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
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.
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.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response (OR), defined as a complete or partial response
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.
within 18 weeks of therapy
Jeffrey Sosman, MD
Vanderbilt-Ingram Cancer Center
United States: Food and Drug Administration
VICC MEL 1036
|Vanderbilt-Ingram Cancer Center||Nashville, Tennessee 37232-6838|