Clinical Trials /

Tremelimumab and Durvalumab With or Without Radiation Therapy in Patients With Relapsed Small Cell Lung Cancer

NCT02701400

Description:

This randomized clinical trial studies how well tremelimumab and durvalumab with or without radiation therapy works in treating patients with small cell lung cancer that has returned after a period of improvement. Monoclonal antibodies, such as tremelimumab and durvalumab, may limit the ability of tumor cells to grow and spread by enhancing immune function. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving tremelimumab and durvalumab together with radiation therapy may lead to improved clinical benefit.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tremelimumab and Durvalumab With or Without Radiation Therapy in Patients With Relapsed Small Cell Lung Cancer
  • Official Title: A Randomized Study of Tremelimumab Plus Durvalumab Combination With or Without Radiation in Relapsed Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00086004
  • SECONDARY ID: NCI-2016-00026
  • SECONDARY ID: ESR-14-10531
  • SECONDARY ID: Winship3112-15
  • NCT ID: NCT02701400

Conditions

  • Recurrent Small Cell Lung Carcinoma

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Arm I (tremelimumab, durvalumab)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675,206, TicilimumabArm I (tremelimumab, durvalumab)

Purpose

This randomized clinical trial studies how well tremelimumab and durvalumab with or without radiation therapy works in treating patients with small cell lung cancer that has returned after a period of improvement. Monoclonal antibodies, such as tremelimumab and durvalumab, may limit the ability of tumor cells to grow and spread by enhancing immune function. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving tremelimumab and durvalumab together with radiation therapy may lead to improved clinical benefit.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the efficacy (progression free survival [PFS] and objective response rate
      [ORR]) of combined immune checkpoint inhibitor therapy as treatment for relapsed small-cell
      lung cancer (SCLC).

      SECONDARY OBJECTIVES:

      I. To assess the impact of antigen priming using radiation therapy (XRT) on the efficacy of
      immune checkpoint inhibitors.

      II. To determine immune related objective response rate.

      III. To estimate overall survival measured as time from randomization to death from any
      cause.

      TERTIARY OBJECTIVES:

      I. To characterize tumor infiltrating lymphocytes (TILs) and programmed cell death 1 ligand
      1 (PD-L1)/programmed cell death 1 (PD1) expression in paired tumor biopsies at baseline, end
      of cycle 2 and at the time of progression.

      II. To determine dynamic changes in cell free deoxyribonucleic acid (DNA) (cfDNA) and the
      immunophenotype of peripheral blood repertoire of circulating lymphocytes using
      multiparameter flow cytometry.

      III. To determine changes in circulating cytokine mediators of inflammation and immunity
      using Luminex assay.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Treatment
      repeats every 4 weeks for up to 4 courses in the absence of disease progression or
      unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment
      repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable
      toxicity. Patients achieving disease control may restart treatment upon evidence of
      progressive disease, with or without confirmation.

      ARM II: Patients undergo radiation therapy daily for 5 days over 1 week or for 3 fractions
      every other day for 1 week and then receive the same treatment as in Arm I.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (tremelimumab, durvalumab)ExperimentalPatients receive tremelimumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving disease control may restart treatment upon evidence of progressive disease, with or without confirmation.
    Arm II (RT, tremelimumab, durvalumab)Active ComparatorPatients undergo stereotactic body radiation therapy (SBRT) or hypofractionated radiation therapy daily for 5 days over 1 week or for 3 fractions every other day for 1 week and then receive the same treatment as in Arm I.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Written informed consent and any locally-required authorization (e.g.,) obtained from
                   the subject prior to performing any protocol-related procedures, including screening
                   evaluations
      
                -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
      
                -  Hemoglobin ≥ 9.0 g/dL
      
                -  Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L (≥ 1500 per mm³)
      
                -  Platelet count ≥ 100 x 10⁹/L (≥ 100,000 per mm³)
      
                -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); this will not
                   apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
                   hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
                   hepatic pathology), who will be allowed only in consultation with their physician
      
                -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
                   [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                   ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in
                   which case it must be ≤ 5 x ULN
      
                -  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 (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 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 must have baseline evaluations performed prior to the first dose of study
                   drug and must meet all inclusion and exclusion criteria
      
                -  Patients must have histologically or cytologically confirmed small cell lung cancer
      
                -  Patients must have measurable disease, defined as at least one lesion (excluding the
                   lesion for XRT) that can be accurately measured in at least one dimension (longest
                   diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >
                   20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT)
                   scan
      
                -  Patient must have failed or found to be intolerant of standard frontline
                   platinum-based regimens and must not have received > 2 prior lines of therapy (nota
                   bene [NB]: retreatment with a platinum-based doublet for sensitive relapse counts as
                   another line therapy; however substitution of cisplatin with carboplatin or vice
                   versa due to toxicity does not count as a separate regimen)
      
                -  Negative serum pregnancy test within 48 hours before starting study treatment in
                   women with childbearing potential
      
                -  Ability to understand and the willingness to sign a written informed consent document
      
              Exclusion Criteria:
      
                -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
                   staff and/or staff at the study site)
      
                -  Previous enrollment or randomization in the present study
      
                -  Treatment with an investigational product during the last 2 weeks
      
                -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
                   anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab
      
                -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
                   endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
                   antibodies, other investigational agent) ≤ 14 days prior to the first dose of study
                   drug (≤ 7 days or four half-lives, whichever is longer, prior to the first dose of
                   study drug for subjects who have received prior tyrosine kinase inhibitors [TKIs]
                   [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or
                   mitomycin C)
      
                -  Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3
                   electrocardiograms (ECGs) using Fredericia'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 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 grade ≥ 3 immune-related adverse event (irAE) while receiving any previous
                   immunotherapy agent, or any unresolved irAE > grade 1
      
                -  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
      
                -  History of hypersensitivity to durvalumab or any excipient
      
                -  History of hypersensitivity to the combination or comparator agent
      
                -  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
      
                -  Female subjects who are pregnant, breast-feeding or male or female patients of
                   reproductive potential who are not employing an effective method of birth control
      
                -  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
      
                -  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
      
                -  Patients receiving any other investigational agents for any reason or
                   non-investigational agents administered for the purpose of controlling cancer growth
                   (use of conventional external beam radiation therapy will be allowed during protocol
                   therapy solely for palliation of localized painful lesions or bone lesions at risk of
                   fracture provided the radiation field does not encompass any selected target lesions
                   required for assessment)
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Progression free survival (PFS)
      Time Frame:From initiation of systemic therapy to first documented disease progression, assessed through study completion, up to 2 years
      Safety Issue:
      Description:Time from initiation of therapy to objective disease progress or death

      Secondary Outcome Measures

      Measure:Immune-related objective response rate
      Time Frame:Assessed after every 2 cycles (1 cycle = 4 weeks) on treatment; assessed through study completion, up to 2 years
      Safety Issue:
      Description:Disease response to treatment using immune-related response rate (irRR) criteria
      Measure:Overall survival
      Time Frame:From randomization until death from any cause, assessed through study completion, up to 2 years
      Safety Issue:
      Description:Time interval from entering the study until death

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Emory University

      Last Updated

      December 13, 2016