Pembrolizumab, Chemotherapy, and Radiation Therapy With or Without Surgery in Treating Patients With Anaplastic Thyroid Cancer

PRIMARY OBJECTIVES:

I. To assess the efficacy of pembrolizumab in improving overall survival at 6 months (OS-6)
in combination with multimodal therapy involving standard chemo-radiotherapy in anaplastic
thyroid cancer (ATC) in comparison to a historical cohort.

SECONDARY OBJECTIVES:

I. To determine safety and tolerance of pembrolizumab with chemoradiotherapy.

TERTIARY OBJECTIVES:

I. To evaluate locoregional control. II. To evaluate progression of distant metastases. III.
To evaluate the evolution of the immune profile of circulating immune cells in response to
therapy in ATC patents, and to assess potential correlations with outcomes on an exploratory
basis.

IV. To evaluate PD-1 and PD-L1 staining in tumor cells and tumor stroma as candidate
biomarkers for outcomes.

V. To determine if pre-therapy circulating tumor cell load is associated with outcomes.

VI. To examine associations between outcomes and somatic mutational status as assessed by
foundation medicine analysis (for example: presence of BRAF, RAS, P53 and TERT promoter
mutations).

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment with pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation
if no residual disease is found or for up to 35 courses after chemoradiation if residual
disease is found. After 3 days, patients undergo surgery. Within 42 days of surgery, patients
also receive docetaxel IV over 1 hour once weekly (Q1W) and doxorubicin hydrochloride IV Q1W,
and undergo intensity-modulated radiation therapy (IMRT) once daily 5 days per week for 6.5
weeks in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with
pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation if no residual
disease is found or for up to 35 courses after chemoradiation if residual disease is found.
After 3 days, patients also receive docetaxel IV over 1 hour Q1W and doxorubicin
hydrochloride IV Q1W, and undergo IMRT once daily 5 days per week for 6.5 weeks in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until
progressive disease and then every 6 months for up to 5 years.

Inclusion Criteria:

- Histological confirmation of, or cytology reported and confirmed, anaplastic thyroid
cancer

- NOTE: A diagnosis reported as ?poorly differentiated carcinoma consistent with
anaplastic thyroid cancer? will be accepted

- Absence of prior neck radiotherapy

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Hemoglobin >= 9.0 g/dL

- White blood cells (WBC)/leukocytes >= 3500/mm^3

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with
well-documented Gilbert?s syndrome)

- Aspartate transaminase (AST) =< 3 x ULN

- Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 50 ml/min using the
Cockcroft-Gault formula

- Prothrombin time (PT)/activated partial thromboplastin time (PTT) =< 1.5 x ULN, unless
subject is receiving anticoagulant therapy and PT or activated (a)PTT is within
therapeutic range of intended use of anticoagulants

- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only

- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required

- NOTE: Merck requires an additional pregnancy test if eligibility pregnancy test
is > 72 hours prior to first dose

- Persons of childbearing potential must be willing to use an adequate method of birth
control for the course of the study through 120 days after the last dose of study
medication

- NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred
method of contraception for the patient

- Persons able to father a child must agree to use an adequate method of contraception
starting with the first dose of study therapy through 120 days after the last dose of
study therapy

- NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred
method of contraception for the patient

- Provide written informed consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

- History of non-infectious pneumonitis that required steroids or current pneumonitis

- Any of the following:

- Pregnant persons

- Nursing persons

- Persons of childbearing potential who are unwilling to employ adequate
contraception

- Any autoimmune disease such as inflammatory bowel disease, including but not limited
to:

- Ulcerative colitis

- Crohn's disease

- Rheumatoid arthritis

- Systemic sclerosis

- Systemic lupus erythematosus

- Autoimmune hepatitis

- Other autoimmune disease not listed above

- NOTE: Subjects with autoimmune thyroid disease and diabetes mellitus type I will
be allowed

- Uncontrolled intercurrent illness including, but not limited to,

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia, or

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Other active malignancy =< 6 months prior to registration

- EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix or
prostate cancer confined to prostate gland with Gleason score < 6 or
prostate-specific antigen (PSA) < 1

- NOTE: If there is a history of prior malignancy, they must not be receiving other
treatment for their cancer; ongoing adjuvant hormonal treatment for breast cancer
is allowed

- Prior known allergic reaction to pembrolizumab or its excipients

- Untreated brain metastasis

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Received any live vaccine =< 30 days prior to registration

- Any of the following conditions =< 6 weeks prior to registration:

- Cerebrovascular accident (CVA)

- Admission for unstable angina

- Cardiac angioplasty or stenting or coronary artery bypass graft surgery

- Pulmonary embolism or untreated deep venous thrombosis (DVT)

- Arterial thrombosis

- Class III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system