Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer
Condition: Medullary Thyroid Cancer (MTC)
MeSH terms: Thyroid Neoplasms; Carcinoma, Neuroendocrine; Thyroid Diseases
Intervention: Pembrolizumab
Intervention description: Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anti-PD1/PDL1; Vaccine Therapy; TKI-Naive

Summary:

      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.
    

Eligibility criteria:

        -  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).