Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

Study Overview
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Brief Summary
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Objectives: Objectives The primary objective of this study is to: To assess 4-month disease control rate (DCR) in pre-treated patients with unresectable malignant pleural mesothelioma (MPM) treated with alisertib The secondary objectives of this study are to: To assess the response rate (confirmed and unconfirmed complete + partial responses) To assess the progression-free survival. To assess overall survival. To evaluate the side effects and toxicities associated with this treatment regimen. To collect archival tissue, blood, pleural effusion fluid and plasma for correlative studies. Exploratory Objectives: To collect archival or new tissue, blood and pleural effusion fluid for correlative studies. Tissue biomarkers to be evaluated include aurora kinase pathway and c-myc gene amplification. Next generation sequencing (NGS) will be conducted on adequate tumor tissue specimens.

Detailed Description
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Study Drug Administration: If you are found to be eligible to take part in this study, you will take alisertib tablets by mouth 2 times each day on Days 1-7 of each 21-day study cycle. You must take your doses of alisertib at least 6 hours apart with 1 cup (about 8 ounces) of water. If you miss or vomit a dose of alisertib, do not retake that dose. Wait and take the next dose as scheduled. Study Visits: On Day 1 of Cycles 1-3 and then every odd-numbered cycle after that (Cycles 5, 7, 9 and so on): You will have a physical exam. Blood (about 4 teaspoons) will be drawn for routine tests. Every 6 weeks while you are on study, you will have a PET-CT scan of your chest, abdomen, and pelvis to check the status of the disease. Length of Study: You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on this study will be over after you have completed follow-up. Follow up: Your study doctor or study team will follow you up 30 days after your last dose by reviewing your medical chart or calling you to see if the side effects are resolved. After that, you will continue to be followed up at 3 months, 6 months and every 6 months beyond that. The study doctor can explain how the study drug is designed to work. Up to 58 participants will be enrolled in this study. All will take part at MD Anderson.

Official Title
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Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

Conditions
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Lung Cancer, Mesothelioma

Intervention / Treatment
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* Drug: Alisertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent 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. Female subject is either: post-menopausal for at least one year before the screening visit, or surgically sterilized, or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and at least 1 month after the last dose of alisertib. Male subject, even if surgically sterilized (ie, status postvasectomy), agrees to use an acceptable barrier method for contraception (condom with a spermicidal agent), or completely abstain from heterosexual intercourse during the entire study treatment period through 4 months after the last dose of alisertib. Absolute neutrophil count (ANC) > 1500/mm3, platelets > 100,000/mm3, Hgb > 9 g/dL. Total bilirubin </= 1.5 x upper limit of normal (ULN), SGOT (AST) and SGPT (ALT)< 2.5 x ULN. AST and/or ALT may be up to 5X ULN if with known liver mets Adequate renal function as defined by: Calculated creatinine clearance must be >/= 30 mL/minute Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Pathologic diagnosis of malignant mesothelioma (any primary site is acceptable) Have unresectable malignant mesothelioma (any histology) Received at least one prior pemetrexed-based chemotherapy for unresectable disease, unless within 3 months of receiving platinum-pemetrexed therapy for neoadjuvant or adjuvant treatment that has been unsuccessful. Up to 4 prior lines of systemic therapy (biologic or chemotherapy) are allowed. Maintenance therapy after 4-6 cycles of front-line chemotherapy is still considered 1 line of therapy and is not considered 2 separate therapies. Patients must have measurable disease by modified RECIST or RECIST. Examinations for assessment of measurable disease must have been completed within 28 days prior to registration. Patient must be >/= 18 years of age Exclusion Criteria: 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 Known GI disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery with significant removal of the small intestine, and celiac disease Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease. Patients who use CPAP or BIPAP at night and have controlled sleep apnea syndrome are allowed. Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe 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. Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum Beta-human chorionic gonadotropin (Beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Patient has received other investigational drugs with 14 days before enrollment Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study. 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. 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 alisertib and during the study. Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. For guidance in defining active infection for hepatitis B, please refer to the WHO guidelines Prior administration of an Aurora A kinase-targeted agent, including alisertib Receipt of corticosteroids within 7 days prior to the first dose of study treatment, unless patient has been taking a continuous dose of no more than 15 mg/day of prednisone for at least 1 month prior to first dose of study treatment. Low dose steroid use for the control of nausea and vomiting will be allowed. Topical steroid use is permitted. Inhaled steroids are permitted. Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to alisertib. Administration of myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment. Persons who are incarcerated at time of enrollment (e.g., prisoners) or likely to become incarcerated during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib<br>Alisertib administered by mouth at 50 mg twice a day for 7 days in each treatment cycle, followed by a 14-day, treatment-free period. | Drug: Alisertib<br>* 50 mg twice a day on Days 1-7 of each 21-day study cycle.<br>* Other names: MLN8237;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate at 4 Months | Patients who are free of disease progression at 4 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 4 months from treatment started | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From treatment start, every 6 weeks until progression, death, withdrawal of consent or study completion an average of 25 months | 
| Overall Survival | Overall Survival is defined as the time from the date of randomization to the date of death due to any cause. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 35 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or date of death, whichever occurs first. Progression is defined using modified Response Evaluation Criteria In Solid Tumors Criteria (mRECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions or RECIST 1.1 if mRECIST cannot be used. | From treatment start to death/progression or last follow-up, whichever come first assessed up to 25 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPM, MLN8237, Lung Cancer, Mesothelioma, Unresectable malignant pleural mesothelioma, Alisertib