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Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03136055
Recruitment Status : Recruiting
First Posted : May 2, 2017
Last Update Posted : March 5, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE April 18, 2017
First Posted Date  ICMJE May 2, 2017
Last Update Posted Date March 5, 2020
Actual Study Start Date  ICMJE August 10, 2017
Estimated Primary Completion Date February 28, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2020)
Overall Response Rate (ORR) [ Time Frame: Approximately 2 years ]
ORR is defined as the proportion of the subjects in the analysis population who demonstrated complete response (CR) or partial response (PR) radiographically according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by investigator. The analysis will include all subjects treated (ITT) who received at least one dose of the study treatment. If the final study consists of both Part A and Part B, the analysis will be done separately for each part.
Original Primary Outcome Measures  ICMJE
 (submitted: April 26, 2017)
Overall Response Rate [ Time Frame: Over the duration of the study, which is estimated to be approximately 32 months. ]
Proportion of subjects in the analysis population who have a radiographic response according to RECIST 1.1.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2020)
  • Overall Survival (OS) [ Time Frame: Over the duration of the study, which is estimated to be approximately 32 months. ]
    Overall survival is defined as the time from the first day of study treatment with protocol therapy to the date of death due to any cause. Kaplan-Meier method will be used to summarize OS. Median OS and its 95% confidence interval will be obtained for Part A and B (if available) separately.
  • Duration of Response (DOR) [ Time Frame: Over the duration of the study, which is estimated to be approximately 32 months. ]
    Duration of Response is defined as the time from the date of first response (CR or PR) until the date of disease progression or death. Kaplan-Meier method will be used to summarize DOR. Median DOR and its 95% confidence interval will be obtained for Part A and B (if available) separately. Only patients who have a demonstrated response will be used in final analysis.
  • Progression free survival (PFS) [ Time Frame: Over the duration of the study, which is estimated to be approximately 32 months. ]
    Progression free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause, whichever occurs first, as determined by The immune-related response criteria (irRC) for the immune-related progression-free survival (irPFS) and RECIST v1.1 for PFS. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment. Kaplan-Meier method will be used to summarize progression free survival; median irPFS and PFS will be estimated with 95% confidence interval for Part A and B (if available) separately.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2017)
Overall Survival [ Time Frame: Over the duration of the study, which is estimated to be approximately 32 months. ]
The time from the first day of study treatment to death due to any cause.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
Official Title  ICMJE A Pilot Study of Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
Brief Summary 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model 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).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE High Grade Malignant Neuroendocrine Carcinoma (Diagnosis)
Intervention  ICMJE
  • Drug: Pembrolizumab
    200 mg every 3 weeks via IV infusion.
    Other Name: Keytruda
  • Drug: Irinotecan

    For patients in part B receiving pembrolizumab and chemotherapy with irinotecan. The starting dose for the safety lead-in is 125 mg/m2 irinotecan via IV infusion in a 2 weeks on, 1 week off format over 3 week cycles.

    If the initial dose is not tolerated, the dose level will be decreased to 100 mg/m2.

    Other Name: Camptosar
  • Drug: Paclitaxel
    For patients in part B receiving pembrolizumab and chemotherapy with paclitaxel. Patients will receive 80 mg/m2 of paclitaxel via IV infusion every week, with treatment breaks as needed.
    Other Name: Taxol
Study Arms  ICMJE Experimental: High-Grade Extrapulmonary NEC

Part 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.
Interventions:
  • Drug: Pembrolizumab
  • Drug: Irinotecan
  • Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 26, 2017)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 31, 2022
Estimated Primary Completion Date February 28, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
  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 (GEP) neuroendocrine tumors (NET) (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 (HCV)(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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Emily Bergsland, MD 877-827-3222 cancertrials@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03136055
Other Study ID Numbers  ICMJE 169524
NCI-2017-01728 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Emily Bergsland, MD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP