A Phase II Trial of MLN8237 in Patients With Metastatic Castrate Resistant and Neuroendocrine Prostate Cancer

This is a multi-institutional single-arm, open-label Phase 2 trial evaluating MLN8237 in patients with histologically confirmed or clinically suspected metastatic neuroendocrine prostate cancer. Subjects will be treated with MLN8237 at 50 mg twice daily for 7 days repeated every 21 days. Individual dose reductions will be made on the basis of the AEs observed. Therapy will continue until disease progression, unacceptable toxicity as a result of MLN8237, or withdrawal of patient consent. Patients will be followed with history, physical, and blood tests at each visit to monitor for toxicity. Response and progression will be evaluated by CT/MRI scan and bone scan after every 3 cycles and determined using RECIST v1.1. PSA and serum chromogranin A and NSE will be followed every cycle. CTC counts by CellSearch will be performed at baseline, at 4-6 weeks, and upon progression. Patients will be followed for survival endpoints following completion of this study until death.

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.