Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer

Phase 2

Completed

Conditions: Medullary Thyroid Cancer (MTC)

Interventions: Drug: Pembrolizumab

Registration Number: NCT03072160

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed Description: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: Participants that had an immune stimulating cancer vaccine	Pembrolizumab	Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks for two years. Group 1: cancer vaccine
Cohort 2: Participants that have had no vaccine	Pembrolizumab	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

Primary Outcome Measures

Name	Time	Method
Clinical Response	2 years	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.
Percentage of Participants With a Partial Response and Complete Response by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)	2 years	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.

Secondary Outcome Measures

Name	Time	Method
Percentage Change in (Cluster of Differentiation 4 (CD4), CD8, Tregs, and Natural Killer (NK) Cells at Day 1 and 84 Days in All Participants	Day 1 and 84 days	Regulatory T-Cells (CD4, CD8, Tregs, and NK cells) in peripheral blood mononuclear cell (PBMC)s were measured by 7-color flow cytometry.
Number of Participants With a Sustained Decline in Carcinoembryonic Antigen (CEA)	every 3 weeks while on treatment and post treatment, up to 2 years	A sustained 50% decline in CEA. A large magnitude decline in CEA may be associated with tumor responses.
Number of Participants With a Sustained Decline in Calcitonin	every 3 weeks while on treatment and post treatment, up to 2 years	A sustained 50% decline in calcitonin. A large magnitude decline in calcitonin may be associated with tumor responses.
Progression-free Survival (PFS)	3 weeks for up to 2 years while on treatment than 2 weeks after last treatment	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.
Overall Survival at 2 Years	2 years	Percentage of participants who are alive at 2 years.
Number of Participants With Grade ≥1 Adverse Events Possibly, Probably, or Definitely Related to Pembrolizumab	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.	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.
Number of Participants With Grade ≥1 Adverse Events Unlikely or Unrelated to Pembrolizumab	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.	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.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	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.	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.