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High Grade Malignant Neuroendocrine Carcinoma (Diagnosis)Phase 2NCT03136055

Pembrolizumab-based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas

A Phase 2 study testing Pembrolizumab, Irinotecan and Paclitaxel in people with High Grade Malignant Neuroendocrine Carcinoma (Diagnosis), run by University of California, San Francisco at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages 18 years and older
What is being tested?
Pembrolizumab, Irinotecan and Paclitaxel
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
3 sitesUnited States
Study dates
20 Jun 2017to 31 Oct 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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 <=1.5 X upper limit of normal (ULN) OR >=60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
  • Serum total bilirubin <= 1.5 X ULN OR Direct bilirubin <= ULN for subjects with total bilirubin levels > 1.5 ULN
  • aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) <=2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • Albumin >2.5 g/dL
  • International Normalized Ratio (INR) or Prothrombin Time (PT) 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.
  • 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.
  • 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.

Who cannot join

  • 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.
  • 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.
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  • 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
  • Has a known history of active Bacillus Tuberculosis (TB).
  • 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 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-Programmed Death 1 (PD-1), anti-Programmed Death Ligand 1 (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 virus (e.g., HBsAg reactive) or Hepatitis C virus (HCV)(e.g., HCV 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.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • University of California, San Francisco

    San Francisco, California, 94115

Other trials in United States

About this study

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

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

Read the detailed description

PRIMARY OBJECTIVE:

  1. Evaluate the best overall response rate (ORR) of pembrolizumab or pembrolizumab plus chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (investigator-reported).

SECONDARY OBJECTIVE:

  1. To determine the safety and tolerability of pembrolizumab-based therapy in this patient population.
  2. To evaluate duration of response (DOR) in participants receiving pembrolizumab or pembrolizumab plus chemotherapy.
  3. To evaluate progression free survival (PFS) in participants treated with pembrolizumab or pembrolizumab plus chemotherapy (median PFS and 18 wk PFS).
  4. To evaluate overall survival (OS) in participants receiving pembrolizumab or pembrolizumab plus chemotherapy.

OUTLINE:

Part A: Participants are treated with pembrolizumab alone. An adaptive Simon's two-stage design was used, and 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).

Part B: Participants are treated with pembrolizumab plus chemotherapy (physician's choice, paclitaxel or irinotecan). Patients with stable disease (SD) or better after 9 cycles (27 weeks) of pembrolizumab-based therapy will have the option to continue with pembrolizumab alone, unless the first partial response (PR) or complete response (CR) is noted at 27 weeks.

All participants will undergo a pre-treatment tumor biopsy (unless the tumor is inaccessible and/or a biopsy is not felt to be in the participant's best interest). Participants may continue study treatment until progressive disease (PD), unacceptable adverse events, inter-current illness that prevents further administration of treatment, investigator's decision to withdraw the participant, the participant withdraws consent, pregnancy of the participant, noncompliance with trial treatment or procedure requirements, participant receives 35 treatments (approximately 2 years) of pembrolizumab, or administrative reasons requiring cessation of treatment.

Keywords
NEC
Medical subject headings
Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT03136055
Study groupRoleWhat they receive
Part A: Pembrolizumab onlyExperimentalParticipants will receive 200 mg of pembrolizumab via IV over 30 minutes every 3 weeks for 24 months or 35 administrations (whichever comes first).
Receives: Drug: Pembrolizumab
Part B: Pembrolizumab + ChemotherapyExperimentalParticipants will receive 200 mg of pembrolizumab via IV over 30 minutes every 3 weeks for 24 months or 35 administrations (whichever comes first) and chemotherapy treatment of 125 mg/m^2 of irinotecan via IV on days 1 and 8 of each 21-day cycle or paclitaxel via IV on days 1, 8, and 15 of each 21-day cycle per physician discretion
Receives: Drug: Pembrolizumab; Drug: Irinotecan; Drug: Paclitaxel

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response Rate (ORR)

    ORR is defined as the percentage of participants 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.

    Measured: Approximately 2 years

Secondary outcomes (3)

  1. Overall Survival (OS)

    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.

    Measured: Over the duration of the study, which is estimated to be approximately 32 months.

  2. Duration of Response (DOR)

    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. Duration of response will be reported for Part A and B (if available) separately. Only patients who have a demonstrated response will be used in final analysis.

    Measured: Over the duration of the study, which is estimated to be approximately 32 months.

  3. Progression Free Survival (PFS)

    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 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 median PFS with 95% confidence interval for Part A and B (if available) separately.

    Measured: Over the duration of the study, which is estimated to be approximately 32 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2017
  2. Study start20 Jun 2017
  3. Primary completion31 Oct 2021
  4. Study completion31 Oct 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03136055
Sponsor's protocol ID
169524
Other IDs
NCI-2017-01728
Status last verified
Dec 2022
First submitted
18 Apr 2017
Last updated
27 Dec 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Raj N, Chan JA, Wang SJ, Aggarwal RR, Calabrese S, DeMore A, Fong L, Grabowsky J, Hope TA, Kolli KP, Mulvey CK, Munster PN, Perez K, Punn S, Reidy-Lagunes D, Von Fedak S, Zhang L, Bergsland EK. Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas. Br J Cancer. 2023 Aug;129(2):291-300. doi: 10.1038/s41416-023-02298-8. Epub 2023 May 19.

    PubMed 37208512

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab, Irinotecan and Paclitaxel in people with High Grade Malignant Neuroendocrine Carcinoma (Diagnosis), run by University of California, San Francisco at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (ORR) (time frame: Approximately 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03136055, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Dec 2022; AzTrials last refreshed its copy on 6 Nov 2026.

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