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Pembrolizumab with or without Paclitaxel or Irinotecan in Treating Patients with Locally Advanced or Metastatic High Grade Neuroendocrine Cancer

Trial Status: Closed to Accrual

This phase II trial studies how well pembrolizumab with or without paclitaxel or irinotecan works in treating patients with high grade neuroendocrine cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab with or without paclitaxel or irinotecan hydrochloride may work better in treating patients with neuroendocrine cancer.

Inclusion Criteria

  • Be willing and able to provide written informed consent for the trial
  • 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 chemo therapy * No limit to the number of prior chemotherapy regimens * Early progression on/after adjuvant chemotherapy counts as first-line 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 * If fresh tumor tissue cannot be collected, the overall study (lead-site) principal investigator (PI) may approve the use of archival tissue; the use of archival tissue in lieu of a fresh tumor biopsy will be evaluated on a case-by-case basis and must be approved by the overall study (lead-site) PI
  • 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
  • Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 14 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 14 days of treatment initiation)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 14 days of treatment initiation)
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of treatment initiation)
  • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) alanine aminotransaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (within 14 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 14 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 14 days prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 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 bronchial carcinoid and well differentiated G2 gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) are excluded
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency
  • Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Physiologic doses of steroids (e.g. =< 10 mg prednisone/day or equivalent) are allowed; topical, inhaled, nasal and ophthalmic steroids are allowed
  • Has a known history of active TB (Bacillus tuberculosis)
  • History of or high suspicion of Gilbert’s disease (safety run-in, Part B only)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Documented progression on and/or intolerance/hypersensitivity to both paclitaxel and irinotecan (Part B only)
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; * NOTE: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * NOTE: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Concurrent somatostatin analog therapy is allowed (for control of hormone excess) provided patient has been on stable dose for at least two months and tumor progression has been documented * Continuation of androgen deprivation therapy (ADT) allowed for patients with neuroendocrine prostate cancer (in the setting of castration-resistant prostate cancer, CRPC)
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with asymptomatic suspected brain metastases (or small lesions of uncertain significance) < 1 cm that do not require focal therapy are eligible; (Follow up imaging will be allowed on study, and focal radiation with continuation of protocol therapy allowed if there is progressive disease in the brain and systemic imaging shows stable disease/response); subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days [d] of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); * Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Has a history of (non-infectious) pneumonitis/ interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed


San Francisco
UCSF Medical Center-Mount Zion
Contact: Emily K. Bergsland
Phone: 415-514-6520


Dana-Farber Cancer Institute
Contact: Jennifer Ang Chan
Phone: 617-632-6315

New York

New York
Memorial Sloan Kettering Cancer Center
Contact: Nitya P. Raj
Phone: 646-888-4185


I. To evaluate the best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by investigator of pembrolizumab or pembrolizumab plus chemotherapy in subjects with previously treated poorly differentiated neuroendocrine carcinoma.


I. To determine the safety and tolerability of pembrolizumab-based therapy in this patient population.

II. To evaluate duration of response (DOR) in patients receiving pembrolizumab or pembrolizumab plus chemotherapy.

III. To evaluate progression free survival (PFS) in subjects treated with pembrolizumab or pembrolizumab plus chemotherapy (median PFS and 18 week [wk] PFS).

IV. To evaluate overall survival (OS) in subjects receiving pembrolizumab or pembrolizumab plus chemotherapy.


I. To compare ORR, DOR, and PFS based on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) with the same measures assessed by RECIST 1.1.

II. To characterize the molecular features of neuroendocrine carcinomas.

III. To correlate clinical outcomes (ORR, DOR, PFS, OS) with molecular features of neuroendocrine carcinoma.

IV. To describe the relationship between baseline tumor growth rate (TGR) and RECIST measurements for all patients enrolled in Part A and Part B of this study.

V. To examine changes in TGR over time in patients treated with pembrolizumab alone (Part A) and pembrolizumab plus chemotherapy (Part B).


PART A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive pembrolizumab IV over 30 minutes on day 1, and irinotecan IV over 90 minutes on days 1 and 8 OR paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of California San Francisco

Principal Investigator
Emily K. Bergsland

  • Primary ID 169524
  • Secondary IDs NCI-2017-01728, 17-21843
  • ID NCT03136055