A Phase 1 First-in-Human Study Evaluating AMG 900 in Advanced Solid Tumors

Study Overview
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Brief Summary
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This first-in-human study of AMG 900 will be conducted in two parts: dose escalation and dose expansion. The dose escalation part of the study is aimed at evaluating the safety, tolerability and PK of oral AMG 900 in subjects with advanced solid tumors. Up to 50 subjects may be enrolled in dose escalation. The dose expansion part of the study will consist of 42 subjects in three taxane-resistant tumor types. The dose of AMG 900 will be dependent upon data from the dose escalation part of the study

Detailed Description
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that G-CSF must be started at day 5, 1 day after the last day of AMG 900 and be continued until neutrophiles are > 1000 or until day 12, meaning 2 days before the reinduction.

Official Title
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A Phase 1, First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Orally Administered AMG 900 in Adult Subjects With Advanced Solid Tumors

Conditions
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Advanced Malignancy, Advanced Solid Tumors, Cancer, Solid Tumors, Tumors

Intervention / Treatment
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* Drug: Arm 1- Dose Escalation
* Drug: Arm 1- Dose Expansion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥ 18 years old Part 1 Dose Escalation only: advanced solid tumor refractory to standard treatment for which no standard therapy is available or the subject refuses standard therapy Part 1 Dose Escalation only: Measurable or evaluable disease per RECIST guidelines Part 2 Dose Expansion only: Taxane-resistant tumor (defined as refractory to or progression within 6 months of discontinuing paclitaxel or docetaxel) of prespecified histology Part 2 Dose Expansion only: Measurable disease per RECIST guidelines Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Life expectancy of > 3 months, in the opinion of the investigator Willing to provide existing and/or future paraffin-embedded tumor samples Part 1 Dose Escalation: must have tumor tissue that is accessible for biopsy by fine needle aspiration (FNA) and must consent to undergo biopsies of their tumor (subjects in non-accelerated phase only) Ability to take oral medications Competent to sign and date an Institutional Review Board approved informed consent form Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin > 9 g/dL Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN) Serum creatinine < 2.0 mg/dL Calculated creatinine clearance ≥ 50 ml/min AST < 2.5 x ULN (if liver or bone metastases are present, ≤ 5 x ULN) ALT < 2.5 x ULN (if liver or bone metastases are present, ≤ 5 x ULN) Alkaline phosphatase < 2.0 x ULN (if liver or bone metastases are present, ≤ 5 x ULN) Total bilirubin < 1.5 x ULN Exclusion Criteria: Active parenchymal brain metastases. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade < 1; b) no dexamethasone requirement; and c) follow-up MRI shows no new lesions appearing Prior bone marrow transplant (autologous or allogeneic) History or presence of hematological malignancies History of bleeding diathesis Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication Active peptic ulcer disease Gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (eg, Crohn's disease, ulcerative colitis) Active infection requiring intravenous (IV) antibiotics 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 toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia Anti-tumor therapy within 28 days of study day 1; concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer is permitted Treatment with immune modulators including, but not limited to, corticosteroids, cyclosporine and tacrolimus within two weeks prior to enrollment Therapeutic or palliative radiation therapy within two weeks of study day 1 Systemic anticoagulation therapy, including warfarin, within 28 days of day 1 Prior treatment with aurora inhibitors Prior participation in an investigational study (drug or device) within 28 days of study day 1 Major surgery within 28 days of study day 1 Any co-morbid medical disorder that may increase the risk of toxicity, in the opinion of the investigator or sponsor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1- Dose Expansion<br>The dose expansion part of the study will begin after completion of the dose escalation phase and will consist of 3 cohorts of 14 subjects each. One taxane-resistant tumor type will be evaluated in each cohort. | Drug: Arm 1- Dose Expansion<br>* AMG 900 is a small molecule inhibitor of aurora kinases A, B and C. AMG 900 will be administered daily for 4 days every 2 weeks (i.e., 4 consecutive days of dosing followed by 10 consecutive days off treatment).<br>|
| Experimental: Arm 1- Dose Escalation<br>The dose escalation part of the study is aimed at determining the maximum tolerated dose (MTD) of AMG 900 and if necessary, the MTD with prophylactic GCSF support (MTD-G). | Drug: Arm 1- Dose Escalation<br>* AMG 900 is a small molecule inhibitor of aurora kinases A, B and C. AMG 900 will be administered daily for 4 days every 2 weeks (i.e., 4 consecutive days of dosing followed by 10 consecutive days off treatment).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: subject incidence of adverse events, first-cycle DLTs and clinically significant changes in vital signs, weight, ECGs and clinical laboratory tests |  | 1 year | 
| PK profile: AMG 900 PK parameters including, but not limited to, maximum observed concentration (Cmax), minimum observed concentration, area under the plasma concentration-time curve and, if feasible, half-life |  | 1 year | 
| Change in levels of p-Histone H3 from baseline (part 1 - dose escalation only) |  | 1 year | 
| Response rate in each taxane-resistant tumor type assessed per RECIST guidelines (part 2 - dose expansion only) |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tumor volume from baseline measured by volumetric CT or MRI |  | 1 year | 
| Tumor response measured by CT or MRI and assessed per RECIST guidelines |  | 1 year | 
| Change from baseline in maximum standardized uptake value (SUVmax) using 18FLT-PET/CT (part 2 - dose expansion only) |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen, Phase 1, First in Human, Advanced Solid Tumors, Clinical Trial, Aurora kinase inhibitor, Open-label, Oncology