Pembrolizumab and Stereotactic Body Radiation Therapy in Treating Patients with Liver Metastatic Colorectal Cancer

Status: Active

Description

This phase Ib trial studies the side effects of pembrolizumab and stereotactic body radiation therapy and how well they work in treating patients with colorectal cancer that has spread to the liver. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab and stereotactic body radiation therapy may work better in treating patients with colorectal cancer that has spread to the liver.

Eligibility Criteria

Inclusion Criteria

  • Be willing and able to provide written informed consent/assent for the trial
  • Have a diagnosis of histologically confirmed metastatic colorectal cancer to the liver (no other sites of metastatic disease) * Histologic confirmation of a colorectal primary tumor is acceptable if accompanied by radiographic evidence of metastatic disease
  • Tumor must be mismatch repair (MMR) proficient as determined by microsatellite instability or immunohistochemistry for MMR proteins * Microsatellite instability testing must be microsatellite instability (MSI)-stable or MSI-low * Or immunohistochemistry (IHC) for MMR proteins must demonstrate intact MMR proteins
  • Patient must be a candidate for SBRT to at least one intrahepatic lesion; there is no limit on the number of intrahepatic lesions the patient may have
  • Patient must be a surgical candidate with therapeutic goal of eradicating all known disease with one additional surgery; portal venous embolization is permitted to ensure resectability
  • Prior resection of extra-hepatic metastatic disease allowed if completed more than 12 months previous to study enrollment and no new extra-hepatic disease has been found
  • Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Fresh or archived colorectal cancer tissue, preferably from a hepatic metastatic site; archival tissue is acceptable for enrollment into this study; subjects who have no archival tissue available do not need to undergo a new biopsy solely for the purpose of this study
  • Subjects must have received at least one prior line of chemotherapy including an irinotecan or oxaliplatin-fluoropyrimidine-based systemic treatment for colorectal cancer
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Completed within 10 days of SBRT treatment initiation: Absolute neutrophil count (ANC) >= 1,500 /mcL
  • Completed within 10 days of SBRT treatment initiation: Platelets >= 100,000 / mcL
  • Completed within 10 days of SBRT treatment initiation: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Completed within 10 days of SBRT treatment initiation: Serum creatinine =< 1.5 X upper limit of normal (ULN) OR
  • Completed within 10 days of SBRT treatment initiation: Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
  • Completed within 10 days of SBRT treatment initiation: Serum total bilirubin =< 1.5 X ULN OR
  • Completed within 10 days of SBRT treatment initiation: Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Completed within 10 days of SBRT treatment initiation: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 5 X ULN for subjects with liver metastases
  • Completed within 10 days of SBRT treatment initiation: Albumin >= 2.5 mg/dL
  • Completed within 10 days of SBRT treatment initiation: International normalized ratio (INR) or prothrombin time (PT) =<1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Completed within 10 days of SBRT treatment initiation: 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 test within 10 days of initiating SBRT; 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

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 4 weeks of the initiation of SBRT
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 (first day of SBRT treatment) 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., =< grade 1 or at baseline) from adverse events due to a previously administered agent; prior radiotherapy to the liver is not allowed * 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
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the initiation of SBRT
  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • 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; subjects with previously resected brain metastases may participate provided it has been at least 6 months and no CNS progression has been identified
  • 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 known history of, or any evidence of active, non-infectious 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 cell death protein 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (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 or quantitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are not allowed

Locations & Contacts

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: Active
Contact: Dustin Alan Deming
Phone: 608-265-1700
Email: ddeming@medicine.wisc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab in combination with stereotactic body radiation therapy (SBRT) to the liver.

II. To determine the recurrence rate at 1 year following clearance of metastatic disease in the setting of treatment with SBRT and pembrolizumab.

SECONDARY OBJECTIVES:

I. To evaluate time to recurrence, disease free survival and overall survival in these patients.

TERTIARY OBJECTIVES:

I. To evaluate novel imaging biomarkers using positron emission tomography (PET)/magnetic resonance imaging (MR) to potentially improve noninvasive determination of response to therapy.

II. To determine if ablative radiotherapy in combination with pembrolizumab is able to induce an immune response in colorectal cancer (CRC) tumors indicated by an increase in tumor-infiltrating lymphocytes.

III. To investigate expression levels of PDL1 in CRC liver metastases following treatment with SBRT and pembrolizumab.

OUTLINE:

Patients undergo SBRT on day 0. After 2-4 weeks of SBRT, patients receive pembrolizumab intravenously (IV) over 30 minutes and then undergo surgery. After 4-12 weeks following surgery, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days and every 12 weeks thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Wisconsin Hospital and Clinics

Principal Investigator
Dustin Alan Deming

Trial IDs

Primary ID UW15063
Secondary IDs NCI-2016-01077, 2016-0303
Clinicaltrials.gov ID NCT02837263