Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial.
• Be at least 18 years of age on day of signing informed consent.
• Have a histologically proven locally advanced or metastatic high grade (G3) poorly differentiated neuroendocrine carcinoma (NEC).
• Includes small cell and large cell neuroendocrine carcinoma of unknown primary or any extrapulmonary site (and poorly differentiated NEC, not otherwise specified)
• Includes neuroendocrine prostate cancer (de novo or treatment-emergent) of prostate if small cell or large cell histology (histologic evidence of both adenocarcinoma and neuroendocrine carcinoma may be present in same patient).
• Other mixed tumors, e.g. mixed neuroendocrine neoplasms (MINENs) with NEC plus adenocarcinoma, squamous or acinar cell component are allowed if the high grade (small or large cell) NEC component comprises >50% of the original sample or subsequent biopsy.
• Have progressed during or after completion of first line systemic chemotherapy.
• No limit to the number of prior chemotherapy regimens.
• Early progression on/after adjuvant chemotherapy counts as firstline therapy.
• Have at least one measurable disease based on RECIST 1.1.
• Patients must agree to have a biopsy of primary tumor or metastatic tissue at baseline, and there must be a lesion that can be biopsied with acceptable clinical risk (as judged by the investigator).
• Patients with unsuccessful baseline biopsies may undergo an additional biopsy attempt (at the same or a different site, determined by the investigator).
• For patients with an intact primary and no metastatic site that can be safely biopsied, biopsy of the primary is acceptable, but must be approved by the principal investigator.
• Baseline tumor biopsy may be omitted if the tumor is inaccessible and/or a biopsy is not thought to post exceptionally high procedural risk due to location or other factors
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Have a life expectancy of greater than 3 months.
• Demonstrate adequate organ function, all screening labs should be performed within 14 days of treatment initiation.
• Absolute neutrophil count (ANC) >=1, 500 /microliter (mcL)
• Platelets >=100,000 / mcL
• Hemoglobin >= 9 g/dL or >=5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine OR Measured or calculated creatinine clearance (CrCl) (Creatinine clearance should be calculated per institutional standard. Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl =60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Serum total bilirubin 1.5 ULN
• aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) 2.5 g/dL
• International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria

• Has Merkel cell carcinoma, small cell lung carcinoma, or large cell NEC of lung
• Intermediate grade neuroendocrine tumors are excluded
• Well differentiated Grade 3 neuroendocrine tumors are excluded
• Metastatic high-grade prostate carcinoma with evidence of focal neuroendocrine differentiation on prostate biopsy (e.g., positive chromogranin staining by immunohistochemistry) without small cell or large cell NEC morphology are excluded, as are neuroendocrine prostate cancers with phenotype intermediate between adenocarcinoma and small cell
• Atypical and typical bronchial carcinoids and well differentiated G1 and G2 gastroe