Tremelimumab and Durvalumab With or Without Radiation Therapy in Patients With Relapsed Small Cell Lung Cancer
Condition: Recurrent Small Cell Lung Carcinoma
MeSH terms: Small Cell Lung Carcinoma
Intervention: Durvalumab; Hypofractionated Radiation Therapy; Stereotactic Body Radiation Therapy; Tremelimumab
Intervention description: Given IV; Undergo hypofractionated radiation therapy; Undergo SBRT; Given IV
Intervention MeSH terms: Durvalumab; Ipilimumab; Tremelimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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)