A Multicenter Phase II Study of Pembrolizumab (MK-3475) in Patients With Advanced Small Bowel Adenocarcinomas
A Multicenter Phase II Study of Pembrolizumab (MK-3475) in Patients With Advanced Small Bowel Adenocarcinomas
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.
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.
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
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 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
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