Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer

Background:

- Anti PD1/PDL1 therapies have had clinical success in a minority of unselected patients
across multiple tumor types

- While many questions remain about optimal PD1/PDL1 staining techniques to pre-select
responders, less focus is being place on how to optimize responses in a broader cohort
of patients

- Emerging preclinical and clinical data supports the hypothesis that a strong immunologic
response in the tumor microenvironment induces PDL1 expression on the tumor and is
associated with better clinical response to anti-PD1/PDL1 therapies

- Therapeutic cancer vaccines are one strategy to induce an immunologic response to the
tumor, thereby enhancing PDL1 expression and optimizing clinical responses across all
patients

- Limited clinical data exists about the potential benefit of sequential therapy with a
therapeutic cancer vaccine followed by PD1/PDL1 inhibition

- This study will explore the role of PD1 inhibition in medullary thyroid cancer and
evaluate the potential differences based on previous vaccine therapy

Objective:

-The primary objective of this trial is to determine whether administering a PD1 inhibitor to
patients with medullary thyroid cancer will permit a modest fraction to be able to experience
a 50% or greater decline in calcitonin levels or experience a partial/complete response on
imaging

Key Eligibility:

- Patients greater than or equal to 18 years of age with evidence of metastatic medullary
thyroid cancer including disease that is evaluable on bone, CT scan or MRI

- Must have elevated calcitonin levels greater than 40 pg/mL

- Patients with minimal or no disease related-symptoms (minimal symptoms will include
those that do not affect activities of daily living or pain that does not require
regularly schedule narcotics)

- ECOG 0-1

- Should have no autoimmune diseases; no evidence of being immunocompromised; no serious
inter-current medical illness

- No brain metastasis, history of seizures, encephalitis, or multiple sclerosis

Design:

- This is a phase II, open label, single center clinical trial where all patients receive
the anti-PD1/PDL1 therapy pembrolizumab

- Patients will enroll in one of two cohorts: patients with previous vaccine therapy or
patients without previous vaccine therapy

- All patients will be TKI -na(SqrRoot) ve, with minimal symptoms (consistent with the
eligibility for our current study)

- Based on our calcitonin findings with our current study of 30 patients, we have
determined that a confirmed calcitonin decline of 50% would be a rare finding, providing
compelling preliminary evidence of clinical activity

- A total of 30 patients will be enrolled in the proposed study (15 patients in each
cohort). Given that we already have 30 patients on a study with vaccine, we would only
need to identify and recruit 15 na(SqrRoot) ve patients for the vaccine-naive cohort.
This accrual could be done in 18 months based on our current accrual rates

- Based on these metrics, we could have >6 months of calcitonin data in 30 patients within
2 years from trial initiation

- Additional immune correlative capitalizing on the extensive immune monitoring experience
of the LTIB will allow for assessments of antigen specific T-cells and 123 immune
subsets. These findings could provide the basis for biomarker development when taken
together with biochemical and clinical responses seen in this study

- INCLUSION CRITERIA:

- Diagnosis: Patients must have histologically confirmed medullary thyroid cancer by the
Laboratory of Pathology or a pathology report and history consistent with medullary
thyroid cancer. It is not uncommon for a secondary, minor pathologic focus of another
form of thyroid cancer to be coincidentally found in 15-20% of patients with medullary
thyroid cancer. In such cases, eligibility is based on the discretion of the
investigator.

- Patients must have evidence of metastatic medullary thyroid cancer including disease
that is evaluable on bone, CT scan or MRI. (Patients who are surgical candidates and
potentially rendered disease free with surgical resection are not eligible.)

- Patients must have elevated calcitonin levels greater than 40 pg/mL

- Patients must have minimal or no disease related-symptoms (Minimal symptoms will
include those that do not affect activities of daily living or pain that does not
require regularly scheduled narcotics.)

- Patients must have evaluable disease on imaging

- No history of seizures, encephalitis, or multiple sclerosis.

- Age greater than or equal to 18 years

- ECOG performance status of 0-1 at study entry (Karnofsky greater than or equal to 70).

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.

- Female subjects of childbearing potential must be willing to use an adequate method of
contraception, Contraception, 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 contraception for the subject

- Male subjects of childbearing potential must agree to use an adequate method of
contraception. 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 contraception for the subject

- Willing to travel to the NIH for follow-up visits

- Able to understand and sign informed consent.

- Demonstrate adequate organ function, all screening labs should be performed within 10
days of treatment initiation.

- Adequate Organ Function Laboratory Values

- Hematological

---Absolute neutrophil count (ANC) greater than or equal to1,000 /mcL

- Platelets greater than or equal to 100,000 / mcL

- Hemoglobin greater than or equal to 9 g/dL or greater than or equal to 5.6 mmol/L
without transfusion or EPO dependency (within 7 days of assessment)

- Renal

- Serum creatinine less than or equal to1.5 X upper limit of normal (ULN) OR

- Measured or calculated* creatinine clearance (GFR can also be used in place
of creatinine or CrCl) greater than or equal to 60 mL/min for subject with
creatinine levels > 1.5 X institutional ULN

- Hepatic

- Serum total bilirubin less than or equal to 1.5 X ULN OR Direct bilirubin
less than or equal to ULN for subjects with total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (SGPT) less than or equal to 2.5 X ULN OR less than or
equal to 5 X ULN for subjects with liver metastases

- Albumin >2.5 mg/dL

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT) less than or
equal to1.5 X ULN unless subject is receiving anticoagulant therapy as long
as PT or PTT is within therapeutic range of intended use of anticoagulants

- Activated Partial Thromboplastin Time (aPTT) less than or equal to1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants

- Creatinine clearance should be calculated per Cockcroft-Gault equation

EXCLUSION CRITERIA:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., less than or equal to Grade 1 or at baseline)
from adverse events due to agents administered more than 4 weeks earlier.

- Has had prior targeted small molecule therapy, or radiation therapy within 2 weeks
prior to study Day 1 or who has not recovered (i.e., less than or equal to Grade 1 or
at baseline) from adverse events due to a previously administered agent. Note:
Subjects with less than or equal to Grade 2 neuropathy are an exception to this
criterion and may qualify for the study. Note: If subject received major surgery, they
must have recovered adequately from the toxicity and/or complications from the
intervention prior to starting therapy.

- Has 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). 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.

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable for 6 months (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 at least 7 days prior to trial treatment. This exception does
not include carcinomatous meningitis which is excluded regardless of clinical
stability.

- Has history of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a 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.

- 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 trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Has received a live vaccine within 30 days of planned start of study therapy

- Concurrent use of systemic steroids, except for physiologic doses of systemic steroid
replacement or local (topical, nasal, eye drops or inhaled) steroid use. Limited doses
of systemic steroids (e.g., in patients with exacerbations of reactive airway disease
or to prevent IV contrast allergic reaction or anaphylaxis in patients who have known
contrast allergies) are allowed.

- Serious inter-current medical illness which would interfere with the ability of the
patient to carry out the treatment program.

- Patients with second malignancy within 3 years of enrollment; Patients curatively
treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not
excluded. Patients with MEN2 and a history of pheochromocytoma will also not be
excluded. In addition patients with prostate cancer who do not require systemic
therapy will not be excluded. (A secondary, minor pathologic focus of another form of
thyroid cancer may be coincidentally found in 15-20% of patients with medullary
thyroid cancer. In such cases, eligibility is based on the discretion of the
investigator.)

- Patients with previous history of vandetanib or cabozantinib treatment for more than
28 days of treatment (patients have discontinued treatment for 28 days before
enrolling).