Lenvatinib and Pembrolizumab in DTC

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)

TERTIARY 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
courses in the absence of disease progression or unacceptable toxicity. Patients may continue
treatment for up to 35 courses.

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 =< 30 days
prior to registration, as confirmed by the site study PI

- 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 (eg., 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