MEDI4736 (Durvalumab) in Patients With Brain Metastasis From Epithelial-derived Tumors
Condition: Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer; Breast Cancer; Cancer of Breast; Cancer of the Breast; Gastroesophageal Cancer; Pancreatic Cancer; Cancer of the Pancreas; Colorectal Cancer; Colorectal Carcinoma; Renal Cancer; Kidney Cancer; Cancer of the Kidney; Cancer of Kidney; Ovarian Cancer; Ovary Cancer; Cancer of the Ovary; Cancer of Ovary
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Pancreatic Neoplasms; Ovarian Neoplasms; Brain Neoplasms; Kidney Neoplasms; Carcinoma, Renal Cell; Breast Neoplasms
Intervention: MEDI4736
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Brain metastases are the most common intracranial malignancy occurring in 20-40% of all
      cancers, and the presence of CNS metastases is associated with a poor prognosis. As such, the
      median overall survival of patients with symptomatic brain lesions is a dismal 2-3 months
      regardless of tumor type. Because standard chemotherapy largely does not cross the blood
      brain barrier at a meaningful concentration, standard treatment is limited and usually
      involves surgical resection and/or stereotactic radiosurgery for isolated lesions and whole
      brain radiation for multiple lesions. Unfortunately, the median overall survival is only
      improved by about 6 months with this multimodality approach2, and there is a paucity of
      second-line therapies to treat recurrence. Furthermore, re-resection and re-radiation are
      often not feasible options due to concern for increasing complications or neurotoxicity,
      respectively. Thus, there is a dire clinical need for additional treatment options for this
      patient population.

      Checkpoint blockade therapy, in particular PD-1 and PD-L1 inhibition, has recently shown
      clinical efficacy in multiple types of solid tumors. The investigators propose to study the
      efficacy of checkpoint blockade therapy in patients with solid tumors and
      refractory/recurrent brain metastases. The investigators will assess the efficacy of
      MEDI4736, a novel PD-L1 inhibitory monoclonal antibody, in this study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Cohort A: Histologically confirmed metastatic non-small cell lung cancer (all
             histologic subtypes allowed) with radiographic evidence by MRI of at least one
             measurable brain lesion as defined by RANO criteria that does not require
             corticosteroids for symptomatic control.

          -  Cohort B: Histologically confirmed metastatic solid tumor of epithelial origin,
             excluding NSCLC, including but not limited to ovarian cancer, colorectal cancer,
             pancreatic cancer, gastric cancer, renal cancer, bladder cancer, or breast cancer with
             radiographic evidence by MRI of at least one measurable brain lesion as defined by
             RANO criteria that does not require corticosteroids for symptomatic control.

          -  Cohort C: Histologically confirmed metastatic solid tumor of epithelial origin,
             including both NSCLC and non-NSCLC, with radiographic evidence by MRI of at least one
             measurable brain lesion as defined by RANO criteria that requires corticosteroids for
             symptomatic control.

          -  At least one prior treatment to a CNS-based lesion is required. Prior therapy must be
             completed > 2 weeks prior to enrollment. A previously treated lesion must be
             demonstrated by MRI to have progressed following treatment in order to be eligible.
             The subsequent development of a new CNS lesion that was not previously treated will be
             permitted and dose not require treatment followed by progression prior to enrollment.
             Treatment of a single CNS lesion with local therapy in the context of multifocal
             disease is permitted as long as at least one untreated lesions meets criteria for
             measurable disease. Patients should have received minimum of one line of systemic
             therapy.

          -  At least 18 years of age.

          -  ECOG performance status of 0 to 2

          -  Adequate bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcL

               -  Platelets ≥ 100,000/mcL

               -  Hemoglobin ≥ 8.0 g/dL

               -  Serum bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

               -  Creatinine clearance ≥ 40 mL/min/1.73 m2 by the Cockcroft-Gault formula or by
                  24-hour urine collection for determination of creatinine clearance

          -  Negative antiviral serology:

               -  Negative human immunodeficiency virus (HIV) antibody.

               -  Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc)
                  antibody or undetectable hepatitis B (HBV) DNA by quantitative polymerase chain
                  reaction (PCR) testing.

               -  Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA)
                  by quantitative PCR.

          -  Mean QT interval corrected for heart rate (QTc) < 470 msec calculated from 3 ECGs
             performed at least 2 minutes apart using Frediricia's Correction.

          -  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 upon study entry.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Diagnosis of leptomeningeal carcinomatosis.

          -  Diagnosis of melanoma or other non-epithelial based malignancy such as sarcoma,
             neuroendocrine tumor, small cell lung cancer.

          -  Presence of unstable systemic disease (e.g., visceral crisis or rapid progression) in
             the judgment of the investigator.

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only or
             carcinoma in situ of the cervix.

          -  Currently receiving any other investigational agents.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to MEDI4736 or other agents used in the study.

          -  Previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI4736, or a CTLA-4
             inhibitory agent.

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of MEDI4736 with the exceptions of intranasal and inhaled corticosteroids, or
             systemic corticosteroids in Cohort C.

          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) 21 days prior to the first dose of study
             drug.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension (>180/110),
             unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or
             gastritis, active bleeding diatheses, or psychiatric illness/social situations that
             would limit compliance with study requirements.

          -  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 prior immunodeficiency.

          -  History of allogeneic organ transplant.

          -  Known history of previous clinical diagnosis of tuberculosis.

          -  Receipt of live attenuated vaccination within 30 days prior to first dose of MEDI4736.

          -  Pregnant and/or breastfeeding 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