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Pembrolizumab in Treating Patients With Small Bowel Adenocarcinoma That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02949219
Recruitment Status : Active, not recruiting
First Posted : October 31, 2016
Results First Posted : January 10, 2020
Last Update Posted : January 10, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
This phase II trial studies how well pembrolizumab works in treating patients with small bowel adenocarcinoma that has spread to other places in the body or that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Metastatic Small Intestinal Adenocarcinoma Recurrent Small Intestinal Carcinoma Unresectable Small Intestinal Carcinoma Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether pembrolizumab administered to small bowel adenocarcinoma (SBA) patients demonstrates antitumor activity as measured by the confirmed response rate.

SECONDARY OBJECTIVES:

I. To assess survival endpoints (overall survival [OS], progression free survival [PFS]), including stratified analysis by tumor site.

II. To assess whether pembrolizumab is safe in SBA patients by assessing adverse events.

TERTIARY OBJECTIVES:

I. To determine whether PD-L1 expression, as measured by immunohistochemistry (IHC), or microsatellite instability (MSI) status is associated with the response rate overall.

II. To determine if Bim levels in tumor-reactive CD11ahighPD-1+CD8+ peripheral blood T cells can objectively monitor responses to pembrolizumab and to determine if excessive release of soluble B7-H1 (soluble [s]PD-L1) by the tumor leads to Bim upregulation and treatment resistance in SBA.

III. To determine if other tissue-based factors, such as total mutational burden, correlate with response to pembrolizumab.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until disease progression, and then every 6 months for up to 5 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Phase II Study of Pembrolizumab (MK-3475) in Patients With Advanced Small Bowel Adenocarcinomas
Actual Study Start Date : March 24, 2017
Actual Primary Completion Date : January 31, 2019
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Overall Confirmed Response Rate [ Time Frame: 1 year (up to 18 cycles) ]
    The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients.


Secondary Outcome Measures :
  1. Progression Free Survival [ Time Frame: From study entry to the first of either disease progression or death from any cause, assessed up to 2 years ]
    Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

  2. Overall Survival [ Time Frame: From study entry to death from any cause, assessed up to 2 years ]
    Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

  3. Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events Regardless of Attribution [ Time Frame: Up to 2 years ]
    number of participants who experienced at least one grade 3 or higher adverse events regardless of attribution assessed by National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03


Other Outcome Measures:
  1. Biomarker Levels [ Time Frame: Up to 5 years ]
    Correlated with clinical data (i.e. response, overall survival, progression free survival, adverse events). These correlations will be done using the Chi-square or Fisher?s exact test for categorical data and Kaplan-Meier methods (including the log-rank test) for the survival endpoints. Univariate Cox regression models will also be done to assess for marker effects on survival endpoints. Descriptive statistics and graphical methods will be used to summarize the data as well. All these analyses will be done overall and by MMR/microsatellite instability status.



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have biopsy-proven adenocarcinoma of the small bowel at any site (duodenum, jejunum, ileum), excluding ampullary and appendiceal tumors
  • Have locally advanced (unresectable) or metastatic small bowel adenocarcinoma
  • Willing and able to provide written informed consent for the trial
  • Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Had at least one prior line of systemic chemotherapy for metastatic disease; adjuvant therapy would not count toward first-line therapy unless patient recurs less than 6 months after completion of that regimen
  • Willing to provide blood and tissue (can be archival) samples for mandatory research purposes
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (1.50 x 10^9 /L) obtained =< 28 days prior to registration
  • Platelet count >= 100,000/mm^3 (100 x 10^9 /L) obtained =< 28 days prior to registration
  • Hemoglobin >= 9.0 g/dL (5.6 mmol/L or 90 g/L) without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) obtained =< 28 days prior to registration
  • Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN obtained =< 28 days prior to registration
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases obtained =< 28 days prior to registration
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance must be >= 60 mL/min for subjects with creatinine levels > 1.5 X ULN using the Cockcroft-Gault formula (glomerular filtration rate [GFR] >= 60 mL/min [1.0 mL/s/m^2] can also be used in place of creatinine or creatinine clearance [CrCl]) obtained =< 28 days prior to registration
  • Female subject of childbearing potential have a negative urine or serum pregnancy =< 7 days prior to registration; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

    • Note: 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

Exclusion Criteria:

  • Non-adenocarcinoma histology
  • Adenocarcinoma originating in the ampulla or appendix; (duodenal tumors that involve the ampulla but originate in the duodenum are eligible)
  • Currently participating and receiving study therapy, or have participated in a study of an investigational agent and received study therapy, or used an investigational device =< 4 weeks of registration
  • Diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy =< 7 days prior to registration
  • History of active TB (bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Any of the following:

    • Prior anti-cancer monoclonal antibody (mAb) =< 4 weeks prior to registration
  • Prior chemotherapy, targeted small molecule therapy, or radiation therapy =< 2 weeks prior to registration or who has not recovered to =< grade 1 or baseline from adverse events due to the previously administered agent

    • Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
  • Received major surgery =< 2 weeks prior to registration, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Known additional malignancy that is progressing or requires active treatment or that may interfere with interpretation of response evaluation, in the judgment of the investigator
  • 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 =< 4 weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids =< 7 days prior to registration; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Active autoimmune disease (including but not limited to: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn?s disease, patients with a history of symptomatic disease [e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener?s granulomatosis)]; CNS or motor neuropathy considered of autoimmune origin [e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis]) 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
  • Known history of or any evidence of active, non-infectious pneumonitis
  • Active infection requiring systemic therapy
  • 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
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • 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
  • Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or other immune checkpoint inhibitor (e.g. anti-CTLA4)
  • History of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid RNA [qualitative] is detected)
  • 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): NCT02949219


Locations
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United States, Arizona
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, District of Columbia
MedStar Georgetown University Hospital
Washington, District of Columbia, United States, 20007
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, South Dakota
Rapid City Regional Hospital
Rapid City, South Dakota, United States, 57701
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Robert McWilliams Academic and Community Cancer Research United
  Study Documents (Full-Text)

Documents provided by Academic and Community Cancer Research United:

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT02949219    
Other Study ID Numbers: RU021502I
NCI-2016-01577 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU021502I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: October 31, 2016    Key Record Dates
Results First Posted: January 10, 2020
Last Update Posted: January 10, 2020
Last Verified: December 2019

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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.: No
Additional relevant MeSH terms:
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Carcinoma
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents