Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)
Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)
This phase II trial studies how well pembrolizumab and lenvatinib work in treating patients
 with differentiated thyroid cancer that has spread to other places in the body or has come
 back and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as
 pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
 the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES:

 I. To investigate the clinical efficacy, as indicated by the rate of complete response (CR)
 per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, of combination therapy with
 pembrolizumab and lenvatinib in lenvatinib-naive patients with progressive
 radioiodine-refractory differentiated thyroid cancers (DTC). (Cohort 1) II. To determine the
 overall response rate (ORR) by the addition of pembrolizumab to patients with
 radioiodine-refractory DTC who have progressive disease on lenvatinib alone. (Cohort 2)

 SECONDARY OBJECTIVES:

 I. To determine the safety profile and toxicity of combination therapy with pembrolizumab and
 lenvatinib in patients with progressive DTC. (Cohort 1 and cohort 2) II. To determine
 progression-free survival (PFS) and overall survival (OS). (Cohort 1 and cohort 2)

 CORRELATIVE RESEARCH OBJECTIVES:

 I. To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ T cells in
 the primary and/or metastatic tumor. (Cohort 1 and cohort 2) II. To correlate tumor response
 (RECIST 1.1) with pretreatment PD-L1 and PD-L2 levels in the primary and/or metastatic tumor.
 (Cohort 1 and cohort 2) III. To correlate tumor response (RECIST 1.1) with pretreatment
 frequency of lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+
 macrophages. (Cohort 1 and cohort 2) IV. To correlate tumor response (RECIST 1.1) with the
 phenotype and frequency of key leukocyte subsets (i.e., PD-1+ T cells, regulatory T cells
 [Tregs], myeloid subsets) in the peripheral blood before, at 6 and 18 weeks on therapy, and
 at 54 weeks (study completion), progressive disease (PD), or study withdrawal. (Cohort 1) V.
 To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional capacity. (Cohort 1)
 VI. To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin antibody levels
 assessed before, and at 18 weeks on therapy. (Cohort 1 and 2) VII. To correlate tumor
 response (RECIST 1.1) with tumor mutation status. (Cohort 1) VIII. To broadly investigate
 mechanisms of response and resistance to combination therapy, gene expression profiles will
 be generated from frozen biopsies for analysis by ribonucleic acid-sequencing (RNA-Seq).
 (Cohort 1)

 OUTLINE:

 Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab
 intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 19
 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue
 treatment for up to 35 cycles.

 After completion of study treatment, patients are followed up every 3 months for up to 3
 years.
Inclusion Criteria:

 -  Locally recurrent and unresectable and/or distant metastatic differentiated thyroid
 cancer (DTC), histologically or cytologically confirmed; the diagnosis of DTC includes
 the following subtypes: papillary thyroid cancer (PTC) (including but not limited to
 variants such as follicular variant, tall cell, columnar cell, Hurthle cell variant of
 papillary carcinoma, and poorly differentiated), follicular thyroid cancer (FTC),
 including insular variant, Hurthle cell carcinoma and poorly differentiated thyroid
 cancer

 -  Measurable disease meeting the following criteria:

 -  At least 1 lesion of >= 1.0 cm in the longest diameter for a non-lymph node or >=
 1.5 cm in the short-axis diameter for a lymph node which is serially measurable
 according to RECIST 1.1 using computerized tomography/magnetic resonance imaging
 (CT/MRI); if there is only one target lesion and it is a non-lymph node, it
 should have a longest diameter of >= 1.5 cm

 -  Lesions that have had external beam radiotherapy (EBRT) or loco-regional
 therapies such as radiofrequency (RF) ablation must show evidence of progressive
 disease based on RECIST 1.1 to be deemed a target lesion

 -  For cohort 1 only: evidence of disease progression =< 14 months prior to registration
 according to RECIST 1.1, as confirmed by the site study principal investigator (PI)

 -  For cohort 2 only: progressive disease (PD) on lenvatinib per RECIST 1.1 =< 60 days
 prior to registration, as confirmed by the site study PI; patients need to have
 documented imaging and measurement of RECIST target lesions within 30 days of starting
 pembrolizumab

 -  Radioiodine (RAI)-resistant disease as defined by one or more of the following
 criteria:

 -  One or more measurable lesions that do not demonstrate RAI uptake

 -  One or more measurable lesions progressive by RECIST 1.1 =< 14 months of prior
 RAI therapy

 -  One or more measurable lesions present after cumulative RAI dose of >= 600 mCi

 -  One or more measurable lesions that are fludeoxyglucose F-18 (FDG)-avid (> 5
 standardized uptake value [SUV]), if positron emission tomography (PET)/CT scan
 performed; these lesions may also be RAI-avid

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

 -  Absolute neutrophil count (ANC) >= 1,500 /mcL (obtained =< 30 days prior to
 registration)

 -  Platelets >= 100,000 / mcL (obtained =< 30 days prior to registration)

 -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin dependency
 (=< 7 days prior to registration) (obtained =< 30 days prior to registration)

 -  Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
 creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
 creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
 levels > 1.5 X institutional ULN (obtained =< 30 days prior to registration)

 -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
 bilirubin levels > 1.5 ULN (obtained =< 30 days prior to registration)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
 ULN OR =< 5 X ULN for subjects with liver metastases (obtained =< 30 days prior to
 registration)

 -  Albumin >= 2.5 mg/dL (obtained =< 30 days prior to registration)

 -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
 subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
 time (PTT) is within therapeutic range of intended use of anticoagulants (obtained =<
 30 days prior to registration)

 -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
 anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
 of anticoagulants (obtained =< 30 days prior to registration)

 -  Adequately controlled blood pressure with or without antihypertensive medications
 defined as blood pressure (BP) < 150/90 mmHg at screening

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

 -  Ability to complete patient medication and blood pressure diaries by themselves or
 with assistance

 -  Willing and able to provide informed written consent

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

 -  Note: during the active monitoring phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting
 institution for follow-up

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

 Exclusion Criteria:

 -  Cohort 1 only: prior treatment with previous VEGFR active multikinase inhibitor

 -  Cohort 2 only: discontinued lenvatinib due to toxicity

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

 -  Female subjects of childbearing potential: unwilling or unable to use 2 methods of
 birth control or be surgically sterile, or abstain from heterosexual activity for the
 course of the study through 120 days after the last dose of study medication; NOTE:
 subjects of childbearing potential are those who have not been surgically sterilized
 or have not been free from menses for > 1 year

 -  Male subjects: unwilling or unable 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

 -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
 of the investigator, would make the patient inappropriate for entry into this study or
 interfere significantly with the proper assessment of safety and toxicity of the
 prescribed regimens

 -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
 positive (HIV 1/2 antibodies) and currently receiving antiretroviral therapy

 -  Currently participating and receiving study therapy (except lenvatinib for patients in
 cohort 2) or has participated in a study of an investigational agent and received
 study therapy within 4 weeks prior to registration

 -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
 form of immunosuppressive therapy =< 7 days prior to the first dose of trial treatment

 -  Known history of active TB (Bacillus tuberculosis)

 -  Hypersensitivity to pembrolizumab or any of its excipients

 -  Prior anti-cancer monoclonal antibody (mAb) =< 4 weeks prior to registration or who
 has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
 administered >= 4 weeks prior to registration

 -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
 weeks prior to study day 1 (except lenvatinib for patients in cohort 2) or who has not
 recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously
 administered agent

 -  NOTE:

 -  Subjects with =< grade 2 neuropathy are an exception to this criterion and
 may qualify for the study

 -  If subject received major surgery, they must have recovered adequately from
 the toxicity and/or complications from the intervention prior to
 registration, as deemed by treating investigator or site PI

 -  Known additional malignancy that is progressing or requires active treatment;
 exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
 skin that has undergone potentially curative therapy or in situ cervical cancer

 -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis;
 NOTE: subjects with previously treated brain metastases may participate provided they
 are stable (without evidence of progression by imaging for at least four weeks prior
 to the first dose of trial treatment and any neurologic symptoms have returned to
 baseline), have no evidence of new or enlarging brain metastases, and are not using
 steroids for >= 7 days prior to trial treatment; this exception does not include
 carcinomatous meningitis which is excluded regardless of clinical stability

 -  Active autoimmune disease that has required systemic treatment in the past 2 years
 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
 drugs); NOTE: replacement therapy (e.g., thyroxine, insulin, or physiologic
 corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
 not considered a form of systemic treatment

 -  Known history of, or any evidence of active, non-infectious pneumonitis that required
 steroids

 -  Active infection requiring systemic therapy

 -  History or current evidence of any condition, therapy, or laboratory abnormality that
 might confound the results of the trial, interfere with the subject's participation
 for the full duration of the trial, or is not in the best interest of the subject to
 participate, in the opinion of the treating investigator

 -  Known psychiatric or substance abuse disorders that would interfere with cooperation
 with the requirements of the trial

 -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

 -  Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
 hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
 detected)

 -  Received a live vaccine =< 30 days of planned start of study therapy; NOTE: seasonal
 influenza vaccines for injection are generally inactivated flu vaccines and are
 allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated
 vaccines, and are not allowed

 -  Proteinuria > 1+ on dipstick urinalysis; patients with > 1+ proteinuria on dipstick
 urinalysis will undergo 24-hour urine collection for quantitative assessment; NOTE:
 patients with > 1 g/24 hours will be ineligible

 -  Clinically significant gastrointestinal malabsorption syndrome

 -  New York Heart Association congestive heart failure of grade II or above, unstable
 angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia
 associated with significant cardiovascular impairment within the past 6 months;
 ejection fraction (EF) by multi-gated acquisition (MUGA) or echo should not be less
 than the institutional lower limit of normal

 -  Corrected QT (QTc) prolongation > 480 msec, as calculated by either the Bazett or
 Fridericia formula, as per institutional standard

 -  Active hemoptysis (bright red blood > 1 teaspoon on more than one occasion) =< 3 weeks
 prior to registration

 -  Cohort 2 only: more than one prior treatment with VEGFR active multikinase inhibitor
 prior to original start of lenvatinib