Durvalumab and Tremelimumab ± Platinum-Based Chemotherapy in Patients With Metastatic Squamous or Non-Squamous NSCLC
Condition: Lung Cancer Metastatic
MeSH terms: Lung Neoplasms
Intervention: Durvalumab; Tremelimumab; Platinum-Based Drug
Intervention description: MEDI4736; Tremelimumab; Pemetrexed, cisplatin, carboplatin or gemcitibine
Intervention MeSH terms: Durvalumab; Tremelimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 301.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Durvalumab is a new type of drug for many kinds of cancer. It is considered "immunotherapy"
      and not "chemotherapy". Laboratory tests show that it works by allowing the immune system to
      detect cancer and reactivate the immune response. This may help to slow down the growth of
      cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in
      animals and has been studied in more than 5000 people and seems promising.

      Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to
      durvalumab and may improve the effect of durvalumab. Tremelimumab may also help slow the
      growth of the cancer cells or may cause cancer cells to die. It has been shown to shrink
      tumours in animals and has been studied in over 1200 people and seems promising.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically and/or cytologically confirmed diagnosis of squamous
             or non-squamous, non-small cell carcinoma of the lung. Patients with poorly
             differentiated tumours will only be eligible if NSCLC is confirmed by
             immunohistochemistry markers (TTF1/P63 or P40/CK5). Patients with known sensitizing
             EGFR mutations or known ALK-fusion are not eligible.

          -  Patients must have stage IV disease according to the 8th TNM version staging.

          -  Patients must have an adequate histopathology specimen and must consent to release
             this specimen for protocol required testing. This is a mandatory component of the
             study.

          -  Patient must consent to provision of samples of blood in order that the specific
             correlative marker assays proscribed may be conducted.

          -  All patients must have measurable disease as defined by RECIST 1.1 All radiology
             studies must be performed within 28 days prior to randomization (within 35 days if
             negative).

        The criteria for defining measurable disease are as follows:

          -  CT scan (with slice thickness of 5 mm) ≥ 10 mm --> longest diameter

          -  Physical exam (using calipers) ≥ 10 mm

          -  Lymph nodes by CT scan ≥ 15 mm --> measured in short axis

        Measurable lesions must be outside a previous radiotherapy field if they are the sole site
        of disease, unless disease progression has been documented.

          -  Patients must be 18 years of age or older.

          -  ECOG performance status of 0 or 1.

          -  Absolute neutrophils ≥ 1.5 x 10^9/L

          -  Platelets ≥ 100 x 10^9/L

          -  Hemoglobin ≥ 90 g/L

          -  Bilirubin ≤ 1.5 x UNL (upper limit of normal)

          -  AST and ALT ≤ 2.5 x UNL (if liver metastases are present, ≤5 x UNL) Creatinine < 1.25
             UNL or Creatinine clearance ≥ 45 mL/min

          -  Cytotoxic Chemotherapy: Patients may not have received prior cytotoxic chemotherapy
             for advanced/metastatic disease.

          -  Adjuvant Chemotherapy: Patients may have had prior adjuvant therapy for completely
             resected disease, providing it has been completed at least 12 months prior to
             randomization.

          -  Patients treated with concurrent chemotherapy/radiation regimens for unresectable
             locally advanced Stage III disease will be eligible providing it has been completed at
             least 12 months prior to randomization.

          -  Other Systemic Therapy: Patients may not have received prior EGFR or alk inhibitors.
             Patients may not have received prior treatment with immune-based therapy, including
             durvalumab and tremelimumab vaccines or oncolytic viral therapy. Patients must have
             recovered from any reversible treatment related toxicities prior to randomization.

          -  Prior external beam radiation is permitted provided a minimum of 14 days (2 weeks)
             have elapsed between the last dose of radiation and date of randomization. Concurrent
             radiotherapy is not permitted.

        Patients must have recovered from any acute toxic effects from radiation prior to
        randomization.

          -  Patients must have recovered from any acute toxic effects from radiation prior to
             randomization.

          -  Surgery: Previous surgery is permitted provided that wound healing has occurred and at
             least 14 days have elapsed (major surgery) prior to randomization.

          -  Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of
             life and health economics questionnaires.

          -  Patient consent must be appropriately obtained in accordance with applicable local and
             regulatory requirements.

          -  Patients must be accessible for treatment and follow-up. All randomized patients must
             be followed and treated at participating centres.

          -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
             of patient randomization.

          -  Female patients of childbearing potential who are sexually active with a
             non-sterilized male partner must use at least one highly effective method of
             contraception while on study and for 6 months after the last dose of durvalumab and
             tremelimumab or for 3 months after the last dose of durvalumab alone

        Exclusion Criteria:

          -  Patients with a history of other malignancies, except: adequately treated non-melanoma
             skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours
             curatively treated with no evidence of disease for ≥ 3 years. Patients with a history
             of other malignancies detected at an early stage and whom the investigator believes
             have been curatively treated and are at low risk of recurrence MAY be eligible.
             Contact CCTG to discuss eligibility prior to enrolling.

          -  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, celiac disease or other serious gastrointestinal chronic
             conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
             syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid
             arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of
             treatment. The following are exceptions to this criterion:

               -  Patients with alopecia.

               -  Patients with Grave's disease, vitiligo or psoriasis not requiring systemic
                  treatment (within the last 2 years).

               -  Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
                  hormone replacement.

          -  History of primary immunodeficiency, history of allogenic organ transplant that
             requires therapeutic immunosuppression and the use of immunosuppressive agents within
             28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated
             toxicity from other immune therapy or grade ≥ 3 infusion reaction.

          -  Live attenuated vaccination administered within 30 days prior to randomization

          -  History of hypersensitivity to durvalumab or tremelimumab or any excipient. Patients
             who have received other treatment or other antibodies must not have had intolerable
             toxicity or required steroids to manage toxicity.

          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec
             in screening ECG measured using standard institutional method or history of familial
             long QT syndrome.

          -  Patients who have untreated and/or uncontrolled cardiovascular conditions and/or have
             symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial
             infarction within the previous year or cardiac ventricular arrhythmias requiring
             medication, history of 2nd or 3rd degree atrioventricular conduction defects).
             Patients with a significant cardiac history, even if now controlled, should have a
             LVEF ≥ 45%. (Note: patients with uncomplicated controlled hypertension do not require
             LVEF measurement in the absence of other significant cardiac history)

          -  Concurrent treatment with other investigational drugs or anti-cancer therapy

          -  Patients with untreated brain or meningeal metastases are not eligible. Patients with
             treated CNS disease who have radiologic AND clinical evidence of stable brain
             metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are
             eligible providing that they are asymptomatic and do not require corticosteroids (must
             have discontinued steroids at least 1 week prior to randomization).

          -  Pregnant or Lactating Women: Women of childbearing potential must have a pregnancy
             test (urine or serum) proven negative within 14 days prior to randomization. If urine
             test is positive, pregnancy testing may then include an ultrasound to rule-out
             pregnancy if a false-positive is suspected. For example, when beta-human chorionic
             gonadotropin is high and partner is vasectomized, it may be associated with tumour
             production of hCG, as seen with some cancers. Patient will be considered eligible if
             an ultrasound is negative for pregnancy. Men and women of child-bearing potential must
             agree to use adequate contraception.

          -  Patients with serious illnesses or medical conditions which would not permit the
             patient to be managed according to the protocol (including corticosteroid
             administration), or would put the patient at risk. This includes but is not limited
             to:

               -  Contraindications to the use of pemetrexed, gemcitabine, cisplatin and/or
                  carboplatin (consult product monograph);

               -  History of significant neurologic or psychiatric disorder which would impair the
                  ability to obtain consent or limit compliance with study requirements;

               -  Active infection requiring systemic therapy; (including any patient known to have
                  active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or
                  tuberculosis);

               -  Active peptic ulcer disease or gastritis;

               -  Known pneumonitis or pulmonary fibrosis with clinically significant impairment of
                  pulmonary function.