A Phase II Trial of MLN8237 in Patients With Metastatic Castrate Resistant and Neuroendocrine Prostate Cancer
Condition: Small Cell Prostate Cancer; Neuroendocrine Prostate Cancer; Prostate Adenocarcinoma Plus > 50% Immunohistochemical Staining for Neuroendocrine Markers
MeSH terms: Prostatic Neoplasms
Intervention: MLN8237
Intervention description: MLN8237 will be administered orally. The study drug will be administered on an empty stomach with the patient remaining nothing by mouth (NPO), except for water and prescribed medications, for 2 hours before and 1 hour after each dose. Patients will be instructed to take each oral dose of MLN8237 with 8 ounces (1 cup, 240 mL) of water.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic prostate carcinoma

Summary:

      This study will evaluate the response rate of MLN8237 in patients with histologically
      confirmed or clinically suspected metastatic neuroendocrine prostate cancer (NEPC). MLN8237
      is an orally administered Aurora kinase A inhibitor that has demonstrated broad antitumor
      activity in vitro and in vivo. In preclinical models, aurora kinase inhibition resulted in
      dramatic and preferential anti-tumor activity in NEPC with suppression of neuroendocrine
      marker expression.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Metastatic prostate carcinoma and at least one of the following:

               -  Histologic diagnosis of small cell or neuroendocrine prostate cancer

               -  Histologic diagnosis of prostate adenocarcinoma plus > 50% immunohistochemical
                  staining for neuroendocrine markers (chromogranin, synaptophysin or neuron
                  specific enolase)

               -  Development of liver metastases in the absence of PSA progression as defined by
                  PCWG2

          -  Serum chromogranin A level >5 x upper limit of normal and/or serum neuron specific
             enolase (NSE) >2x upper limit of normal

          -  Measurable disease by RECIST 1.1 with PCWG2 modifications

          -  Patients with pure small cell neuroendocrine carcinoma on histology are not required
             to have received prior androgen deprivation therapy (ADT) or castrate levels of
             testosterone, but their testosterone state should be maintained for the duration of
             the study. Other patients are required to have surgical or ongoing chemical
             castration, with baseline testosterone level <50ng/dL.

          -  Patients capable of fathering children must agree to use an effective method of
             contraception for the duration of the trial and should continue use for 4 months after
             last dose of study drug

          -  Subjects must be able to take oral medication and to maintain a fast as required for 2
             hours before and 1 hour after MLN8237 administration.

          -  ANC > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained without
             need for myeloid growth factor or platelet transfusion support within 14 days,
             however, erythrocyte growth factor is allowed as per published ASCO guidelines.

          -  Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)< 1.5 x ULN. AST and/or ALT may be up
             to 5X ULN if with known liver metastases provided bilirubin is normal.

          -  Adequate renal function as defined by serum creatinine ≤ 1.5 x ULN. If creatinine >1.5
             x ULN, calculated or measured creatinine clearance must be ≥ 40 mL/minute
             (Cockcroft-Gault).

          -  ECOG performance status 0-2

          -  Estimated life expectancy > 3 months

          -  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.

        Exclusion Criteria:

          -  Radiation therapy to 25% of bone marrow within 2 weeks of first dose

          -  Residual > Grade 2 toxicity from prior treatment must have resolved with the exception
             of those explicitly described elsewhere in entry criteria

          -  Known history of uncontrolled sleep apnea syndrome and other conditions that could
             result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
             disease; requirement for supplemental oxygen.

          -  Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
             pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed (see
             section 5.5)

          -  Severe or uncontrolled systemic 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.

          -  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.

          -  Currently active other malignancy excluding controlled non-melanoma skin cancer.
             Patients are considered NOT to have "currently active" malignancy if they have
             completed any necessary therapy and are considered by their physician to be at less
             than 30% risk of relapse.

          -  Treatment with 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

          -  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.