Clinical Trials /

Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas

NCT03136055

Description:

This is a pilot study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinoma

Related Conditions:
  • Neuroendocrine Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
  • Official Title: A Pilot Study of Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas

Clinical Trial IDs

  • ORG STUDY ID: 169524
  • NCT ID: NCT03136055

Conditions

  • High Grade Malignant Neuroendocrine Carcinoma (Diagnosis)

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaHigh-Grade Extrapulmonary NEC
IrinotecanCamptosarHigh-Grade Extrapulmonary NEC
PaclitaxelTaxolHigh-Grade Extrapulmonary NEC

Purpose

This is a pilot study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinoma

Detailed Description

      There are two parts of the study. In Part A, subjects are treated with pembrolizumab alone,
      and in Part B with pembrolizumab plus chemotherapy (physician's choice, paclitaxel or
      irinotecan). Adaptive Simon's two-stage design is used. The overall plan hinges on the
      activity of single agent pembrolizumab in the first stage of Part A. If there is sufficient
      activity in the first stage of Part A, the study will expand to the second stage of Part A
      and forgo Part B. If there is insufficient activity in the first stage of Part A, the study
      will proceed to the first stage of Part B (pembrolizumab plus chemotherapy).
    

Trial Arms

NameTypeDescriptionInterventions
High-Grade Extrapulmonary NECExperimentalPart A: 200 mg of pembrolizumab will be given every three weeks via IV infusion. Part B: 200 mg of pembrolizumab will be given every three weeks via IV infusion and, either 125 mg/m2 of irinotecan will be given via IV infusion in a two weeks on, one week off format in 3 week cycles, or 80 mg/m2 of paclitaxel will be given every week via IV infusion.
  • Pembrolizumab
  • Irinotecan
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be at least 18 years of age on day of signing informed consent.

          3. Have a histologically proven locally advanced or metastatic high grade (G3) poorly
             differentiated neuroendocrine carcinoma (NEC)

               1. Includes small cell and large cell neuroendocrine carcinoma of unknown primary or
                  any extrapulmonary site (and poorly differentiated NEC, not otherwise specified)

               2. 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)

               3. Other mixed tumors, e.g. mixed neuroendocrine neoplasms (MINENs) with NEC plus
                  adenocarcionoma, 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

          4. Have progressed during or after completion of first line systemic chemotherapy

               1. No limit to the number of prior chemotherapy regimens

               2. Early progression on/after adjuvant chemotherapy counts as firstline therapy

          5. Have at least one measurable disease based on RECIST 1.1

          6. 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).

               1. Patients with unsuccessful baseline biopsies may undergo an additional biopsy
                  attempt (at the same or a different site, determined by the investigator).

               2. 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.

               3. 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

          7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          8. Have a life expectancy of greater than 3 months.

          9. Demonstrate adequate organ function, all screening labs should be performed within 10
             days of treatment initiation.

         10. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours 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.

         11. 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 (Reference
             Section 5.7.2). Subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year.

         12. 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:

          1. 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
                  gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are excluded

          2. 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.

          3. Has a diagnosis of immunodeficiency

          4. 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

          5. Has a known history of active Bacillus Tuberculosis (TB).

          6. History of or high suspicion of Gilbert's disease (safety run-in, Part B only)

          7. Hypersensitivity to pembrolizumab or any of its excipients.

          8. 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.

          9. Documented progression on and/or intolerance/hypersensitivity to both paclitaxel and
             irinotecan (Part B only)

         10. 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)

         11. 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.

         12. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and 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.

         13. 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.

         14. Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

         15. Evidence for interstitial lung disease

         16. Has an active infection requiring systemic therapy.

         17. 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.

         18. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         19. 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.

         20. Has received prior therapy with an anti-Programmed Death 1 (PD-1), anti-Programmed
             Death Ligand 1 (PD-L1), or anti-PD-L2 agent.

         21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         22. Has known active Hepatitis B virus (e.g., HBsAg reactive) or Hepatitis C virus (e.g.,
             HCV RNA [qualitative] is detected).

         23. Has received a live vaccine within 30 days of planned start of study therapy.

        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
        vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:Over the duration of the study, which is estimated to be approximately 32 months.
Safety Issue:
Description:Proportion of subjects in the analysis population who have a radiographic response according to RECIST 1.1.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:Over the duration of the study, which is estimated to be approximately 32 months.
Safety Issue:
Description:The time from the first day of study treatment to death due to any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • NEC

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