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

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ClinicalTrials.gov Identifier: NCT01316692
Recruitment Status : Terminated (low accrual)
First Posted : March 16, 2011
Results First Posted : May 30, 2016
Last Update Posted : May 30, 2016
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Jeffrey A. Sosman, MD, Vanderbilt-Ingram Cancer Center

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Recurrent Melanoma
Stage IIIc Melanoma
Stage IV Melanoma
Interventions Other: laboratory biomarker identification and analysis
Procedure: biopsy
Other: immunohistochemistry/tissue microarrays
Genetic: TdT-mediated dUTP nick end labeling assay
Other: mass spectrometry
Enrollment 12
Recruitment Details Participants on this study were treated at Vanderbilt-Ingram Cancer Center. The study was conducted from October 2011- August 2015
Pre-assignment Details A total of 19 patients consented to participate in this study. Four of 19 patients were screen failures and therefore were not eligible, 3 patients were eligible, but withdrew before treatment.
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Period Title: Overall Study
Started 12
Completed 0
Not Completed 12
Reason Not Completed
Adverse Event             5
Disease Progression             7
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Baseline Participants 12
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
<=18 years
0
   0.0%
Between 18 and 65 years
5
  41.7%
>=65 years
7
  58.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
Female
3
  25.0%
Male
9
  75.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
12
 100.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
1
   8.3%
White
11
  91.7%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants
12
1.Primary Outcome
Title Overall Response Rate
Hide Description 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.
Time Frame At 18 weeks
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Hide Analysis Population Description
All patients with Objective Response, defined as a complete or partial response.
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants
0
(0 to 0.265)
2.Secondary Outcome
Title Progression-free Survival
Hide Description 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.
Time Frame On treatment date to last follow-up, disease progression or death for any reason, up to 5 years
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Hide Analysis Population Description
All patients are included in the analysis on intention‐to treat basis. Analysis is by Kaplan‐Meier method, where death is an event, with censoring for non‐expired patients at greater of off‐study date or last known alive date.
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 12
Median (95% Confidence Interval)
Unit of Measure: days
111
(45 to 187)
3.Secondary Outcome
Title Overall Survival
Hide Description 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
Time Frame On treatment date to last follow-up or death for any reason, up to 5 years
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Hide Analysis Population Description
All patients are included in the analysis on intention‐to-treat basis. Analysis is by Kaplan‐Meier method, where death is an event, with censoring for non‐expired patients at greater of off‐study date or last known alive date.
Arm/Group Title MLN8237
Hide Arm/Group Description:

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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 12
Median (95% Confidence Interval)
Unit of Measure: days
256
(136 to 419)
4.Secondary Outcome
Title Number of Grade 3 and 4 Study-related Toxicities
Hide Description 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.
Time Frame at 18 weeks
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Hide Analysis Population Description
total numbers of adverse events, patients experiencing grade 3 and 4 related to study treatment
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: toxicities
Grade 3 Toxicities 6
Grade 4 Toxicities 3
Grade 5 Toxicities1 0
5.Other Pre-specified Outcome
Title Characterize the de Novo Molecular Mutation Profile of the Melanomas for Association Between Objective Responses to MLN8237 in Patients With Pre-treatment Melanoma Tissue.
Hide Description 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
Time Frame At 24 weeks
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Hide Analysis Population Description
Collected samples of tumors were very limited. It did not allow us to perform the described assays
Arm/Group Title MLN8237
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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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
6.Other Pre-specified Outcome
Title Correlation Between MLN8237-induced Selective Aurora Kinase A Inhibition in Post-treatment Tumor Sites and Clinical Benefit of MLN8237
Hide Description 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
Time Frame At 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
unable to collected the required number of tumor samples
Arm/Group Title MLN8237
Hide Arm/Group Description:

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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame 3 years, 10 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title MLN8237
Hide Arm/Group Description

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.

laboratory biomarker identification and analysis: Correlative studies

biopsy: Correlative studies

immunohistochemistry/tissue microarrays: Correlative studies

TdT-mediated dUTP nick end labeling assay: Correlative studies

mass spectrometry: Correlative studies

All-Cause Mortality
MLN8237
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
MLN8237
Affected / at Risk (%) # Events
Total   2/15 (13.33%)    
Blood and lymphatic system disorders   
Anemia  1/15 (6.67%)  1
Gastrointestinal disorders   
Diarrhea  1/15 (6.67%)  1
Dehydration  1/15 (6.67%)  1
Investigations   
Platelet count decreased  1/15 (6.67%)  1
Respiratory, thoracic and mediastinal disorders   
Upper respiratory infection  1/15 (6.67%)  1
Vascular disorders   
Thromboembolic event  1/15 (6.67%)  1
Bronchial infection  1/15 (6.67%)  1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MLN8237
Affected / at Risk (%) # Events
Total   12/12 (100.00%)    
Blood and lymphatic system disorders   
Anemia  7/12 (58.33%)  22
Cardiac disorders   
Palpitations  1/12 (8.33%)  1
Gastrointestinal disorders   
Diarrhea  7/12 (58.33%)  10
Mucositis oral  6/12 (50.00%)  7
Nausea  6/12 (50.00%)  9
Vomiting  3/12 (25.00%)  4
Abdominal pain  2/12 (16.67%)  2
Bloating  1/12 (8.33%)  1
Constipation  1/12 (8.33%)  1
Flatulence  1/12 (8.33%)  1
Gastroesophageal reflux disease  1/12 (8.33%)  1
General disorders   
Fatigue  8/12 (66.67%)  11
Chills  2/12 (16.67%)  2
Pain  2/12 (16.67%)  2
Fever  1/12 (8.33%)  1
administration site conditions  1/12 (8.33%)  1
Infections and infestations   
Bladder infection  1/12 (8.33%)  1
Upper respiratory infection  1/12 (8.33%)  1
Investigations   
Lymphocyte count decreased  6/12 (50.00%)  14
White blood cell decreased  6/12 (50.00%)  12
Neutrophil count decreased  5/12 (41.67%)  9
Platelet count decreased  3/12 (25.00%)  9
Alkaline phosphatase increased  2/12 (16.67%)  4
Aspartate aminotransferase increased  2/12 (16.67%)  2
Creatinine increased  1/12 (8.33%)  2
Metabolism and nutrition disorders   
Hyperglycemia  11/12 (91.67%)  17
Anorexia  4/12 (33.33%)  5
Hyponatremia  3/12 (25.00%)  3
Hypokalemia  1/12 (8.33%)  2
Hypophosphatemia  1/12 (8.33%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia  1/12 (8.33%)  1
Back pain  1/12 (8.33%)  1
Generalized muscle weakness  1/12 (8.33%)  1
Nervous system disorders   
Dizziness  1/12 (8.33%)  2
Headache  1/12 (8.33%)  1
Nystagmus  1/12 (8.33%)  1
Tremor  1/12 (8.33%)  1
Syncope  1/12 (8.33%)  1
Psychiatric disorders   
Confusion  1/12 (8.33%)  1
Depression  1/12 (8.33%)  1
Renal and urinary disorders   
Hematuria  2/12 (16.67%)  5
Respiratory, thoracic and mediastinal disorders   
Cough  2/12 (16.67%)  2
Dyspnea  1/12 (8.33%)  1
Nasal congestion  1/12 (8.33%)  1
Sneezing  1/12 (8.33%)  1
Skin and subcutaneous tissue disorders   
Alopecia  10/12 (83.33%)  12
Hyperhidrosis  1/12 (8.33%)  1
Pruritus  1/12 (8.33%)  1
Rash acneiform  1/12 (8.33%)  1
Rash maculo-papular  1/12 (8.33%)  1
Vascular disorders   
Hypotension  1/12 (8.33%)  1
Thromboembolic event  1/12 (8.33%)  1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Jeff Sosman, MD
Organization: Vanderbilt-Ingram Cancer Center
Phone: 615-875-8359
Responsible Party: Jeffrey A. Sosman, MD, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT01316692     History of Changes
Other Study ID Numbers: VICC MEL 1036
NCI-2010-02322 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
R01FD003522 ( U.S. FDA Grant/Contract )
First Submitted: March 15, 2011
First Posted: March 16, 2011
Results First Submitted: April 21, 2016
Results First Posted: May 30, 2016
Last Update Posted: May 30, 2016