Clinical Trials /

Immunotherapy Combined With Y-90 and SBRT for Colorectal Liver Metastases

NCT03802747

Description:

This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver metastases for patients with microsatellite stable colorectal cancer.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy Combined With Y-90 and SBRT for Colorectal Liver Metastases
  • Official Title: Phase I Study of Dual Immune Checkpoint Blockade (Anti-PD-L1 (Durvalumab) (MEDI4736) and Anti-CTLA4 (Tremelimumab) Plus Yttrium-90 (Y-90) Radioembolization & Stereotactic Body Radiation Therapy (SBRT) in Refractory Metastatic MSS (Microsatellite Stable) Colorectal Cancer With Liver Metastases

Clinical Trial IDs

  • ORG STUDY ID: 18-0710.cc
  • SECONDARY ID: ESR-17-13132
  • NCT ID: NCT03802747

Conditions

  • Colorectal Cancer

Interventions

DrugSynonymsArms
DurvalumabY-90, SBRT, and Durvalumab Alone
Durvalumab and TremelimumabY-90, SBRT, and Durvalumab + Tremelimumab
Y-90 Selective Internal Radiation Therapy (SIRT)Y-90, SBRT, and Durvalumab Alone
Stereotactic Body Radiation Therapy (SBRT)Y-90, SBRT, and Durvalumab Alone

Purpose

This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver metastases for patients with microsatellite stable colorectal cancer.

Trial Arms

NameTypeDescriptionInterventions
Y-90, SBRT, and Durvalumab AloneExperimentalSix patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab.
  • Durvalumab
  • Y-90 Selective Internal Radiation Therapy (SIRT)
  • Stereotactic Body Radiation Therapy (SBRT)
Y-90, SBRT, and Durvalumab + TremelimumabExperimentalSix patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab + Tremelimumab.
  • Durvalumab and Tremelimumab
  • Y-90 Selective Internal Radiation Therapy (SIRT)
  • Stereotactic Body Radiation Therapy (SBRT)

Eligibility Criteria

        Inclusion Criteria:

          1. Histologic or cytologic confirmation of metastatic microsatellite stable colorectal
             cancer

          2. Liver metastases not amenable to resection for which palliative Y-90 and SBRT is
             considered appropriate standard therapy

          3. Patients should have received at least one prior standard therapy for metastatic
             disease. Prior therapies should include regimens containing oxaliplatin and irinotecan
             in combination with a fluoropyrimidine if appropriate (e.g., FOLFOX and FOLFIRI or
             their variants) unless contraindicated, not tolerated, or declined.

          4. Male or female, age 18 or older

          5. ECOG performance status of 0 or 1

          6. Body weight >30 kg

          7. Life expectancy of greater than 6 months

          8. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women <50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

          9. Patients must have acceptable organ and marrow function as defined below:

               -  Hemoglobin ≥9.0 g/dL

               -  Absolute neutrophil count (ANC ≥1.0 x (> 1000 per mm3))

               -  Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).

               -  Total bilirubin : < 2x upper limit of normal

               -  AST (SGOT)/ALT (SGPT): <2.5x institutional upper limit of normal

               -  Creatinine: <1.5x upper limit of normal OR Creatinine clearance >40mL/min for
                  patients with creatinine levels above institutional normal

         10. Ability to understand and willingness to sign a written informed consent document

         11. Residual or on-going ≥ Grade 3 treatment-related toxicity from previous chemotherapy
             should be resolved.

        Exclusion Criteria:

          1. Participation in another clinical study with an investigational drug during the last 4
             weeks.

          2. Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

               -  Patients with Grade >2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab or tremelimumab may be included only after consultation
                  with the Study Physician.

          4. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable.

          5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
             acceptable.

          6. History of allogenic organ transplantation.

          7. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

          8. Prior therapy with an anti-PD-1 or anti-PD-L1, including durvalumab antibody within 6
             months prior to enrollment and anti-CTLA4 (including tremelimumab)

          9. Prior abdominal radiotherapy

         10. Child-Pugh class B or higher

         11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, uncontrolled hypertension, insterstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirements, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent

         12. History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease ≥2 years
                  before the first dose of IP and of low potential risk for recurrence

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease

         13. History of leptomeningeal carcinomatosis

         14. History of active primary immunodeficiency

         15. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and TB testing in line with
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
             hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

         16. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

         17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP.

         18. Contraindication to IV contrast

         19. Pregnant and breastfeeding women are excluded. Women of child-bearing potential who
             are unwilling or unable to use an acceptable method of birth control to avoid
             pregnancy from screening to 90 days after the last dose of durvalumab monotherapy or
             180 days after the last dose of durvalumab + tremelimumab combination therapy are
             excluded. This applies to any woman who has experienced menarche and who has not
             undergone successful surgical sterilization or is not postmenopausal (defined as
             amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy
             with serum FSH levels greater than 35 mIU/mL). A negative urine or serum pregnancy
             test must be obtained within 14 days prior to the start of study therapy in all women
             of child-bearing potential. Male subjects must also agree to use effective
             contraception for the same time period as above.

         20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

         21. Use of any prohibited concomitant medications, including:

               -  Traditional herbal medicines, as their use may result in unanticipated drug-drug
                  interactions that may cause or confound assessment of toxicity.

               -  Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1 Day
                  1 or at any time during the study and for at least 5 months after the last dose
                  of durvalumab.

               -  Use of steroids to premedicate patients for whom MRI scans with contrast are
                  contraindicated (i.e., patients with contrast allergy or impaired renal
                  clearance)

               -  Immunomodulatory agents, including but not limited to interferons or
                  interleukin-2, during the entire study; these agents could potentially increase
                  the risk for autoimmune conditions when administered with durvalumab.

               -  Immunosuppressive medications, including but not limited to cyclophosphamide,
                  azathioprine, methotrexate, and thalidomide; these agents could potentially alter
                  the activity and the safety of durvalumab

               -  Systemic corticosteroids and tumor necrosis factor-α (TNF-α) inhibitors may
                  attenuate potential beneficial immunologic effects of treatment with durvalumab.
                  Therefore, in situations where systemic corticosteroids or TNF-α inhibitors would
                  be routinely administered, alternatives, including antihistamines, should be
                  considered first by the treating physician. If the alternatives are not feasible,
                  systemic corticosteroids and TNF-α inhibitors may be administered at the
                  discretion of the treating physician (see Section 4.4.2)

               -  Initiation or increased dose of granulocyte colony-stimulating factors (e.g.,
                  granulocyte colony stimulating factor, granulocyte/macrophage colony-stimulating
                  factor, and/or pegfilgrastim) is prohibited.

         22. Shunt Fraction greater than 20% (Requires more than 30gy dose to the lungs in order
             receive therapeutic dose of Y-90).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment Related Adverse Events
Time Frame:Start of study to 3 months post treatment completion, up to 5 years
Safety Issue:
Description:Adverse events related to Y-90, SBRT, and durvalumab plus tremelimumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Duration of Response (DoR)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
Measure:Progression Free Survival for Three Months (PFS)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
Measure:Overall Response Rate (ORR)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
Measure:Overall Survival for Two Years (OS)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:Measure of overall survival rate by examining the incidence of death over a two year period.
Measure:Liver Progression Free Survival for One Year (L-PFS)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
Measure:Pathological Response Rates (PRR)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:Measured by the percentage of viable tumor throughout and post treatment
Measure:Time to Tumor Progression (TTP)
Time Frame:Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
Safety Issue:
Description:The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

  • Liver Metastases
  • Phase 1
  • Durvalumab
  • Tremelimumab
  • Yttrium-90
  • Radioembolization
  • Stereotactic Body Radiation Therapy

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