Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma
Condition: Lung Cancer; Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: Alisertib
Intervention description: 50 mg twice a day on Days 1-7 of each 21-day study cycle.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lung Cancer; Mesothelioma; Unresectable malignant pleural mesothelioma; MPM; Alisertib; MLN8237

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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             not part of normal medical care, with the understanding that consent may be withdrawn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.

          2. 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.

          3. 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.

          4. Absolute neutrophil count (ANC) > 1500/mm3, platelets > 100,000/mm3, Hgb > 9 g/dL.

          5. 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

          6. Adequate renal function as defined by: Calculated creatinine clearance must be >/= 30
             mL/minute

          7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          8. Pathologic diagnosis of malignant mesothelioma (any primary site is acceptable)

          9. Have unresectable malignant mesothelioma (any histology)

         10. 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.

         11. 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.

         12. 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.

         13. Patient must be >/= 18 years of age

        Exclusion Criteria:

          1. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
             considered to be over 25%.

          2. Prior allogeneic bone marrow or organ transplantation

          3. 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

          4. 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.

          5. Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
             pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed.

          6. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first
             dose of study drug, or other severe infection.

          7. 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.

          8. 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.

          9. Patient has received other investigational drugs with 14 days before enrollment

         10. Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

         11. 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.

         12. 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.

         13. 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.

         14. 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

         15. Prior administration of an Aurora A kinase-targeted agent, including alisertib

         16. 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.

         17. Inability to swallow oral medication or inability or unwillingness to comply with the
             administration requirements related to alisertib.

         18. Administration of myeloid growth factors or platelet transfusion within 14 days prior
             to the first dose of study treatment.

         19. Persons who are incarcerated at time of enrollment (e.g., prisoners) or likely to
             become incarcerated during the study.