Clinical Trials /

Immunotherapy With Y90-RadioEmbolization for Metastatic Colorectal Cancer

NCT04108481

Description:

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).

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With Y90-RadioEmbolization for Metastatic Colorectal Cancer
  • Official Title: Immunotherapy Combined With Yttrium-90 RadioEmbolization in the Treatment of Colorectal Cancer With Liver Metastases [iRE-C - Clinical Trial]

Clinical Trial IDs

  • ORG STUDY ID: 201909709
  • NCT ID: NCT04108481

Conditions

  • Colorectal Cancer Metastatic
  • Colon Cancer
  • Metastatic Colorectal Cancer
  • Rectal Cancer
  • Liver Metastasis Colon Cancer
  • Colo-rectal Cancer
  • Colorectal Adenocarcinoma
  • Colorectal Neoplasms
  • Liver Metastases
  • Colorectal Carcinoma

Interventions

DrugSynonymsArms
DurvalumabIMFINZI, MEDI4736, MEDI-4736, Anti-PDL1Y90-RE in combination with immunotherapy (durvalumab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Y90-RE in combination with immunotherapy (durvalumab)ExperimentalThe 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.
  • Durvalumab

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 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
             protocol).

          -  Willingness to provide mandatory tissue specimens for correlative research (detailed
             in protocol). NOTE: If tissue is deemed inaccessible, patient cannot participate in
             study.

          -  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.

        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

               -  Nursing persons

               -  Persons of childbearing potential who are unwilling to employ adequate
                  contraception

          -  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
             prescribed regimens.

          -  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
                  II)

               -  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
             period.

          -  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
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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 Outcome Measures

Measure:Incidence of adverse events (AE) per CTCAE version 5.0
Time Frame:Initiation of screening up to 2 years
Safety Issue:
Description:The number and severity of all adverse events (overall, by dose-level, and by tumor molecular subtype) will be tabulated and summarized.
Measure:Determine overall response rate (ORR)
Time Frame:Up to 2 months post treatment
Safety Issue:
Description:Overall response rate is defined as the proportion of evaluable patients that have achieved a complete response (CR) or partial response (PR) by RECIST v1.1 as well as mRECIST and iRECIST.
Measure:Determine the disease control rate (DCR)
Time Frame:Up to 2 months post treatment
Safety Issue:
Description:Disease control rate is defined as the proportion of evaluable patients that have achieved a complete response (CR), partial response (PR), or stable disease (SD) by RECIST v1.1 as well as mRECIST and iRECIST.
Measure:Determine liver-specific progression free survival
Time Frame:Up to 2 months post treatment
Safety Issue:
Description:Progression free survival is defined as the proportion of evaluable patients that have achieved liver-specific progression free survival (Liver-PFS)
Measure:Determine overall progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Progression free survival is defined as the proportion of evaluable patients that have achieved overall progression free survival (PFS)
Measure:Determine overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival (OS) is defined as the time from randomization to death of any cause.
Measure:Determine duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:Duration of response (DOR) is defined as the time measurement criteria for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Iowa

Trial Keywords

  • Y90
  • Y90-RE
  • Radioembolization
  • Y90-Radioembolization
  • y-90
  • Yttrium
  • Yttrium-90
  • Microsatellite Stable
  • MSS
  • CRC
  • mCRC
  • Colorectal
  • Liver Metastases
  • Liver Metastasis
  • Durvalumab
  • Anti-PD1
  • Anti-PDL1
  • Immunotherapy
  • Colorectal Cancer
  • Mismatch repair proficient
  • pMMR
  • KRAS
  • NRAS
  • BRAF
  • BRAF-V600E

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