Pembrolizumab for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma (Pembro NEC)
Primary Purpose
Neuroendocrine Tumors
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab Injection
Sponsored by
![University of Utah](https://trials-media.s3.amazonaws.com/orgs/university-of-utah.jpeg)
About this trial
This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring high grade
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed, metastatic or unresectable neuroendocrine carcinoma of non-pulmonary origin, high grade as indicated by Ki-67 >20% and/or > 20 mitoses/10 hpf. Patients must have existing Ki-67 results from archival tissue or available tissue for Ki-67 testing. If no archival tissue is available the subject must agree to a fresh biopsy for testing to qualify for the study.
- Patients must have progressed during or after first-line treatment for metastatic or unresectable disease with either a platinum-based regimen (e.g. carboplatin + etoposide (VP-16), cisplatin + VP-16, FOLFOX) OR temozolomide-based regimen. Patients must have failed at least one line of therapy but no maximum number of therapies is exclusionary (i.e. second-line therapy and beyond).
- Have measurable disease based on Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST).
- Be greater than or equal to 18 years of age on day of signing informed consent.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- Demonstrate adequate organ function as defined in the protocol, all screening labs should be performed within 14 days of treatment initiation.
- Subjects with a history of known central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment. Definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy.
- 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.
- Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy.
- Last dose of any antineoplastic therapy greater than or equal to 2 weeks (including chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents). Patients receiving hormone manipulation (e.g. selective estrogen receptor modulators (SERMs), aromatase inhibitors, luteinizing hormone-releasing hormone (LHRH} agonist, etc.) for reasons other than treatment of metastatic breast cancer may continue this treatment at the discretion of the investigator.
- Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion Criteria:
- 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 2 weeks of the first dose of treatment.
- Has a diagnosis of immunodeficiency or receiving steroid therapy of any other form of immunosuppressive therapy within 7 days prior to first dose of trial treatment. Subjects who receive daily steroid replacement therapy serve as an exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone equivalent doses) is an example of replacement therapy.
- Has a known history of active Bacillus Tuberculosis (TB).
- 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.
- 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., less than or equal to Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with less than or equal to 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. Patients receiving hormone manipulation (e.g. tamoxifen, aromatase inhibitors, LHRH agonist, etc.) for reasons other than treatment of metastatic breast cancer may continue this treatment at the discretion of the investigator.
- 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. Patients on long-term adjuvant therapy with no evidence of disease are not excluded if felt appropriate by investigator.
- 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 2 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.
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, 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 known history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- 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 (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., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
- 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.
Sites / Locations
- Huntsman Cancer Institute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Pembrolizumab, all patients
Arm Description
Outcomes
Primary Outcome Measures
Overall Response Rate
Overall response was measured using Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST). At baseline, lesions found on CT or MRI imaging are cataloged as "target" or "non-target" lesions, and the longest dimensions of target lesions (or shortest dimension of target lymph nodes) are summed. irRECIST defines Complete Response (irCR) as a complete disappearance of all lesions after baseline. Partial Response (irPR) is defined as a 30% or more decrease in the target lesion measurements. Overall response rate is defined the percentage of participants with a best response of irCR + irPR.
Secondary Outcome Measures
Clinical Benefit Rate
Clinical benefit was measured using irRECIST. At baseline, lesions found on CT or MRI imaging are cataloged as "target" or "non-target" lesions, and the longest dimensions of target lesions (or shortest dimension of target lymph nodes) are summed. irRECIST defines irCR as a complete disappearance of all lesions after baseline. irPR is defined as a 30% or more decrease in the target lesion measurements. Progressive Disease (irPD) is a defined as a 20% or more increase in target lesion measurements. Stable Disease (irSD) is neither a sufficient shrinkage to qualify as irPR or irCR nor an increase that would qualify as irPD. Clinical Benefit Rate is defined as the percentage of participants with a best response of irCR + irPR + irSD.
Median Progression Free Survival
Progression free survival (PFS) is the length of time during and after treatment that a participant lives and the disease does not get worse. PFS was measured as the time from first dose of pembrolizumab until disease progression by irRECIST criteria (>= 20% increase in target lesion measurements), and is reported as the median number of days patients survived without disease progression as calculated by the Kaplan-Meier method.
Median Overall Survival
Overall survival (OS) is the length of time from the start of treatment that a participant lives. OS was measured as the time from first dose of pembrolizumab until the death of the participant or the end of follow-up (whichever was first), and is reported as the median number of days patients survived as calculated by the Kaplan-Meier method. This study was intended to follow participants up to four years after the initiation of study treatment, but the study and the follow-up period were terminated prematurely. The maximum follow up was 360 days.
Number of Patients With Adverse Events Reported
Adverse Events were reported using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Each adverse event reported is assigned a severity grade from 1 to 5, where 1 is mild, 2 is moderate, 3 is severe, 4 is life threatening, and 5 indicates the event resulted in death. The number of patients experiencing any Grade 1-2 event and the number of patients experiencing any Grade 3 event are reported. There were no Grade 4 or Grade 5 events reported on this study. AEs were reported during study treatment and up to 90 days after last dose of treatment.
Full Information
NCT ID
NCT03190213
First Posted
June 13, 2017
Last Updated
June 18, 2021
Sponsor
University of Utah
Collaborators
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT03190213
Brief Title
Pembrolizumab for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma
Acronym
Pembro NEC
Official Title
Pembrolizumab for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Terminated
Why Stopped
Update on clinical development: after discussions with the drug manufacturer, the PI has decided to discontinue the trial.
Study Start Date
December 4, 2017 (Actual)
Primary Completion Date
December 13, 2018 (Actual)
Study Completion Date
March 11, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah
Collaborators
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is an open label, non-randomized phase 2 study to assess overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression free survival (PFS) in patients with high grade neuroendocrine tumors treated with pembrolizumab 200mg Q 3 Weeks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors
Keywords
high grade
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is an open label, non-randomized phase 2 study
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pembrolizumab, all patients
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab Injection
Intervention Description
Pembrolizumab at a dose of 200 mg will be administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or discontinuation due to unacceptable toxicity for a maximum of 2 years. We anticipate on average patients will remain on treatment for approximately 24 weeks.
Primary Outcome Measure Information:
Title
Overall Response Rate
Description
Overall response was measured using Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST). At baseline, lesions found on CT or MRI imaging are cataloged as "target" or "non-target" lesions, and the longest dimensions of target lesions (or shortest dimension of target lymph nodes) are summed. irRECIST defines Complete Response (irCR) as a complete disappearance of all lesions after baseline. Partial Response (irPR) is defined as a 30% or more decrease in the target lesion measurements. Overall response rate is defined the percentage of participants with a best response of irCR + irPR.
Time Frame
planned for up to two years from baseline; actual time was up to 230 days (average of 70.5 days)
Secondary Outcome Measure Information:
Title
Clinical Benefit Rate
Description
Clinical benefit was measured using irRECIST. At baseline, lesions found on CT or MRI imaging are cataloged as "target" or "non-target" lesions, and the longest dimensions of target lesions (or shortest dimension of target lymph nodes) are summed. irRECIST defines irCR as a complete disappearance of all lesions after baseline. irPR is defined as a 30% or more decrease in the target lesion measurements. Progressive Disease (irPD) is a defined as a 20% or more increase in target lesion measurements. Stable Disease (irSD) is neither a sufficient shrinkage to qualify as irPR or irCR nor an increase that would qualify as irPD. Clinical Benefit Rate is defined as the percentage of participants with a best response of irCR + irPR + irSD.
Time Frame
planned for up to two years from baseline; actual time was up to 230 days (average of 70.5 days)
Title
Median Progression Free Survival
Description
Progression free survival (PFS) is the length of time during and after treatment that a participant lives and the disease does not get worse. PFS was measured as the time from first dose of pembrolizumab until disease progression by irRECIST criteria (>= 20% increase in target lesion measurements), and is reported as the median number of days patients survived without disease progression as calculated by the Kaplan-Meier method.
Time Frame
planned for up to four years from baseline; actual time was up to 230 days (average of 70.5 days)
Title
Median Overall Survival
Description
Overall survival (OS) is the length of time from the start of treatment that a participant lives. OS was measured as the time from first dose of pembrolizumab until the death of the participant or the end of follow-up (whichever was first), and is reported as the median number of days patients survived as calculated by the Kaplan-Meier method. This study was intended to follow participants up to four years after the initiation of study treatment, but the study and the follow-up period were terminated prematurely. The maximum follow up was 360 days.
Time Frame
planned for up to four years from baseline; actual time was up to 230 days (average of 70.5 days)
Title
Number of Patients With Adverse Events Reported
Description
Adverse Events were reported using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Each adverse event reported is assigned a severity grade from 1 to 5, where 1 is mild, 2 is moderate, 3 is severe, 4 is life threatening, and 5 indicates the event resulted in death. The number of patients experiencing any Grade 1-2 event and the number of patients experiencing any Grade 3 event are reported. There were no Grade 4 or Grade 5 events reported on this study. AEs were reported during study treatment and up to 90 days after last dose of treatment.
Time Frame
planned for up to two years of treatment plus 90 days; actual time was up to 338 days (average of 170 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed, metastatic or unresectable neuroendocrine carcinoma of non-pulmonary origin, high grade as indicated by Ki-67 >20% and/or > 20 mitoses/10 hpf. Patients must have existing Ki-67 results from archival tissue or available tissue for Ki-67 testing. If no archival tissue is available the subject must agree to a fresh biopsy for testing to qualify for the study.
Patients must have progressed during or after first-line treatment for metastatic or unresectable disease with either a platinum-based regimen (e.g. carboplatin + etoposide (VP-16), cisplatin + VP-16, FOLFOX) OR temozolomide-based regimen. Patients must have failed at least one line of therapy but no maximum number of therapies is exclusionary (i.e. second-line therapy and beyond).
Have measurable disease based on Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST).
Be greater than or equal to 18 years of age on day of signing informed consent.
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
Demonstrate adequate organ function as defined in the protocol, all screening labs should be performed within 14 days of treatment initiation.
Subjects with a history of known central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment. Definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy.
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.
Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy.
Last dose of any antineoplastic therapy greater than or equal to 2 weeks (including chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents). Patients receiving hormone manipulation (e.g. selective estrogen receptor modulators (SERMs), aromatase inhibitors, luteinizing hormone-releasing hormone (LHRH} agonist, etc.) for reasons other than treatment of metastatic breast cancer may continue this treatment at the discretion of the investigator.
Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion Criteria:
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 2 weeks of the first dose of treatment.
Has a diagnosis of immunodeficiency or receiving steroid therapy of any other form of immunosuppressive therapy within 7 days prior to first dose of trial treatment. Subjects who receive daily steroid replacement therapy serve as an exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone equivalent doses) is an example of replacement therapy.
Has a known history of active Bacillus Tuberculosis (TB).
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.
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., less than or equal to Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with less than or equal to 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. Patients receiving hormone manipulation (e.g. tamoxifen, aromatase inhibitors, LHRH agonist, etc.) for reasons other than treatment of metastatic breast cancer may continue this treatment at the discretion of the investigator.
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. Patients on long-term adjuvant therapy with no evidence of disease are not excluded if felt appropriate by investigator.
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 2 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.
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, 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 known history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
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 (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., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
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.
Facility Information:
Facility Name
Huntsman Cancer Institute
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Pembrolizumab for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma
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