This clinical trial will be conducted as a single-center, open-label, Phase I/2 trial to
evaluate the feasibility and safety of Yttrium-90 radioembolization (Y90-RE) in combination
with a fixed dose of of immunotherapy (durvalumab - 750 mg) in subjects with
liver-predominant, metastatic colorectal cancer (mCRC), which is mismatch repair
proficient/microsatellite stable (pMMR/MSS).
The purpose of this clinical trial is to find out more about the side effects of
immunotherapy with a form of radiation treatment for the cancer in the liver called
Yttrium-90 RadioEmbolization (Y90-RE). An immunotherapy drug, durvalumab, will be given
intravenously every 2 weeks. Investigators are studying what doses of durvalumab are safe for
people in combination with this form of radiation treatment. Patients in this study will
receive durvalumab, which is experimental and not approved by the U.S. Food and Drug
Administration (FDA) for metastatic colorectal cancer. Microscopic radioactive particles
(TheraSphere®) will be used for radioembolization to deliver the Y90 drug to the liver.
The number of doses of the immunotherapy drug (range: 2 to 5) will depend on the cohort
patients are assigned to. There is no placebo. Everyone on the study is treated with
immunotherapy alongside Y90-RadioEmbolization.
- Age ≥18 years
- Histological or cytological confirmation of colorectal cancer with metastasis to the
liver. Mismatch repair or microsatellite instability status of the tumor needs to be
known. Tumors need to be mismatch repair proficient (for mismatch repair deficient
tumors immunotherapy is already approved).
- Patient must have at least 1 liver lesion measurable as defined in the protocol
- Must have liver metastases and be appropriate for treatment with Y-90
radioembolization therapy as determined by the treating medical oncologist and
interventional radiologist/oncologist, and nuclear medicine physician(s). NOTE: the
goal of therapy is safety and parenchymal sparing. Typically, since the treatment is
personalized, the goal is to have at least 30% liver parenchymal sparing post
- Must have a metastatic focus amendable to biopsy. It is permissible to use same or
alternative lesion for biopsy for assessment for tumor response and changes in
microenvironment (mandatory pre- and post-Y90-RE biopsy).
- At least 2 but no more than 3 lines of therapy allowed in metastatic setting. These
include at least treatment with a fluoropyrimidine, oxaliplatin, and/or
irinotecan-based therapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR
therapy, unless deemed intolerant or not suitable by the treating oncologist. NOTE:
adjuvant and/or maintenance chemotherapy does not count as an additional line of
therapy. (Patients with more than 3 lines of therapy are at risk for liver disease
from prior systemic therapies and would not be reasonable candidates for Y90-RE).
- ECOG Performance Status (PS) 0 or 1.
- Negative serum pregnancy test done ≤7 days prior to registration, for persons of
childbearing potential only.
- Females of childbearing potential (FOCBP), must use appropriate method(s) of
contraception. FOCBP are defined as those who are not surgically sterile (i.e.,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
postmenopausal (defined as 12 months with no menses without an alternative medical
cause). Additionally, FOCBP must agree to follow instructions for method(s) of
contraception for the duration of treatment with durvalumab plus 5 half-lives of
durvalumab (13 weeks) plus 30 days (duration of ovulatory cycle) for a total of 17
weeks post-treatment completion (details in appendix).
- Men who are sexually active with FOCBP must agree to follow instructions for method(s)
of contraception for the duration of treatment with durvalumab plus 5 half-lives of
durvalumab plus 90 days (duration of sperm turnover) for a total of 25 weeks
post-treatment completion (details in appendix).
- Provide written informed consent.
- Ability to complete questionnaire(s) by themselves or with assistance.
- Willingness to provide mandatory blood specimens for correlative research (detailed in
- Willingness to provide mandatory tissue specimens for correlative research (detailed
in protocol). NOTE: If tissue is deemed inaccessible, patient cannot participate in
- Willingness to return to enrolling institution for follow-up (during the Active
Monitoring Phase of the study).
- Must have a life expectancy of at least 6 months.
- Any of the following laboratory abnormalities:
- Hemoglobin <8.0 g/dL
- Absolute neutrophil count (ANC) <1500/mm3
- Platelet count <100,000/mm3
- Total bilirubin >1.5 x ULN (except in subjects with Gilbert Syndrome, who cannot
have a total bilirubin > 3.0 mg/dL)
- Alanine aminotransferase (ALT) and Aspartate transaminase (AST) >2.5 x ULN
- Serum creatinine > 1.5 x ULN OR
- Calculated creatinine clearance <30 ml/min using the Cockcroft-Gault formula
- Any of the following because this study involves an agent that has known genotoxic,
mutagenic and teratogenic effects:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
- Untreated central nervous system (CNS) metastatic disease (including spinal cord and
leptomeningeal disease). NOTE: Patients with previously treated CNS metastases that
are radiographically and neurologically stable for ≥ 6 weeks are permitted.
- Uncontrolled intercurrent illness including, but not limited to, autoimmune disease,
ongoing or active infection, or psychiatric illness/social situations that would limit
compliance with study requirements. EXCEPTION: Patients who have adequately controlled
autoimmune disease with or without medications are permitted as long as deemed
reasonable by treating physician.
- Received any other investigational agent incorporating chemotherapy and/or biologics
within 14 days prior to first dose of durvalumab which would be considered as a
treatment for the primary neoplasm. For patients on active treatment, last treatment
and 1st dose of Durvalumab should be at least ≥ 14 days. EXCEPTION: Other forms of
concurrent observational studies are permitted.
- Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanoma skin
cancer, lentigo maligna- in-situ, or carcinoma-in-situ of the cervix. Also prior
malignancy already treated with curative intent and with no known active disease
present would be considered eligible.
- History of unstable cardiac disease defined as one of the following:
- Congestive heart failure > class II New York Heart Association (NYHA). (Appendix
- Unstable angina (angina symptoms at rest) or new onset angina (began ≤ 3 months
prior to registration)
- Myocardial infarction ≤ 3 months
- Uncontrolled cardiac ventricular arrhythmias. EXCEPTION: Subjects that are stable
on anti-arrhythmic therapy are eligible.
- Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within
14 days of first dose of durvalumab. NOTE: Subjects can be screened during washout
- History of severe allergic reactions (i.e. Grade 4 allergy, anaphylactic reaction from
which the subject did not recover ≤ 6 hours of initiation of supportive care)
- Failure to recover from toxicities from prior anti-cancer therapy, defined as having
not resolved to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤ 1.
EXCEPTIONS: Alopecia and laboratory values listed per the exclusion criteria. Also
subjects with irreversible toxicity that is not reasonably expected to be exacerbated
by any investigational products (i.e. hearing loss) will be permitted.
- Use of steroids. EXCEPTIONS: Systemic glucocorticoids will be permitted as long as it
is ≤20 mg of prednisone equivalent. Topical steroids, such as bronchodilators and
local steroid injections are also permitted if clinically required.
- Patients with renal failure currently requiring dialysis of any kind.
- Active HIV, Hepatitis B or C with uncontrolled disease. EXCEPTION: Patient with
non-active, controlled disease will be allowed to participate in study. NOTE: A
detailed assessment of HIV and Hepatitis B/C medical history must be done at screening
for all patients. HIV 1/2 antibodies, HBsAg and HCV Ab Screen w/Reflex testing are
required at screening for all patients.
- Patients weighing <30kg will be excluded from enrollment
- History of allogenic organ transplantation