Lenvatinib and Pembrolizumab for the Treatment of Stage IVB Locally Advanced and Unresectable or Stage IVC Metastatic Anaplastic Thyroid Cancer

Inclusion Criteria:

• Pathologic findings supporting the clinical impression of anaplastic thyroidcarcinoma. Diagnosis may include consistent with or suggestive of terminologyassociated with: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamouscarcinoma; carcinoma with spindled, giant cell, or epithelial features; poorlydifferentiated carcinoma with pleomorphism, extensive necrosis with tumor cellspresent

• Patients deemed to have unresectable locoregional disease or metastatic disease.Patients who are unwilling to undergo surgery or external beam radiation are alsoeligible. Patients with a BRAFV600E mutation who are unable to receive the Food andDrug Administration (FDA) approved drugs, dabrafenib/trametinib, are eligible aslong as this is documented

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Total bilirubin ≤ 3 x ULN forpatients with Gilbert's syndrome

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x ULN, (5 x ULN for patients with concurrent liver metastases)

• Serum creatinine ≤ within 1.5 x ULN

• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

• Platelets ≥ 100 x 10^9/L

• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen andstable institutional normalized ratio (INR) during the 28 days immediately precedinginitiation of study treatment

• Subjects must be willing to undergo tumor biopsy prior to and after treatment withlenvatinib/pembrolizumab, unless in the opinion of the treating physician, a biopsyis not feasible or safe

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 7 days prior to the date ofallocation/randomization

• Age >/= 18 years

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial

• A male participant must agree to use a contraception in Appendix A during thetreatment period and for at least 6 months after the last dose of study treatment

• A female participant is eligible to participate if she is not pregnant (see AppendixA), not breastfeeding, and at least one of the following conditions applies: a.) Nota woman of childbearing potential (WOCBP) OR b.) A WOCBP who agrees to follow thecontraceptive guidance in Appendix A during the treatment period and for at least 6months after the last dose of study treatment

Exclusion Criteria:

• Uncontrolled blood pressure (systolic blood pressure [BP] > 140 mmHg or diastolic BP > 90 mmHg) in spite of an optimized regimen of antihypertensive medication

• In patients with clinically significant electrolyte abnormalities (in the opinion ofthe treating physician) specifically, low calcium, potassium and magnesium, musthave replacement therapy initiated or modified prior to study entry.

• Significant cardiovascular impairment: history of congestive heart failure greaterthan New York Heart Association (NYHA) class II, unstable angina, myocardialinfarction or stroke within 6 months of the first dose of study drug, or cardiacarrhythmia requiring medical treatment at screening

• Patients with clinically significant hemoptysis or tumor bleeding within two weeksprior to first dose of targeted therapy. Patients with suspected tracheal oresophageal invasion can be included on a case-by-case basis after a discussion withthe principal investigator. The degree of tumor invasion/infiltration of major bloodvessels (e.g. carotid artery) should be considered because of the potential risk ofsevere hemorrhage and tracheoesophageal fistula associated with tumorshrinkage/necrosis following lenvatinib therapy

• Major surgery within 3 weeks prior to first dose of study interventions. Note:Adequate wound healing after major surgery must be assessed clinically, independentof time elapsed for eligibility

• Patients with open wounds or fistulas are excluded

• Subjects having > 2+ proteinuria on urine dipstick testing unless a 24-hour urinecollection for quantitative assessment indicates that the urine protein is <1 g/24hours

• Untreated brain metastases

• Prior chemotherapy within <1 week prior to study Day 1 or patients who have notrecovered (i.e., ≤ Grade 2) from adverse events due to a previously administeredagent.

• Previous anti-angiogenic targeted therapy is excluded

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment

• History of human immunodeficiency virus (HIV) or active hepatitis B (chronic oracute) or hepatitis C infection. Patients with past or resolved hepatitis Binfection (defined as having a negative hepatitis B surface antigen [HBsAg] test anda positive anti-HBc [antibody to hepatitis B core antigen] antibody test) areeligible. However, patients with past or resolved HBV should be monitored forreactivation by a specialist. Patients positive for hepatitis C virus (HCV) antibodyare eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleicacid (RNA)

• 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 ofimmunosuppressive therapy within 7 days prior to the first dose of study drug

• Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

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

• Has had an allogenic tissue/solid organ transplant

• Has a LVEF below the institutional (or local laboratory) normal range, as determinedby multigated acquisition (MUGA) or echocardiogram (ECHO).

• Prolongation of QTcF interval to >480 ms

• Gastrointestinal malabsorption or any other condition that might affect theabsorption of lenvatinib

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Females who are breastfeeding or pregnant at Screening or Baseline (as documented bya positive beta-human chorionic gonadotropin [beta-hCG] (or human chorionicgonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent unitsof beta-hCG [or hCG]). A women of childbearing potential (WOCBP) who has a positiveurine pregnancy test within 72 hours prior to the first infusion will be excluded.If the urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required