Phase II Trial of Pembrolizumab in Metastatic or Locally Advanced Anaplastic/Undifferentiated Thyroid Cancer

Inclusion Criteria:

   - Histologically- or cytologically-confirmed diagnosis of anaplastic thyroid cancer
   (ATC) or undifferentiated thyroid cancer (UTC). A diagnosis of possible ATC/UTC will
   be allowed if the clinical presentation is consistent with anaplastic or
   undifferentiated thyroid cancer.

   - Disease characteristics one of the following:

      - Unresectable ATC/UTC limited to the neck:

Subjects must have received radiation therapy or surgery to primary tumor and have
subsequent evidence of ATC/UTC.

   - Metastatic ATC/UTC: either with entirely surgically-removed cancer/metastatic only
   disease, or with disease in the neck not requiring radiation or surgery to the neck
   mass

      - Measurable disease per RECIST v1.1. Lesions situated in a previously-irradiated
      area are considered measurable if progression has been demonstrated in such
      lesions.

      - ≥ 18 years of age.

      - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (within 7
      days prior to the first dose of pembrolizumab).

      - Absolute neutrophil count (ANC) ≥ 1500/µL (within 10 days prior to the first dose
      of pembrolizumab).

      - Platelets ≥ 100 000/µL (within 10 days prior to the first dose of pembrolizumab).

      - Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (within 10 days prior to the first dose of
      pembrolizumab). Criteria must be met without erythropoietin dependency and
      without packed red blood cell (pRBC) transfusion within last 2 weeks.

      - Creatinine ≤ 1.5 × ULN OR Measured or calculated creatinine clearance per
      institutional standard ≥ 30 mL/min for subject with creatinine levels >1.5 ×
      institutional ULN (GFR can also be used in place of creatinine or CrCl) (test
      within 10 days prior to the first dose of pembrolizumab).

      - Total bilirubin ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for participants with total
      bilirubin levels >1.5 × ULN (test within 10 days prior to the first dose of
      pembrolizumab).

      - AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver
      metastases) (test within 10 days prior to the first dose of pembrolizumab).

      - International normalized ratio (INR) ≤ 1.5 × ULN OR Prothrombin time (PT) ≤ 1.5 ×
      ULN (Exception: subject is receiving anticoagulant therapy and PT or aPTT is
      within therapeutic range of intended use of anticoagulants)

      - The subject [or legally acceptable representative (LAR) if applicable] has the
      apparent ability to understand and the willingness to personally sign the written
      IRB-approved informed consent document.

      - Not a woman of childbearing potential (WOCBP), or if WOCBP, not pregnant
      (negative urine pregnancy test within 72 hours prior to first dose of
      pembrolizumab), not breastfeeding, and agrees to follow contraceptive guidance
      per protocol Appendix A. NOTE: if the urine test is positive or cannot be
      confirmed as negative, a negative serum pregnancy test is required.

Exclusion Criteria:

   - Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
   an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
   OX-40, CD137).

   - Has received prior systemic anti-cancer therapy including investigational agents
   within 4 weeks prior to study treatment start. Note: Participants must have recovered
   from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤
   Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤ 2
   requiring treatment or hormone replacement may be eligible. Note: If the participant
   had major surgery, the participant must have recovered adequately from the procedure
   and/or any complications from the surgery prior to starting study intervention. Note:
   Patients who have most recently been treated with dabrafenib and/or trametinib and/or
   lenvatinib require a washout period of 1 week from their last dose.

   - Has received prior radiotherapy within 2 weeks of start of study intervention.
   Participants must have recovered from all radiation-related toxicities, not require
   corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
   for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

   - Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
   first dose of study drug. Administration of killed vaccines is allowed.

   - Is currently participating in or has participated in a study of an investigational
   agent or has used an investigational device within 4 weeks prior to the first dose of
   study intervention. Subject in the follow-up phase of an investigational study may
   participate as long as it has been ≥4 weeks after the last dose of the previous
   investigational agent.

   - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
   (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
   immunosuppressive therapy within 7 days prior to the first dose of study drug.

   - Has a known additional malignancy that is progressing or is requiring active treatment
   within the past 1 year. Subjects with basal cell carcinoma of the skin, squamous cell
   carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in
   situ) that have undergone potentially curative therapy are not excluded.

   - Has known active CNS metastases and/or carcinomatous meningitis. Participants with
   previously treated brain metastases may participate provided they are radiologically
   stable, ie, without evidence of progression for at least 4 weeks by repeat imaging
   (note that the repeat imaging should be performed during study screening), clinically
   stable and without requirement of steroid treatment for at least 14 days prior to
   first dose of study intervention.

   - Has a history of non-infectious pneumonitis/interstitial lung disease that required
   steroids or has current pneumonitis/interstitial lung disease (ILD).

   - Has an active infection requiring systemic therapy.

   - Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: HIV testing
   is not required unless mandated by local health authority.

   - Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
   reactive) or known active Hepatitis C virus (defined as HCV RNA is detected)
   infection. Note: no testing for Hepatitis B and Hepatitis C is required unless
   mandated by local health authority

   - Has active autoimmune disease that has required systemic treatment in the past 2 years
   (ie, with use of disease modifying agents, corticosteroids or immunosuppressive
   drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
   replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a
   form of systemic treatment and is allowed.

   - Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.

   - Has other co-morbid disease or intercurrent illness.

   - Has a history or current evidence of any condition, therapy, or laboratory abnormality
   that might confound the results of the study, interfere with the participant's
   participation for the full duration of the study, or is not in the best interest of
   the participant to participate, in the opinion of the treating investigator.

   - Has known psychiatric or substance abuse disorders that would interfere with
   cooperation with the requirements of the trial.

   - Is pregnant or breastfeeding or expecting to conceive or father children within the
   projected duration of the study, starting with the screening visit through 120 days
   after the last dose of trial treatment.

   - Has had an allogenic tissue/solid organ transplant.