A Clinical Trial of Durvalumab and Tremelimumab, Administered With Radiation Therapy or Ablation in Patients With Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: durvalumab; tremelimumab; Radiotherapy (RT); ablation
Intervention description: 1500 mg durvalumab via IV infusion; 75 mg tremelimumab via IV infusion; Radiotherapy (RT) will be performed using external beam ionizing radiation as standard therapy in accordance with institutional standard practice.; Ablation will be performed percutaneously under image guidance as standard therapy at the discretion of the interventional radiologist in accordance with institutional standard practice.
Intervention MeSH terms: Durvalumab; Tremelimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be a Simon two-stage design, phase II study. It will be conducted to determine the efficacy and safety of (1) durvalumab and tremelimumab plus RT in subjects with metastatic CRC who are undergoing RT as standard therapy; and, (2) durvalumab and tremelimumab plus ablation in subjects with metastatic CRC who are undergoing ablation as standard therapy.
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Durvalumab; Tremelimumab; Radiation Therapy; Ablation; 17-139

Summary:

      The purpose of this study is to test the safety and effectiveness of two investigational
      drugs (drugs that are not currently approved by the FDA) given in combination with radiation
      therapy or ablation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent for the trial.

          -  Histologically- or cytologically- confirmed CRC.

          -  Metastatic CRC.

          -  Subjects have received at least two standard chemotherapy regimens for which they
             would be considered eligible (at least one containing a 5-fluoropyrimidine), or
             systemic chemotherapy is not indicated in the setting of low volume metastatic
             disease.

          -  At least one tumor for which palliative RT is considered appropriate standard therapy
             (cohort 1); or, at least one tumor for which palliative ablation is considered
             appropriate standard therapy (cohort 2).

          -  At least one index lesion that will not undergo RT or ablation, and which is
             measurable based on RECIST 1.1.

          -  Be ≥ 18 years of age on day of signing informed consent.

          -  Consent for tumor biopsies (for patients enrolled in stage 1 only) and blood draws for
             research purposes (for all patients).

          -  Consent for use of available archived tissue and tumor obtained during a standard
             procedure, for research purposes.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
             history: ≥60 years old and no menses for ≥ 1 year without an alternative medical
             cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
             of bilateral oophorectomy) or must have a negative serum pregnancy test within 2 weeks
             prior to starting treatment.

          -  Demonstrate adequate organ function as defined all screening labs should be performed
             within 4 weeks prior to treatment initiation.

               -  Hemoglobin ≥ 8.0 g/dL

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Platelets ≥100,000 / mcL

               -  Serum creatinine ≤1.5 X upper limit of normal (ULN) OR

               -  Measured or calculated creatinine clearance (GFR can also be used in place of
                  creatinine or CrCl) OR

               -  Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
                  1976) or by 24-hour urine collection for determination of creatinine clearance.

               -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver
                  metastases.

        aCreatinine clearance should be calculated per institutional standard.

        Exclusion Criteria:

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          -  Chemotherapy, monoclonal antibody, targeted small molecule therapy, within 4 weeks
             prior to dose #1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
             adverse events due to a previously administered agent (excluding alopecia or toxicity
             not anticipated to interfere with planned treatment on study).

          -  Known or suspected MSI-H CRC.

          -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1, including anti-PD-1, anti-PD-L1,
             anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting
             T-cell co-stimulation or checkpoint pathways, except for endocrinopathies and
             asymptomatic amylase/lipase.

          -  If subject received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention per clinical discretion of the
             investigator prior to starting therapy.

          -  Concurrent active malignancy that requires systemic treatment.

          -  Known CNS metastases and/or carcinomatous meningitis. Subjects with previously treated
             brain metastases may participate provided they are stable without evidence of new or
             enlarging brain metastases, and are not using steroids for at least 7 days prior to
             trial treatment. The use of topical steroids is permitted.

          -  Active autoimmune disease requiring systemic immune suppressive treatment within the
             past 2 years. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not
             requiring systemic treatment (within the past 2 years) are not excluded.

          -  Has active, non-infectious pneumonitis.

          -  Active or prior documented inflammatory bowel disease.

          -  History of allogeneic organ transplant.

          -  Has an active infection requiring systemic therapy.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active and untreated Hepatitis B (e.g., HBsAg reactive) or active Hepatitis
             C (e.g., HCV RNA [qualitative] is detected).

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment.

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab with the exceptions of premedication and
             intranasal, topical and inhaled corticosteroids or systemic corticosteroids at
             physiological doses, which are not to exceed 10mg/day of prednisone, or an equivalent
             corticosteroid.

          -  Hypersensitivity to durvalumab or tremelimumab, or any excipients on the formulation.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 180 days after the last dose of durvalumab + tremelimumab combination
             therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
             longer time period.

          -  QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 1 electrocardiogram
             (ECG) using Fridericia's Correction.

          -  History of primary immunodeficiency.

          -  Known history of previous clinical diagnosis of tuberculosis.

          -  Subjects with uncontrolled seizures.