Immunotherapy and Stereotactic Body Radiotherapy (SBRT) for Metastatic Anaplastic Thyroid Cancer
Immunotherapy and Stereotactic Body Radiotherapy (SBRT) for Metastatic Anaplastic Thyroid Cancer
The purpose of this study is to test the safety of durvalumab (MEDI4736) and tremelimumab in
 combination with radiation therapy and find out what effects, if any, this combination has on
 people, and whether it improves overall survival.
Inclusion Criteria:

 -  Histopathologic confirmation of anaplastic thyroid cancer (or histopathologic report
 consistent with anaplastic thyroid cancer) at Memorial Sloan Kettering Cancer Center
 with clinical evidence of metastatic disease not curable by either surgery or
 radiation therapy

 -  Age ≥ 18 years at time of study entry

 -  ECOG Performance Status of 0-2

 -  Adequate normal organ and marrow function as defined below:

 -  Hemoglobin ≥ 9.0 g/dL

 -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm^3)

 -  Platelet count ≥ 100 x 109/L (≥100,000 per mm^3)

 -  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
 hyperbilirubinaemia that is predominantly unconjugated in the absence of
 hemolysis or hepatic pathology), who will be allowed only in consultation with
 their physician

 -  AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver
 metastases are present, in which case it must be ≤ 5x ULN

 -  Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
 1976) or by 24-hour urine collection for determination of creatinine clearance:

 -  Males:

 Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL)

 °Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
 (mg/dL)

 -  Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
 history: ≥51 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

 -  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

 -  Measurable disease as per RECIST 1.1 besides the tumor that is expected to be
 radiated. See Section 12.2.1 for detailed description. Bony lesions without soft
 tissue component are not measurable lesions

 -  Patient must agree to allow 2 separate biopsies of any malignant lesion. Biopsies do
 not need to be done if:

 A. Tumor is not considered accessible by either the investigator or the person performing
 the biopsy (it is determined the risk is too high due to location near vital organs or too
 great of a risk of an adverse event).

 B. Patient is on anticoagulation and it would be unsafe to temporarily hold the
 anticoagulation.

 C.Consent of the PI not to have a biopsy done.

 Exclusion Criteria:

 -  Any previous treatment with an anti-CTLA4, including tremelimumab or any previous
 treatment with a PD1 or PDL1 inhibitor

 -  Receipt of the last dose of any line of anti-cancer therapy (chemotherapy,
 immunotherapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
 antibodies, and other investigational agent) 7 days prior to the first dose of study
 drug and within 6 weeks for nitrosourea or mitomycin C Prior radiation therapy to
 targets other than the site currently being treated is permitted.

 -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from a single
 electrocardiogram or average from 3 electrocardiograms (ECGs) using Frederica's
 Correction

 -  Current or prior use of immunosuppressive medication within 28 days before the first
 dose of durvalumab (MEDI4736) 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 any corticosteroid for more than 4
 consecutive days

 -  Any unresolved toxicity (CTCAE grade > 1) from previous anti-cancer systemic therapy
 unless approved by one of the principal investigators (Drs. Lee or Sherman) Rare
 exceptions that would not affect the study (e.g., radiaton induced dysphagia) allowed
 with the consent of either principal investigators (Drs. Lee or Sherman)

 -  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. Rare exceptions allowed with the consent of both
 principal investigators (Drs. Lee and Sherman)

 -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
 ulcerative colitis).

 -  Confirmed pneumonitis or interstitial lung disease

 -  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, Any subject known to have evidence of acute or chronic active
 hepatitis B, hepatitis C (PCR positive) 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 active tuberculosis (This does not
 include a history of being PPD positive)

 -  History of leptomeningeal carcinomatosis or active brain metastases receiving
 concurrent treatment inclusive of but not limited to surgery, radiation and/or
 corticosteroids. Note: Brain metastases that have been treated for anticancer purposes
 where there has been no MRI evidence of progression for at least 8 weeks after
 treatment are permitted on study

 -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
 30 days of receiving durvalumab (MEDI4736) 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
 Subjects with uncontrolled seizures

 -  Female patients who are pregnant or breast feeding 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 (MEDI4736) + tremelimumab
 combination therapy or 90 days after the last dose of durvalumab (MEDI4736)
 monotherapy, whichever is the longer time period

 -  Prior active malignancy within the previous 3 years except for locally curable cancers
 such as basal or squamous cell cancer superficial bladder, low risk prostate cancer,
 breast, or cervix cancer unless it is believed the malignancy will not affect the
 study outcome