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Recurrent MelanomaPhase 2NCT01316692

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

A Phase 2 study testing laboratory biomarker identification and analysis, biopsy and immunohistochemistry/tissue microarrays in people with Recurrent Melanoma and Stage IIIc Melanoma, run by Vanderbilt-Ingram Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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 Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
laboratory biomarker identification and analysis, biopsy and immunohistochemistry/tissue microarrays
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteUnited States
Study dates
Oct 2011to Aug 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 without growth factor support
  • Hemoglobin ≥ 9.0g/dL (without need for transfusion support within 30 days; growth factor allowed)
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  • Platelet count ≥100,000 cells/mm3 without transfusion or growth factor requirement
  • INR<1.5,
  • 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).
  • 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.

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232-6838

Other trials in United States

About this study

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

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

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

Being tested
laboratory biomarker identification and analysis, biopsy, immunohistochemistry/tissue microarrays, TdT-mediated dUTP nick end labeling assay, mass spectrometry
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • laboratory biomarker identification and analysisOther

    Also called protein expresssion analysis

    Correlative studies

  • biopsyProcedure or surgery

    Also called selective tissue excision

    Correlative studies

  • immunohistochemistry/tissue microarraysOther

    Correlative studies

  • TdT-mediated dUTP nick end labeling assayGenetic

    Also called TUNEL assay

    Correlative studies

  • mass spectrometryOther

    Correlative studies

Study groups in NCT01316692
Study groupRoleWhat they receive
MLN8237ExperimentalPatients 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.
Receives: Other: laboratory biomarker identification and analysis; Procedure: biopsy; Other: immunohistochemistry/tissue microarrays; Genetic: TdT-mediated dUTP nick end labeling assay; Other: mass spectrometry

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response Rate

    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.

    Measured: At 18 weeks

Secondary outcomes (3)
  1. Progression-free Survival

    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.

    Measured: On treatment date to last follow-up, disease progression or death for any reason, up to 5 years

  2. Overall Survival

    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

    Measured: On treatment date to last follow-up or death for any reason, up to 5 years

  3. Number of Grade 3 and 4 Study-related Toxicities

    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.

    Measured: at 18 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Mar 2011 (estimated)
  2. Study startOct 2011
  3. Primary completionNov 2014
  4. Study completionAug 2015

Why it stopped: low accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01316692
Sponsor's protocol ID
VICC MEL 1036
Other IDs
NCI-2010-02322, R01FD003522
Status last verified
Apr 2016
First submitted
15 Mar 2011
Last updated
30 May 2016
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing laboratory biomarker identification and analysis, biopsy and immunohistochemistry/tissue microarrays in people with Recurrent Melanoma and Stage IIIc Melanoma, run by Vanderbilt-Ingram Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 May 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 May 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (time frame: At 18 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 May 2016.

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