Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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 : April 9, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Emily Bergsland, University of California, San Francisco

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

Condition or disease Intervention/treatment Phase
High Grade Malignant Neuroendocrine Carcinoma (Diagnosis) Drug: Pembrolizumab Drug: Irinotecan Drug: Paclitaxel Phase 2

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).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
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
Official Title: A Pilot Study of Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
Actual Study Start Date : June 20, 2017
Estimated Primary Completion Date : June 19, 2019
Estimated Study Completion Date : June 19, 2020


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03136055


Contacts
Layout table for location contacts
Contact: Emily Bergsland, MD 877-827-3222 clinicaltrials@ucsf.edu

Locations
Layout table for location information
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94115
Contact: Clinical Trials Office - UCSF Helen Diller Family Comprehensi    877-827-3222    cancertrials@ucsf.edu   
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Clinical Trials Office    877-442-3324      
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Nitya Raj, MD    646-888-4185    rajn@mskcc.org   
Sponsors and Collaborators
University of California, San Francisco
Merck Sharp & Dohme Corp.
Investigators
Layout table for investigator information
Principal Investigator: Emily Bergsland, MD University of California, San Francisco

Layout table for additonal information
Responsible Party: Emily Bergsland, Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03136055     History of Changes
Other Study ID Numbers: 169524
First Posted: May 2, 2017    Key Record Dates
Last Update Posted: April 9, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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

Keywords provided by Emily Bergsland, University of California, San Francisco:
NEC

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Carcinoma, Neuroendocrine
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Paclitaxel
Albumin-Bound Paclitaxel
Pembrolizumab
Irinotecan
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors