Immunotherapy Combined With Yttrium-90 RadioEmbolization in the Treatment of Colorectal Cancer With Liver Metastases [iRE-C - Clinical Trial]
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Colorectal Cancer Metastatic
- Sponsor
- University of Iowa
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Determine the maximum tolerated dose (MTD) of Yttrium-90 radioembolization combined with immunotherapy durvalumab to treat liver-predominant metastatic colorectal cancer (mCRC)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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).
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 treatment.
- •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
- •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).
Exclusion Criteria
- •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
Arms & Interventions
Y90-RE in combination with immunotherapy (durvalumab)
The treatment phase starts of with the immunotherapy drug (durvalumab) - "priming doses" every 2 weeks prior to patient getting mapped and ready for treatment with Y90-RadioEmbolization. Post-Y90-RE, treatment is approximately 2 months in combination with fixed doses (750 mg) of durvalumab. The number and timing of doses of durvalumab each patient will receive will depend on the dose level the patient is assigned to (range 2-5 doses of immunotherapy). A single patient will be treated per dose level until the first dose limiting toxicity (DLT) is recorded. Once the first DLT is recorded, two additional patients are treated at the same dose level and the trial reverts to a standard 3+3 design. Up to 6 patients will be treated at each dose level. The maximum tolerated dose (MTD) will be defined as the highest dose level for which at most 1 out of 6 patients experience a DLT.
Intervention: Durvalumab
Y90-RE in combination with immunotherapy (durvalumab)
The treatment phase starts of with the immunotherapy drug (durvalumab) - "priming doses" every 2 weeks prior to patient getting mapped and ready for treatment with Y90-RadioEmbolization. Post-Y90-RE, treatment is approximately 2 months in combination with fixed doses (750 mg) of durvalumab. The number and timing of doses of durvalumab each patient will receive will depend on the dose level the patient is assigned to (range 2-5 doses of immunotherapy). A single patient will be treated per dose level until the first dose limiting toxicity (DLT) is recorded. Once the first DLT is recorded, two additional patients are treated at the same dose level and the trial reverts to a standard 3+3 design. Up to 6 patients will be treated at each dose level. The maximum tolerated dose (MTD) will be defined as the highest dose level for which at most 1 out of 6 patients experience a DLT.
Intervention: Yttrium-90 RadioEmbolization
Outcomes
Primary Outcomes
Determine the maximum tolerated dose (MTD) of Yttrium-90 radioembolization combined with immunotherapy durvalumab to treat liver-predominant metastatic colorectal cancer (mCRC)
Time Frame: Initiation of treatment up to 8 weeks and 2 doses ("priming") of immunotherapy prior to Y90-RE.
MTD will be defined as the highest dose level for which at most 1 out of 6 patients experience a dose-limiting toxicity (DLT) using CTCAE version 5.0.
Secondary Outcomes
- Determine duration of response(Up to 2 years)
- Determine overall response rate (ORR)(Up to 2 months post treatment)
- Incidence of adverse events (AE) per CTCAE version 5.0(Initiation of screening up to 2 years)
- Determine the disease control rate (DCR)(Up to 2 months post treatment)
- Determine liver-specific progression free survival(Up to 2 months post treatment)
- Determine overall progression free survival(Up to 2 years)
- Determine overall survival(Up to 2 years)