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A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Orally Administered AMG 900 in Adult Subjects with Acute Leukemias and Related Disorders
|Leukemia, Acute Myeloid (AML)
- To evaluate the safety and tolerability of AMG 900 in subjects with acute leukemias and related disorders
- To evaluate the pharmacokinetics (PK) of AMG 900 after multiple oral administrations
- To determine the maximum tolerated dose (MTD) of AMG 900 in subjects with acute leukemias and related disorders
- To evaluate the anti-tumor activity of AMG 900 in acute leukemias and related disorders
- To evaluate the pharmacodynamic (PD) effects of drug exposure on p-Histone H3 expression in leukemic blasts
- To explore pharmacokinetic/pharmacodynamic (PK/PD) relationships for safety and/or efficacy endpoints
- To explore the relationship of tumor biomarkers (eg, Ki67, aurora A and B, mRNA or protein expression, Pgp and BCRP1 expression, survivin mRNA, cell cycle analysis, status of p53 and mutation analysis) to clinical response
- To explore molecular profiles to identify signatures that predict response
- To investigate the effect of genetic variation in drug metabolism genes, cancer genes, and drug target genes on subject response to AMG 900. This part of the study is optional and additional optional pharmacogenetic informed consent is required.
- Subject or subject's legally acceptable representative has provided informed consent.
- Men or women ≥ 18 years old
- Pathologically documented, definitively diagnosed AML that has failed standard treatments or for which no standard therapy is available or the subject refuses standard therapy
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
- Life expectancy of > 3 months, in the opinion of the investigator
- Must consent to undergo bone marrow biopsies per schedule of assessments
- Ability to take oral medications
- QTcF ≤ 470 msec (based on average from screening triplicates prior to day 1)
- Renal function, as follows:
- Serum creatinine ≤ ULN, OR
- CrCl > 45 ml/min/1.73m2 (Modification of Diet in Renal Disease- MDRD)
- Hepatic function, as follows:
- AST< 3.0 x ULN
- ALT < 3.0 x ULN
- Alkaline phosphatase < 3.0 x ULN
- Total bilirubin < 1.5 x ULN (unless suspected Gilbert's syndrome or extrahepatic source by increased indirect bilirubin fraction)
- White blood cell greater than 20 x 103/uL
- History of or active central nervous system leukemia
- Clinically significant bleeding within 2 weeks of screening (ie, GI bleeds, intracranial hemorrhage) or active peptic ulcer disease
- Prior allogeneic bone marrow transplant
- History of clinically meaningful bleeding diathesis
- Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), uncontrolled hypertension (diastolic > 100 mmHg) unstable angina, or unstable cardiac arrhythmia requiring medication
- History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past year
- Treatment with Pegfilgrastim within 14 days of study day 1
- History of gastrointestinal surgery or disease that would impair intestinal absorption
- Uncontrolled infection requiring intravenous (IV) antibiotics or antifungals within 2 weeks of study enrollment (day 1)
- Known positive test for HIV
- Active or chronic hepatitis B or hepatitis C infection, determined by serologic tests.
- Unresolved non-hematologic toxicities from prior anti-tumor therapy, defined as not having resolved to baseline level, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 6 months)
- Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy, hypomethylating therapy, differentiating therapy or investigational agent) within 14 days or 5 half lives of study day 1
- Treatment with systemic immune modulators including, but not limited to, systemic corticosteroids, cyclosporine and tacrolimus within two weeks prior to study day 1
- Therapeutic or palliative radiation therapy within two weeks of study day 1
- Treatment with known substrates or inhibitors of the CYP2C family including but not limited to sulphaphenazole, tolbutamide, phenytoin, warfarin, gemfibrozil, montelukast and omeprazole within 2 weeks prior to study day 1 (other CYP2C inhibitors may be allowed if there is agreement between the sponsor and investigator)
- Treatment with known inhibitors of CYP3A4 including but not limited to amiodarone, azithromycin, clarithromycin, delavirdine, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, mibefradil, miconazole, saquinavir, telithromycin, troleandomycin, or diltiazem within 2 weeks prior to study day 1; treatment with voriconasole will be permitted but dosing must be withheld for approximately 1 day before and approximately 1 day after each treatment cycle with AMG 900 (4 or 7 days respectively). Treatment with caspofungin and posaconazole antifungals is permitted.
- Treatment with known inducers of CYP3A4 including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort and glitazones (thiazolidinediones) within 4 weeks prior to study day 1 (other CYP3A4 inducers may be allowed if there is agreement between the sponsor and investigator)
- Treatment with hydroxyurea to control peripheral blood leukemic cell counts, within 5 half lives (1 day) of study day 1
- Treatment with medications known to cause QTc interval prolongation within 7 days of study day 1 (use of posaconazole is permitted with appropriate replacement of electrolytes and careful monitoring)
- Family history of long QT syndrome
- Therapeutic anticoagulation therapy, including warfarin, within 28 days of day 1
- Prior treatment with aurora kinase inhibitors
- Currently receiving treatment in another investigational device or drug study, or less than 14 days since ending treatment on another investigational device or drug study(s), or receiving other investigational agent(s).
- Major surgery within 28 days of study day 1
- Subjects who fulfill any of the following criteria are not eligible for the study:
- Men and woman of reproductive potential, unwilling to practice a highly effective method of birth control for the duration of the study and continuing for 1 week after for women; and 2 months after for men after receiving the last dose of study drug. Highly effective methods of birth control include sexual abstinence (men, women); vasectomy or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or IUD (women).
- Women who are lactating/breastfeeding
- Women with a positive pregnancy test
- Women planning to become pregnant during the duration of the study
- History of other malignancy within the past 3 years with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before screening 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 in situ disease
- Prostatic intraepithelial neoplasia without evidence of prostate cancer
- Subject has known sensitivity to any of the products to be administered during dosing
- Subject previously has entered this study or has been previously exposed to AMG 900
- Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator's knowledge
- Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
- Men with pregnant partners or whose partners become pregnant during the study must practice sexual abstinence or use a condom for the remainder of the study and for 2 months following the last dose of study drug. The pregnant partner information will be reported to Amgen as per Pregnancy Notification Worksheet.
- Women who become pregnant during the study will not receive subsequent scheduled doses and will be followed for safety to study closeout. Pregnancy information will be reported to Amgen as per Pregnancy Notification Worksheet.
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