Aurora A Kinase Inhibitor MLN8237 in Treating Patients With Unresectable Stage III-IV Melanoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Aurora A kinase inhibitor MLN8237 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well Aurora A kinase inhibitor MLN8237 works in treating patients with unresectable stage III-IV melanoma Funding Source - FDA OOPD

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Estimate the degree of clinical benefit based primarily on objective clinical responses with AURKA inhibitor, MLN8237 in patients with metastatic melanoma in a phase II, 2-stage trial for patients with measurable unresectable disease. SECONDARY OBJECTIVES: I. Assess the progression-free survival and overall survival for all patients enrolled. II. Define toxicities due to MLN8237 and characterize their severity both over a short and prolonged duration of administration. III. In patients entered on stage 1 of clinical trial whenever possible through pre-treatment biopsy and post-treatment surgical specimen, we will define target inhibition at tumor sites based on: AURKA autophosphorylation (AURKAThr288/AURKA), intra-tumoral drug levels, expression of p53-induced NOXA and PUMA expression, TPX2, (by IHC) and TUNEL as markers of apoptosis, cell cycle changes (mitotic index), proliferation (Ki-67), aneuploidy, and AKT phosphorylation. IV. All phase II trial patients enrolled on the 2nd stage will have pre- and post-treatment biopsies (post-day 7+/-3 days) to demonstrate that AURKA is inhibited based on autophosphorylation AURKA/AURKA^Thr 288, Histone H3 (at S10) phosphorylation, AKT phosphorylation, cell cycle changes (mitotic index), TPX2 (by IHC), proliferation (Ki-67), aneuploidy, and p53-induced NOXA and PUMA expression, and TUNEL as markers of apoptosis. V. Demonstrate any correlation between MLN8237 induced target inhibition at tumor sites and clinical benefit of MLN8237. VI. Characterize the de novo molecular mutational profile of the melanomas from all patients entered using a developed SNaPshot assay for melanoma in addition loss of regulatory proteins (i.e., PTEN), DNA copy numbers and gene expression (AURKA), and autophosphorylation of AURKA as well as AURKA localization by IHC. OUTLINE: Patients receive oral Aurora A kinase inhibitor MLN8237 every 12 hours on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 5 years.

Official Title
-----------------
A Phase II Correlative Clinical Trial of MLN8237, a Selective Aurora Kinase A (AURKA) Inhibitor, in Patients With Unresectable Stage III or Stage IV Melanoma Disease

Conditions
-----------------
Recurrent Melanoma, Stage IIIc Melanoma, Stage IV Melanoma

Intervention / Treatment
-----------------
* Other: laboratory biomarker identification and analysis
* Procedure: biopsy
* Other: immunohistochemistry/tissue microarrays
* Genetic: TdT-mediated dUTP nick end labeling assay
* Other: mass spectrometry


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Stage IIIc or IV histologically proven melanoma (confirmed by Vanderbilt pathologists), that is not curable by standard surgery, radiation therapy, or chemotherapy. No available effective therapy (i.e.; therapy known to be curative,). Non-biopsied (resected) tumor sites must be measurable for therapy. Patients on stage 2 of the enrollment must have tumor sites that are easily biopsied and be willing to undergo pre- and post-treatment (around day 8 +/- 3 days) tumor biopsies. Adequate performance status for the study, ECOG 0-1 Adequate baseline organ system function, including Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 without growth factor support Hemoglobin ≥ 9.0g/dL (without need for transfusion support within 30 days; growth factor allowed) Platelet count ≥100,000 cells/mm3 without transfusion or growth factor requirement INR<1.5, Creatinine < 1.5x institutional upper limit of normal (IULN), and/or an adequate renal function as defined by: Calculated creatinine clearance must be ≥ 40 mL/minute (Cockcroft-Gault). Aspartate and alanine aminotransferase < 2.5 x institutional upper limit of normal (IULN), bilirubin < 1.5x IULN Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for 3 months after the completion of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study and for 3 months after the completion of the study A single regimen of prior chemotherapy for metastatic melanoma is allowed. Patients also may have received other immunotherapy or biologic therapy (including kinase inhibitors, antibodies to checkpoints CTLA4, PD1, PDL1, etc.) for metastatic melanoma and there is a limit of three therapy regimens No prior Aurora kinase inhibitor Completed prior chemotherapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior immune therapy, 6 weeks for antibodies to checkpoints CTLA4, PD1, PDL1, etc, and 2 weeks for targeted agents (i.e. inhibitors of MEK, BRAF, Akt, PI3K, mTORC1/2) or localized radiation therapy. All treatment All treatment related toxicity must have resolved to grade 2 or less or to a baseline level as well. Patients cannot receive concomitant radiation therapy at enrollment. While on protocol limited palliative radiotherapy extending over a small bone marrow field (10%) is allowed. Patients with brain metastases are allowed only if they are off systemic corticosteroids and stable for a minimum of 8 weeks. Patients must be 18 years of age or above and voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Subject must be able to take oral medication and to maintain a fast as required before and after MLN8237 administration. Exclusion Criteria Uncontrolled or serious infection Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. Patients with thromboembolic disease cannot be on coumadin, but low molecular heparins are allowed. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%. Prior allogeneic bone marrow or organ transplantation. Concurrent therapy for cancer. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. Inability to comply with protocol-specified procedures (i.e., treatment, monitoring, or follow-up) Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Patients with GI absorptive problems making it unlikely to absorb study medication or more likely to experience GI toxicities. Patient is HIV-positive and is receiving combination antiretroviral therapy. Treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and during the study Other serious medical problem that in the view of the investigator makes therapy difficult to comply with or difficult to interpret toxicity If applicable, patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patient has received other investigational drugs with 14 days before enrollment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN8237<br>Patients receive oral Aurora A kinase inhibitor MLN8237 every 12 hours on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Other: laboratory biomarker identification and analysis<br>* Correlative studies<br>* Other names: protein expresssion analysis;Procedure: biopsy<br>* Correlative studies<br>* Other names: selective tissue excision;Other: immunohistochemistry/tissue microarrays<br>* Correlative studies<br>Genetic: TdT-mediated dUTP nick end labeling assay<br>* Correlative studies<br>* Other names: TUNEL assay;Other: mass spectrometry<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | If 2 or more of 23 pts show CR/PR in stage 1, then an additional 33 pts will be enrolled in stage 2. If 6 or more of the total 56 pts show CR/PR at 18 weeks, then further clinical trials will be warranted. Per Response Evaluation Criteria in Solid Tumor (RECIST)1.1: Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD. | At 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) is defined as the duration in time from start of therapy to last follow-up, disease progression, or death for any reason.measured every 6 weeks for 24 weeks, and then every 12 weeks or to last date known alive or death, determined every 6 months for up to 5 years. For those who are alive and without progression, they are censored at the last date known alive. | On treatment date to last follow-up, disease progression or death for any reason, up to 5 years | 
| Overall Survival | Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details) Evaluated every 3 months for 12 months, then every 6 months | On treatment date to last follow-up or death for any reason, up to 5 years | 
| Number of Grade 3 and 4 Study-related Toxicities | Event are graded using National Cancer Institute Common Toxicity Criteria with grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening/disabling, 5 = death. toxicities measured on day 1 of each 21-day cycle. Treatment continues to disease progression, toxicity, or withdrawal for other reasons. | at 18 weeks |