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
|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|
- Overall Response Rate [ Time Frame: At 18 weeks ] [ Designated as safety issue: No ]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.
- Progression-free Survival [ Time Frame: On treatment date to last follow-up, disease progression or death for any reason, up to 5 years ] [ 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.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.
- Overall Survival [ Time Frame: On treatment date to last follow-up or death for any reason, up to 5 years ] [ Designated as safety issue: No ]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
- Number of Grade 3 and 4 Study-related Toxicities [ Time Frame: at 18 weeks ] [ Designated as safety issue: Yes ]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.
- 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: At 24 weeks ] [ Designated as safety issue: No ]In stage 1 patients: tumor biopsies are taken before initiation of treatment and on the 8th day of the first cycle of treatment. Tissue will be assayed for mutations that are neither parent-possessed, nor able to be transmitted, in pre- and in post-treatment tissue and the results will be compared and contrasted with patients' objective clinical responses, as determined by RECIST 1.1, after 18 weeks of treatment
- Correlation Between MLN8237-induced Selective Aurora Kinase A Inhibition in Post-treatment Tumor Sites and Clinical Benefit of MLN8237 [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]In stage 2 patients: tumor biopsies are taken before initiation of treatment and on the 8th day of the first cycle of treatment. Post-treatment tumor tissue will be assayed for MLN8237-induced selective Aurora Kinase A inhibition and compared to pre-treatment tumor tissue and the results will be compared and contrasted with patients' objective clinical responses, as determined by RECIST 1.1, after 18 weeks of treatment
|Study Start Date:||October 2011|
|Study Completion Date:||August 2015|
|Primary Completion Date:||November 2014 (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
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|
|Nashville, Tennessee, United States, 37232-6838|
|Principal Investigator:||Jeffrey Sosman, MD||Vanderbilt-Ingram Cancer Center|