Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Phase II Trial of Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer

Conditions
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Medullary Thyroid Cancer (MTC)

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Participants that had an immune stimulating cancer vaccine<br>Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks for two years. Group 1: cancer vaccine | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks.<br>* Other names: MK-3475;|
| Experimental: Cohort 2: Participants that have had no vaccine<br>Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks for two years. Group 2: had no previous vaccine | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks.<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Participants with medullary thyroid cancer were administered a programmed cell death protein 1 (PD1) inhibitor to determine if any experienced a 50% or greater decline in calcitonin levels. A calcitonin response is defined as participants with a ≥50% decline from baseline that is then confirmed on a subsequent calcitonin assessment at least one week later. | 2 years | 
| Percentage of Participants With a Partial Response and Complete Response by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) | Participants were imaged by CT or MRI and followed for response using the Immune-Related Response Criteria (irRC). Partial Response is a ≥30% decrease in the sum of the largest diameter (SLD) compared with baseline confirmed by a consecutive assessment at least 4 weeks after the first documentation. Complete Response is a 100% disappearance of all lesions, whether measurable or not, and no new lesions, in two consecutive observations not less than 4 weeks from the date first documented. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in (Cluster of Differentiation 4 (CD4), CD8, Tregs, and Natural Killer (NK) Cells at Day 1 and 84 Days in All Participants | Regulatory T-Cells (CD4, CD8, Tregs, and NK cells) in peripheral blood mononuclear cell (PBMC)s were measured by 7-color flow cytometry. | Day 1 and 84 days | 
| Number of Participants With a Sustained Decline in Carcinoembryonic Antigen (CEA) | A sustained 50% decline in CEA. A large magnitude decline in CEA may be associated with tumor responses. | every 3 weeks while on treatment and post treatment, up to 2 years | 
| Number of Participants With a Sustained Decline in Calcitonin | A sustained 50% decline in calcitonin. A large magnitude decline in calcitonin may be associated with tumor responses. | every 3 weeks while on treatment and post treatment, up to 2 years | 
| Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression, assessed by the Immune-Related Response Criteria (irRC), is defined as at least 20% increase in the sum of the largest diameter (SLD) compared with nadir (minimum recorded tumor burden) and an increase of at least 5mm over the nadir, confirmed by a repeat,consecutive observations at least 4 weeks from the date first documented. | 3 weeks for up to 2 years while on treatment than 2 weeks after last treatment | 
| Overall Survival at 2 Years | Percentage of participants who are alive at 2 years. | 2 years | 
| Number of Participants With Grade ≥1 Adverse Events Possibly, Probably, or Definitely Related to Pembrolizumab | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening; urgent intervention indicated. Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately 25 months and 28 days for cohort 1 and 18 months and 12 days for cohort 2. | 
| Number of Participants With Grade ≥1 Adverse Events Unlikely or Unrelated to Pembrolizumab | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening; urgent intervention indicated. Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately 25 months and 28 days for cohort 1 and 18 months and 12 days for cohort 2. | 
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 25 months and 28 days for cohort 1 and 18 months and 12 days for cohort 2. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-PD1/PDL1, Vaccine Therapy, TKI-Naive