Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer
Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer
Background:

 Medullary thyroid cancer (MTC) is a tumor of the thyroid gland. Surgery is the only current
 treatment to cure it. The drug pembrolizumab (MK-3475) is a new type of cancer therapy. It
 works by allowing the immune system to detect and kill tumor cells.

 Objective:

 To test how pembrolizumab affects people with MTC and if it can offer them clinical benefit.

 Eligibility:

 People ages 18 and older with MTC

 Patients who have recurrent or metastatic MTC, for whom surgery is not a curative option

 Patients with some imaging evidence of MTC

 Patients with minimal symptoms related to MTC

 Design:

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Blood, urine, and heart tests

 -  Computed tomography (CT) scan or magnetic resonance imaging (MRI): They lie in a machine
 that takes pictures of the body.

 -  Bone scan

 Participants will be put in a group based on their treatment history:

 -  Group 1 if they have had an immune stimulating cancer vaccine

 -  Group 2 if they have had no vaccine

 Participants will receive the study drug as a 30-minute intravenous (IV) infusion every 3
 weeks. Treatment will continue for up to 2 years as long as they tolerate it and their
 disease does not get worse.

 Participants will have physical exams and blood tests on the day of each infusion. They will
 have CT and bone scans every 3 months.

 Participants may save biopsies before treatment and after starting treatment.

 Participants will have a final visit 3-4 weeks after stopping treatment. This will include a
 physical exam and blood and heart tests.

 After this study, participants can join a long-term follow-up study.
Background:

 -  Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (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, computed tomography (CT)
 scan or magnetic resonance imaging (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)

 -  Eastern Cooperative Oncology Group (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 naive 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 patients for the vaccine-naive cohort.

 -  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 Laboratory of Tumor Immunology and Biology (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, computed tomography (CT) scan or magnetic resonance imaging
 (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

 -  Eastern Cooperative Oncology Group (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 National Institutes of Health (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 erythropoietin (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 (Glomerular filtration rate
 (GFR) can also be used in place of creatinine or creatinine clearance (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

 -  Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase
 (SGOT) and Alanine aminotransferase (ALT) Serum glutamic pyruvic
 transaminase (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 partial thromboplastin time (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 subjects
 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 breast feeding 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-Programmed cell death protein 1 (PD-1), anti-
 programmed cell death-1 ligand 1 (PD-L1), or anti-Programmed death ligand 2 (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., hepatitis C virus
 (HCV) ribonucleic acid (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 intravenous (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 Multiple endocrine neoplasia type 2 (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).