Aurora A Kinase Inhibitor MLN8237 in Treating Patients With Unresectable Stage III-IV Melanoma
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
Stage IIIc Melanoma
Stage IV Melanoma
Other: laboratory biomarker identification and analysis
Other: immunohistochemistry/tissue microarrays
Genetic: TdT-mediated dUTP nick end labeling assay
Other: mass spectrometry
Radiation: positron emission tomography (PET)/computed tomography (CT)
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Objective response (OR), defined as a complete or partial response [ Time Frame: within 18 weeks of therapy ] [ Designated as safety issue: No ]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.
- Progression-free survival [ Time Frame: Baseline to day 120 +/- 3 days ] [ Designated as safety issue: No ]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.
- Overall survival [ Time Frame: date on study to date of death from any cause or last date known alive ] [ Designated as safety issue: No ]Duration in time from start of therapy to last date followup or the date of death for any reason
- Number of patients with each worst-grade toxicity [ Time Frame: from date of study entry to date off-treatment ] [ Designated as safety issue: Yes ]Number of patients with worst-grade toxicity at each of five grades following National Cancer Institute Common Toxicity Criteria with grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening/disabling, 5 = death.
- Characterize the de novo molecular mutation profile of the melanomas for association between objective responses to MLN8237 in patients with pre-treatment melanoma tissue. [ Time Frame: within 18 weeks of therapy ] [ Designated as safety issue: No ]Describe the mutations that are neither parent-possessed, nor able to be transmitted, in patients' available pre-treatment tissues and compare and contrast them with the patients' objective clinical responses, as determined by RECIST 1.1.
- Phase II: correlation between MLN8237-induced selective Aurora Kinase A inhibition in post-treatment tumor sites and clinical benefit of MLN8237 [ Time Frame: At conclusion of treatment ] [ Designated as safety issue: No ]Determine Aurora Kinase A inhibition at patients' post-treatment tumor tissues compared to pre-treatment tissues and compare and contrast this with their objective responses as determined by RECIST 1.1
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||October 2019|
|Estimated Primary Completion Date:||October 2018 (Final data collection date for primary outcome measure)|
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
Other Name: protein expresssion analysisProcedure: biopsy
Other Name: selective tissue excisionOther: immunohistochemistry/tissue microarrays
Correlative studiesGenetic: TdT-mediated dUTP nick end labeling assay
Other Name: TUNEL assayOther: mass spectrometry
Correlative studiesRadiation: positron emission tomography (PET)/computed tomography (CT)
Radiologic imaging techniques
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01316692
|United States, Tennessee|
|Vanderbilt-Ingram Cancer Center||Recruiting|
|Nashville, Tennessee, United States, 37232-6838|
|Contact: Clinical Trials Information Program 800-811-8480|
|Principal Investigator: Jeffrey A. Sosman|
|Principal Investigator:||Jeffrey Sosman, MD||Vanderbilt-Ingram Cancer Center|