OAR-Based, Dose Escalated SBRT With Real Time Adaptive MRI Guidance for Liver Metastases
OAR-Based, Dose Escalated SBRT With Real Time Adaptive MRI Guidance for Liver Metastases
Stereotactic Body Radiation Therapy (SBRT) is a noninvasive local therapy with proven
 efficacy in a number of solid tumor types. However, colorectal cancer (CRC) liver metastases
 have been shown to be particularly resistant to SBRT, and often are found to have
 significantly worse rates of control compared with other histologies. Higher SBRT dose was
 recently shown to improve local control in CRC pulmonary metastases, however, increasing dose
 delivery with SBRT has been limited based on the risk of toxicity to adjacent structures, and
 the ability to visualize them during treatment. This is particularly relevant in treating
 liver tumors, as tumor and small bowel movement can often make tumor targeting and
 organs-at-risk (OAR) avoidance especially difficult. MRI-guided SBRT for liver tumors is both
 safe and feasible and offers an as yet unprecedented opportunity to achieve the highest
 possible safe dose to liver tumors.

 The purpose of this trial is to identify a safe maximum tolerated dose level for MRI-guided
 SBRT treatment of bowel and liver metastases, respectively.

 Eligible participants will be on study for up to 12 months.
Inclusion Criteria:

 -  For Phase I trial, have a diagnosis of histologically confirmed or clinically
 suspected metastatic cancer to the liver; for Phase IB trial have have a diagnosis of
 histologically confirmed or clinically suspected metastatic CRC to the liver.

 -  Participant must be a candidate for SBRT to at least one intrahepatic lesion but no
 more than 6 intrahepatic lesions.

 -  Participant must be a candidate for treatment on the ViewRay treatment unit. Must be
 screened to rule out implants and devices that are not MRI compatible.

 -  Be willing and able to provide written informed consent.

 -  Participants may be chemotherapy-naïve or have had prior chemotherapy up to two weeks
 prior to study entry.

 -  No active central nervous system (CNS) metastatic disease. NOTE: Subjects with CNS
 involvement must meet all of the following to be eligible:

 -  At least 28 days from prior definitive treatment of their CNS disease by surgical
 resection, SBRT or Whole Brain Radiation Therapy (WBRT) at the time of
 registration

 -  AND asymptomatic and off systemic corticosteroids and/or enzyme-inducing
 antiepileptic medications for brain metastases for >14 days prior to
 registration.

 -  Demonstrate adequate organ function as defined in the following table; all screening
 labs should be performed within 28 days of SBRT treatment initiation.

 -  Platelet count greater than or equal to 50000 /µL

 -  Absolute Neutrophil Count (ANC) greater than or equal to 1000 /µL

 -  Hemoglobin (Hgb) greater than or equal to 8 g/dL or greater than or equal to 5.6
 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of
 assessment)

 -  Serum creatinine OR measured or calculated creatinine clearance (GFR can also be
 used in place of creatinine or CrCl) Creatinine/Calculated creatinine clearance
 (CrCl) greater than or equal to 30 mL/min for subject with creatinine levels
 greater than 1.5 X institutional upper limit of normal (ULN)

 -  Bilirubin greater than or equal to 1. 5 × ULN OR direct bilirubin greater than or
 equal to ULN for participants with total bilirubin levels greater than 1.5 ULN

 -  Aspartate aminotransferase (AST) and ALT (SGPT) greater than or equal to 5 × ULN
 for subjects with liver metastases

 -  Alanine aminotransferase (ALT) greater than or equal to 2.5 × ULN, greater than
 or equal to 5 × ULN in setting of metastatic disease

 -  International Normalized Ratio (INR) or Prothrombin Time (PT) greater than or
 equal to 1.5 X ULN unless participant is receiving anticoagulant therapy as long
 as PT or PTT is within therapeutic range of intended use of anticoagulants

 -  Activated Partial Thromboplastin Time (aPTT) greater than or equal to 1.5 X ULN
 unless participant is receiving anticoagulant therapy as long as PT or PTT is
 within therapeutic range of intended use of anticoagulants

 -  For participants enrolled on the liver dose escalation arm, screening labs must be
 consistent with Child Pugh class A unless therapeutic anticoagulation places them in
 Child Pugh B. In that case, trial entry or exclusion will be at the discretion of the
 treating physician.

 -  Have a performance status of 2 or less on the Eastern Cooperative Oncology Group
 (ECOG) performance scale.

 -  Life expectancy of > 12 weeks.

 -  Women of childbearing potential (WOCP) should have a negative urine or serum pregnancy
 test prior to initiation of radiation therapy. If the urine test is positive or cannot
 be confirmed as negative, a serum pregnancy test will be required.

 -  WOCP must not be pregnant or breast-feeding.

 -  WOCP must be willing to use an effective method of birth control such as an oral,
 implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device
 (IUD), use of a double barrier method (condoms, sponge, diaphragm, or vaginal ring
 with spermicidal jellies or cream), or total abstinence for the duration of the
 radiotherapy and 60 days thereafter.

 NOTE: A person of childbearing potential is anyone (regardless of sexual orientation,
 gender identity, having undergone a tubal ligation, or remaining celibate by choice) who
 was born with a uterus and at least one ovary and meets both of the following criteria:

 -  Is post-menarcheal (i.e., has had at least one prior menses)

 -  Has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally
 postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in
 the preceding 12 consecutive months).

 -  Participant is willing and able to comply with the protocol for the duration of the
 study including undergoing treatment and scheduled visits and examinations including
 follow up.

 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.

 -  History of a second invasive cancer in the last 3 years (except for appropriately
 treated low-risk prostate cancer, treated non-melanoma skin cancer, appropriately
 treated ductal carcinoma in situ or early stage invasive carcinoma of breast
 appropriately treated in situ/early stage cervical/endometrial cancer.

 -  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 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 follow up
 scans or visits.

 -  Has a primary tumor histology of germ cell tumor, leukemia, or lymphoma.

 -  Has a primary liver cancer such as cholangiocarcinoma or hepatocellular carcinoma.

 -  Has had prior radiation therapy that significantly overlaps with the liver.

 -  Has a diagnosis of Crohn's disease, ulcerative colitis, or scleroderma.

 -  Participants with Gilbert's disease or other primary disorders of bilirubin metabolism
 will not be allowed on the trial.

 -  Has pre-existing liver disease such that patients are classified as Child Pugh B or
 worse. If the participant is anti-coagulated such that their INR places them in the
 CP-B classification, exclusion or inclusion will be at the discretion of the treating
 physician.

 -  Pregnancy or women of childbearing potential and men who are sexually active and
 refuse to use medically acceptable forms of contraception.

 -  Participants with implanted hardware that would preclude MRIs.