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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2013 by Vanderbilt-Ingram Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Jeffrey A. Sosman, MD, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT01316692
First received: March 15, 2011
Last updated: February 7, 2013
Last verified: February 2013
  Purpose

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


Condition Intervention Phase
Recurrent Melanoma
Stage IIIc Melanoma
Stage IV Melanoma
Other: laboratory biomarker identification and analysis
Procedure: biopsy
Other: immunohistochemistry/tissue microarrays
Genetic: TdT-mediated dUTP nick end labeling assay
Other: mass spectrometry
Radiation: positron emission tomography (PET)/computed tomography (CT)
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Vanderbilt-Ingram Cancer Center:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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


Estimated Enrollment: 56
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)
Arms Assigned Interventions
Experimental: MLN8237
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
Correlative studies
Other Name: protein expresssion analysis
Procedure: biopsy
Correlative studies
Other Name: selective tissue excision
Other: immunohistochemistry/tissue microarrays
Correlative studies
Genetic: TdT-mediated dUTP nick end labeling assay
Correlative studies
Other Name: TUNEL assay
Other: mass spectrometry
Correlative studies
Radiation: positron emission tomography (PET)/computed tomography (CT)
Radiologic imaging techniques

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

    1. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 without growth factor support
    2. Hemoglobin ≥ 9.0g/dL (without need for transfusion support within 30 days; growth factor allowed)
    3. Platelet count ≥100,000 cells/mm3 without transfusion or growth factor requirement
    4. INR<1.5,
    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).
    6. 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01316692

Locations
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         
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Investigators
Principal Investigator: Jeffrey Sosman, MD Vanderbilt-Ingram Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Jeffrey A. Sosman, MD, Professor of Medicine; Director, Melanoma and Tumor Immunotherapy, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT01316692     History of Changes
Other Study ID Numbers: VICC MEL 1036, NCI-2010-02322, R01FD003522
Study First Received: March 15, 2011
Last Updated: February 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on August 27, 2014