to learn the highest tolerable dose that can be given. This is the first study using AMG 330 in humans.
Disease Group: Leukemia
Treatment Agent: AMG 330
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Amgen Inc.
Primary Objectives: Evaluate the safety and tolerability of AMG 330 in adult subjects with relapsed/refractory acute myeloid leukemia (AML) Estimate the maximum tolerated dose (MTD) and/or a biologically active dose [eg, recommended phase 2 does (RP2D)] Secondary Objectives: Evaluate the pharmacokinetics (PK) of AMG 330 Determine the formation of anti-AMG 330 antibodies Evaluate the anti-leukemia activity of AMG 330 by evaluating the number and proportion of subjects who respond to treatment with AMG 330. Response is defined as any of the following: complete remission (CR), CR with incomplete recovery (CRi) or morphologic leukemia-gree state (all according to Revised International Working Group [IWG] response criteria) or CR with partial hematologic recovery (CRh*). the duration of response, time to progression, time to response Exploratory Objectives: Evaluate the protein, nucleic acid, and cellular biomarkers in blood and / or bone marrow, as applicable [eg, cytokines, lymphocyte subsets, minimal residual disease (MRD), leukemic stem cells (LSCs)] Evaluate effects of genetic variations in and phenotype of cancer genes, including apoptotic markers on adverse event profile and treatment response Evaluate mechanisms of resistance Evaluate potential measures of clinical benefit including number of blood products transfused and days of antibiotic treatment of infection Evaluate potential effect of AMG 330-mediated cytokine elevation on hepatic CYP3A activity Evaluate the relationship between AMG 330 exposure and response to treatment.
IRB Review and Approval Date: 10/14/2015
Recruitment Status: Open
Projected Accrual: 50
1) Subject has provided informed consent prior to initiation of any
2) Subjects >/= 18 years of age
3) AML as defined by the WHO Classification persisting or recurring following one or more treatment courses except promyelocytic leukemia (APML) and except AML secondary to prior myelodysplastic syndrome. For Germany, additional requirements are outlined in a country specific protocol supplement.
4) More than 5% blasts in bone marrow
5) Eastern Cooperative Oncology Group (ECOG) Performance Status of </= 2
6) Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30mL/min/1.73 m^2
7) Hepatic function as follows: *Aspartate aminotransferase (AST) and Alainine aminotransferase (ALT) </= 3.0 x upper limit of normal (ULN) * Bilirubin </= 1.5 xULN (unless considered due to Gilbert's syndrome or hemolysis)
1) Active extramedullary AML in testes or central nervous system (CNS).
2) Known hypersensitivity to immunoglobulins or to any other component of the IP formulation
3) Prior malignancy (other than in situ cancer) unless treated with curative intent and without evidence of disease for > 2 years before screening
4) Autologous HSCT within six weeks prior to start of AMG 330 treatment
5) Allogeneic HSCT within three months prior to start of AMG 330 treatment
6) History or evidence of cardiovascular risk including any of the following: * History or evidence of clinically significant arrhythmias (ventricular fibrillation, ventricular tachycardia, supraventricular tachycardia, atrial tachycardia/flutter, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, and sick sinus syndrome) Exception: Subjects with controlled atrial fibrillation for > 30 days prior to study day 1 are eligible. Controlled atrial fibrillation is defined as atrial fibrillation with no rapid ventricular response which requires no change in medication/dosage or addition of new medication or hospital admission within 30 days prior to study day 1. * History of acute coronary syndromes (eg, myocardial infarction and unstable angina) and/or coronary angioplasty within 6 months prior to study day 1 * History or evidence of >/= Class II congestive heart failure as defined by New York Heart Association (NYHA)
7) CONTINUATION OF #6: * Chronic hypertension (defined as a systolic blood pressure [SBP] >140 mm Hg and/or diastolic blood pressure [DBP] > 90 mm Hg which cannot be controlled by anti-hypertensive therapy) * Subjects with intra-cardiac defibrillators * Abnormal cardiac valve morphology (>/= grade 2) (subjects with grade 1 abnormalities [ie, mild regurgitation/stenosis] can be entered on study. Subjects with moderate valvular thickening should not be entered on study)
8) History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 3 months
9) Infection requiring intravenous antibiotics within 1 week of study enrollment (day 1)
10) Known positive test for HIV
11) Positive for Hepatitis B
12) Positive for Hepatitis C or Chronic Hepatitis C • Possible exceptions: Acute Hepatitis C and completely cleared of the virus (demonstrated by negative viral load), Chronic Hepatitis C with undetectable viral load defined by sustained virologic response 24 weeks (SVR24) after completion of anti-Hepatitis C treatment.
13) Unresolved toxicities from prior antitumor therapy, defined as not having resolved to CTCAE, version 4.0 grade 1 (with the exception of myelosuppression, eg, neutropenia, anemia, thrombocytopenia), or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior antitumor therapy that are considered irreversible (defined as having been present and stable for > 2 months) which 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
14) Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) of day 1. Exception: hydroxyurea to control peripheral blood leukemic cell counts is allowed until start of IP treatment.
15) Treatment with systemic immune modulators including, but not limited to, nontopical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment (day 1)
16) All herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to receiving the first dose of AMG 330, and continuing use if applicable, will be reviewed by the investigator and the Amgen medical monitor. Written documentation of this review and Amgen acknowledgment is required for subject participation.
17) For subjects in expansion cohort only: Ingestion of any food or drink containing grapefruit or Seville oranges, or St. John´s wort, within 7 days prior to receiving the first dose of AMG 330
18) Prior treatment with a monoclonal antibody or chimeric antigen receptor T cell (CAR-T) infusion for the treatment of AML (CD33 or other target)
19) Prior participation in an investigational study (drug, procedure or device) within 21 days of study day 1
20) Major surgery within 28 days of study day 1 with the exception of biopsy and long line insertion
21) White blood cells (WBC) > 15,000 cells/mcL at screening
22) 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
23) Men and women of reproductive potential who are unwilling to practice a highly effective method(s) of birth control while on study through 1 week (women) or 12 weeks (men), respectively, after receiving the last dose of study drug. Acceptable methods of highly effective birth control include sexual abstinence (men, women); vasectomy; bilateral tubal ligation/occlusion; or a condom with spermicide (men) in combination with hormonal birth control or intrauterine device (IUD) (women).
24) Women who are lactating/breastfeeding or who plan to breastfeed while on study through 1 week after receiving the last dose of study drug
25) Women with a positive pregnancy test
26) Women planning to become pregnant while on study through 1 week after receiving the last dose of study drug
27) Subjects likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge
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