Pembrolizumab Before Surgery for the Treatment of Resectable MSI-High Colon Cancer
This phase II trial studies the effect of pembrolizumab before surgery in treating patients with microsatellite instability (MSI)-high colon cancer that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study may help researchers learn how to target early stage colon cancer before it has developed resistance to immunotherapy, and to hopefully improve outcomes.
Inclusion Criteria
- Patients must have histologically confirmed colon adenocarcinoma
- No prior chemotherapy, targeted therapy, or immunotherapy for colon cancer
- Deemed to have surgically resectable disease
- Archival tissue block containing colon adenocarcinoma must be confirmed available prior to enrollment. MSI testing should be obtained prior to starting therapy
- Be willing and able to provide written informed consent/assent for the trial
- Be >= 18 years of age on day of signing informed consent
- Have a measurable primary lesion by lower endoscopy or computed tomography (CT)-imaging with a diameter of 1 or more centimeters
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Have no histologically confirmed disseminated disease by CT or positron emission tomography (PET)-CT staging
- Male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 90 days after the last dose of study treatment
- Absolute neutrophil count (ANC) >= 1500/uL (performed within 14 days of treatment initiation)
- Platelets >= 100 000/uL (performed within 14 days of treatment initiation)
- Hemoglobin >= 7.0 g/dL or >= 5.6 mmol/L (performed within 14 days of treatment initiation) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation) * Creatinine clearance (CrCl) should be calculated per institutional standard
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (performed within 14 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (performed within 14 days of treatment initiation)
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (performed within 14 days of treatment initiation)
Exclusion Criteria
- A WOCBP who has a positive urine pregnancy test during screening. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- 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
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Known hypersensitivity to pembrolizumab or any of its excipients
- If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- 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
- 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 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
- Has received prior therapy with an anti-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., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days of planned start of study therapy
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
- Has complications from colon cancer including but not limited to organ fistulas, bleeding and obstruction
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04231526.
PRIMARY OBJECTIVE:
I. To assess the feasibility of neoadjuvant pembrolizumab administration in microsatellite unstable (MSI high) colorectal cancer.
SECONDARY OBJECTIVE:
I. To evaluate tumor and immune response in early stage colon cancer after neoadjuvant pembrolizumab.
TRANSLATIONAL RESEARCH OBJECTIVES:
I. To evaluate tumor infiltrating lymphocyte (TIL) density in archival and resection specimens.
II. To compare the T cell repertoire of TILs, particularly those epitopes associated with high IFN gamma signatures by single cell sequencing, compared to circulating T cell repertoire before and after therapy with pembrolizumab in the neoadjuvant setting.
III. To evaluate changes induced by pembrolizumab in the immune micro-environment between diagnostic biopsy and resection specimens.
IIIa. To evaluate differences in TIL density using CD3, CD8, and CD45 by immunohistochemistry (IHC).
IIIb. To measure interferon-gamma associated gene expression before and after neoadjuvant treatment with pembrolizumab.
IIIc. To characterize infiltrating T cell presence and subtype in responders versus non-responders.
IV. To evaluate the association between fecal microbiome composition and tumor immune cell composition.
V. To characterize fecal microbiome composition diversity upon diagnosis, post-neoadjuvant pembrolizumab, post-operatively, during adjuvant therapy, and during post-adjuvant surveillance.
VI. To correlate TIL density and fecal microbiome composition with radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and pathologic response by Mandard criteria.
VII. To identify germline or somatic alterations associated with immune exclusion from the tumor environment.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within 2-5 weeks, patients undergo surgery, then receive standard of care adjuvant therapy consisting of oxaliplatin IV on day 1 every 2 weeks, leucovorin IV on day 1 every 2 weeks, fluorouracil IV bolus on day 1 then continuous infusion over 46-48 hours; or capecitabine BID on days 1-14 every 3 weeks for 24 weeks; or fluorouracil IV bolus on day 1 then continuous infusion over 46-48 hours and leucovorin IV on day 1 every 2 weeks for 24 weeks.
ARM B: Patients undergo standard of care surgery and receive adjuvant therapy consisting of oxaliplatin IV on day 1 every 2 weeks, leucovorin IV on day 1 every 2 weeks, fluorouracil IV bolus on day 1 then continuous infusion over 46-48 hours; or capecitabine BID on days 1-14 every 3 weeks for 24 weeks; or fluorouracil IV bolus on day 1 then continuous infusion over 46-48 hours and leucovorin IV on day 1 every 2 weeks for 24 weeks.
After completion of study treatment, patients are followed up periodically.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorArdaman Shergill
- Primary IDIRB19-1411
- Secondary IDsNCI-2020-13962
- ClinicalTrials.gov IDNCT04231526