Clinical Trials /

Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver

NCT03005002

Description:

This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver
  • Official Title: A Pilot Feasibility Study of Durvalumab (MEDI4736) and Tremelimumab Following Radioembolization in Patients With Metastatic Microsatellite Stable (MSS) Colorectal Cancer to the Liver

Clinical Trial IDs

  • ORG STUDY ID: 16423
  • SECONDARY ID: NCI-2016-02001
  • SECONDARY ID: 16423
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT03005002

Conditions

  • Metastatic Carcinoma in the Liver
  • MLH1 Gene Mutation
  • MSH6 Gene Mutation
  • PMS2 Gene Mutation
  • Stage IV Colorectal Cancer
  • Stage IVA Colorectal Cancer
  • Stage IVB Colorectal Cancer

Interventions

DrugSynonymsArms
DurvalumabImmunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (durvalumab, tremelimumab)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabTreatment (durvalumab, tremelimumab)

Purpose

This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Establish the safety of durvalumab and tremelimumab following radioembolization with
      selective internal radiation (SIR)-Spheres in patients with microsatellite stable (MSS)
      metastatic colorectal cancer to the liver.

      II. Determine the hepatic response rate of SIR-Spheres followed by durvalumab and
      tremelimumab in patients with MSS metastatic colorectal cancer to the liver.

      SECONDARY OBJECTIVES:

      I. Estimate the progression free survival (PFS) and overall survival (OS) of the overall
      treated population.

      II. Describe the overall response rate of the treated population. III. Describe the
      extra-hepatic response in the treated population (abscopal responses).

      TERTIARY OBJECTIVES:

      I. Describe intra-tumor immune alterations following SIR-Spheres, and following durvalumab
      plus tremelimumab in comparison to baseline through serial hepatic metastases biopsies.

      II. Describe the immune alterations in the blood following SIR-Spheres and following
      durvalumab plus tremelimumab.

      OUTLINE:

      Patients receive durvalumab intravenously (IV) over 60 minutes and tremelimumab IV over 60
      minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of
      disease progression or unacceptable toxicity. Beginning at week 17, patients receive
      durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (durvalumab, tremelimumab)ExperimentalPatients receive durvalumab IV over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Documented informed consent of the subject and/or legally authorized representative
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    
              -  Life expectancy of > 12 weeks
    
              -  Hemoglobin >= 9.0 g/dL
    
              -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
    
              -  Platelet count >= 75 x 10^9/L (>= 75,000 per mm^3)
    
              -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
    
              -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
                 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                 =< 5 x institutional upper limit of normal given that all patients have liver
                 metastases
    
              -  Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by
                 24-hour urine collection for determination of creatinine clearance
    
              -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by
                 history: >= 60 years old and no menses for >= 1 year without an alternative medical
                 cause; AND/OR history of hysterectomy, AND/OR history of bilateral tubal ligation,
                 AND/OR history of bilateral oophorectomy) or must have a negative serum pregnancy
                 test upon study entry
    
              -  Subject is willing and able to comply with the protocol for the duration of the study
                 including undergoing treatment and scheduled visits and examinations including follow
                 up
    
              -  Patients should have microsatellite stable (MSS) tumor by polymerase chain reaction
                 (PCR) assay or mismatch repair protein proficient (MMRP) tumor by
                 immunohistochemistry as confirmed by the presence of MLH1, MSH2, MSH6, and PMS2; the
                 diagnosis of colorectal cancer should be confirmed by pathology either on the primary
                 tumor or from a prior biopsy of a metastatic disease site
    
              -  Patients should have been identified by their respective physicians as candidates for
                 radioembolization and scheduled to undergo such a procedure
    
              -  Patients should agree to serial liver metastases biopsy pre-treatment,
                 post-radioembolization, and post-combination immunotherapy
    
              -  Patients should have measurable metastatic disease in the liver, defined (for the
                 purpose of this study) as at least 1 measurable lesion more than 2 cm in size and
                 readily accessible to ultrasound (US) or computed tomography (CT)-guided biopsy
    
              -  Patients should have received and progressed following at least one line of systemic
                 chemotherapy and should not be deemed candidate for curative hepatic resection
    
            Exclusion Criteria:
    
              -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
                 staff and/or staff at the study site) or previous enrollment in the present study
    
              -  Participation in another clinical study with an investigational product during the
                 last 4 weeks
    
              -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
                 anti-CTLA4, including tremelimumab
    
              -  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 study drug and of low potential risk for
                      recurrence
    
                   -  Adequately treated non-melanoma skin cancer or lentigo maligns without evidence
                      of disease
    
                   -  Adequately treated carcinoma in situ without evidence of disease eg, cervical
                      cancer in situ
    
              -  Receipt of the last dose of chemotherapy or tyrosine kinase inhibitors should be at
                 least 3 weeks prior to durvalumab and tremelimumab dosing; monoclonal antibodies such
                 as bevacizumab, ziv-aflibercept, ramucirumab, cetuximab, and panitumumab should be at
                 least 6 weeks prior to durvalumab and tremelimumab therapy
    
              -  Clinical ascites
    
              -  Liver involvement by > 50% with metastatic disease determined by the investigator
    
              -  Complete portal vein thrombosis on CT scans
    
              -  Failure to satisfy minimum criteria of lung shunting (> 20%) or presence of
                 extrahepatic gastrointestinal activity on microaggregated albumin (MAA) scan or
                 angiogram that preclude SIR-Spheres
    
              -  Prior external beam radiation to the liver
    
              -  Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3
                 electrocardiograms (ECGs) using Fridericia's correction
    
              -  Current or prior use of immunosuppressive medication within 28 days before the first
                 dose of durvalumab or tremelimumab, with the exceptions of intranasal, topical, and
                 inhaled corticosteroids or systemic corticosteroids at physiological doses, which are
                 not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
    
              -  Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE]
                 grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that
                 is not reasonably expected to be exacerbated by the investigational product may be
                 included (e.g., hearing loss, peripherally neuropathy)
    
              -  Any prior systemic anti-cancer immunotherapy treatment
    
              -  Active or prior documented autoimmune disease 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
    
              -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
                 ulcerative colitis)
    
              -  History of primary immunodeficiency
    
              -  History of allogeneic organ transplant
    
              -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
                 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
                 angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
                 bleeding diatheses including any subject known to have evidence of acute or chronic
                 hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
                 illness/social situations that would limit compliance with study requirements or
                 compromise the ability of the subject to give written informed consent
    
              -  Known history of previous clinical diagnosis of tuberculosis
    
              -  History of leptomeningeal carcinomatosis
    
              -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
                 30 days of receiving durvalumab or tremelimumab
    
              -  Any condition that, in the opinion of the investigator, would interfere with
                 evaluation of study treatment or interpretation of patient safety or study results
    
              -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment,
                 inclusive of but not limited to surgery, radiation and/or corticosteroids
    
              -  Subjects with uncontrolled seizures
    
              -  Patients with symptomatic extrahepatic metastases
    
              -  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
    
              -  Known allergy or hypersensitivity to investigational product (IP) or any excipient
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:19 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Hepatic tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:Will be summarized using a 90% exact Clopper-Pearson confidence interval

    Secondary Outcome Measures

    Measure:Extrahepatic disease response assessed by RECIST 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Hepatic PFS
    Time Frame:From study treatment to first progression in the treated liver or death (whichever occurs first), assessed up to 1 year
    Safety Issue:
    Description:
    Measure:OS
    Time Frame:From study treatment to death, assessed up to 1 year
    Safety Issue:
    Description:
    Measure:Overall PFS
    Time Frame:From study treatment to progressive disease (hepatic and extrahepatic) and death, assessed up to 1 year
    Safety Issue:
    Description:
    Measure:Overall response rate (both hepatic and extrahepatic disease) assessed by RECIST 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:

    Details

    Phase:N/A
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:City of Hope Medical Center

    Last Updated

    December 23, 2016