A Study of FRaDCs for Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the response rate to the combination of folate receptor alpha dendritic cells (FRaDCs) plus pembrolizumab in patients with advanced ovarian, fallopian tube, or primary peritoneal cancer. Vaccines made from a person's peptide treated white blood cells may help the body build an effective immune response to kill tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine whether the combination of FRalphaDCs and pembrolizumab has an acceptable toxicity profile in patients with recurrent ovarian cancer (OC). (Phase I) II. To measure the confirmed objective response rate (ORR) to the combination of FRalphaDCs and pembrolizumab in patients with recurrent OC. (Phase II) SECONDARY OBJECTIVES: I. To estimate the disease control rate (DCR-percentage of patients achieving a complete response, partial response, or stable disease) of the combination of FRalphaDCs and pembrolizumab in patients with recurrent OC. II. To estimate the duration of response (DoR) in patients with recurrent OC treated with the combination of FRalphaDCs and pembrolizumab. III. To estimate the progression-free survival (PFS) of patients with recurrent OC treated with the combination of FRalphaDCs and pembrolizumab. IV. To estimate the overall survival (OS) of patients with recurrent OC treated with the combination of FRalphaDCs and pembrolizumab. 2.25 To characterize the adverse event (AE) profile in patients with recurrent OC treated with the combination of FRalphaDCs and pembrolizumab. CORRELATIVE OBJECTIVES: I. To determine whether the combination of FRalphaDCs and pembrolizumab induces an increase in the frequency of FRalpha-specific IL-17-secreting T cells (Th17s) in patients with recurrent OC. II. Characterize the T cell and antibody responses to FRalpha and assess the association between the emergence of immunity and recurrence-free (RFS). III. To determine whether the combination of FRalphaDCs and pembrolizumab induces an increase in the frequency of FRalpha-specific IFNgamma-secreting T cells (Th1s) in patients with recurrent OC. IV. To determine whether the combination of FRalphaDCs and pembrolizumab induces an increase in the frequency of FRalpha-specific IgG antibodies in patients with recurrent OC. V. To determine whether the combination of FRalphaDCs and pembrolizumab induces changes in the immune microenvironment of ovarian tumors. OUTLINE: Patients undergo apheresis for multi-epitope folate receptor alpha-loaded dendritic cell vaccine manufacturing on study. Patients then receive multi-epitope folate receptor alpha-loaded dendritic cell vaccine intradermally (ID) and pembrolizumab intravenously (IV) on study. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) as well as blood sample collection throughout the trial. Patients undergo biopsy on study. Patients are followed up at 90 days after last dose, every 3 months until 24 months after registration or until progression of disease, and then every 6 months up to 5 years after registration.

Official Title
-----------------
FRαDCs Plus Pembrolizumab for Patients With Advanced Stage Ovarian Cancer

Conditions
-----------------
Fallopian Tube Carcinosarcoma, Primary Peritoneal Carcinosarcoma, Recurrent Fallopian Tube Carcinoma, Recurrent Fallopian Tube Clear Cell Adenocarcinoma, Recurrent Fallopian Tube Endometrioid Adenocarcinoma, Recurrent Fallopian Tube High Grade Serous Adenocarcinoma, Recurrent Ovarian Carcinoma, Recurrent Ovarian Carcinosarcoma, Recurrent Ovarian Clear Cell Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Ovarian High Grade Serous Adenocarcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Clear Cell Adenocarcinoma, Recurrent Primary Peritoneal Endometrioid Adenocarcinoma, Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma

Intervention / Treatment
-----------------
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Biological: Multi-epitope Folate Receptor Alpha-loaded Dendritic Cell Vaccine
* Biological: Pembrolizumab
* Procedure: Pheresis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >= 18 years Histologically confirmed recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer NOTE: Histologic confirmation of the primary tumor or recurrent tumor per pathology report is required. Eligible histotypes include high grade serous; endometrioid; and clear cell carcinoma, as these histotypes have high expression of FRalpha (Kalli, Oberg, Keeney, & et al., 2008). Mixed carcinomas, including carcinosarcomas, with >= 50% of the tumor comprised of high grade serous; and/or endometrioid; and/or clear cell carcinoma are eligible Ovarian cancer (OC) recurrence - Platinum sensitivity/resistance Platinum-refractory (defined as recurrence or progression of OC =< 30 days of the last dose of platinum-based chemotherapy) Platinum-resistant (defined as recurrence or progression of OC between 31-180 days of the last dose of platinum-based chemotherapy) Platinum-sensitive (defined as recurrence or progression >=181 days after the last dose of platinum-based chemotherapy). NOTE: Patients with platinum-sensitive recurrent OC must have either received at least two prior courses of platinum-based chemotherapy AND/OR have a documented allergy to carboplatin NOTE: Any number of prior therapies or maintenance regimens for OC are allowed At least one of the following: Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria AND/OR CA-125-evaluable disease, as defined by the Gynecologic Cancer InterGroup (GCIG) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Hemoglobin >= 8.5 g/dL (obtained =< 15 days prior to registration) Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 15 days prior to registration) Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration) Lymphocytes >= 0.3 x 10^9/L (obtained =< 15 days prior to registration) Monocytes >= 0.25 x 10^9/L (obtained =< 15 days prior to registration) Total bilirubin =< 1.5 x upper limit of normal (ULN), unless patient has a documented history of Gilbert's disease, then direct bilirubin must be =< ULN (obtained =< 15 days prior to registration) Aspartate transaminase (AST) =< 3 x ULN (obtained =< 15 days prior to registration) Creatinine clearance >= 30 mL/min per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (obtained =< 15 days prior to registration) Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only Provide written informed consent Willing to provide mandatory blood and tissue specimens for correlative research Willing to provide archival tissue specimen for correlative research Willing to return to Mayo Clinic for follow-up (during the active monitoring phase of the study) Willing to undergo a tetanus vaccination (if not performed =< 365 days prior to registration) Willing to have a central access line placed, if needed (as determined during venous access assessment) Exclusion Criteria: Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown Pregnant persons Nursing persons Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception Prior treatment for ovarian cancer with an anti-PD-1 or anti-PD-L1 monoclonal antibody Treatment with IV anti-cancer therapy =< 3 weeks prior to registration or with oral anti-cancer therapy =< 1 week prior to registration NOTE: Since treatment will begin no sooner than 4 weeks after registration due to the need for apheresis and manufacturing of the FRalphaDC product, a wash-out period of 3 or 1 week(s) prior to registration will cause a gap of at least 7 or 5 weeks between the last anti-cancer treatment and initiation of protocol therapy Grade 2 or higher symptoms attributed to OC OR disease measuring > 5 cm in long axis (non-nodal lesions), or > 5 cm in short axis (nodal lesions) OR disease that, in the judgement of the treating investigator, is likely to become symptomatic in the next 8 weeks (ex. moderate ascites) NOTE: Since patients will not receive therapy for cancer until 3-4 weeks after apheresis-potentially 6-8 weeks after registration-patients with symptomatic OC or an elevated tumor burden may experience significant progression prior starting therapy and should not be treated on this protocol.) Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Known history of human immunodeficiency virus (HIV) infection NOTE: No HIV testing is required unless mandated by local health authority Uncontrolled intercurrent illness including, but not limited to: Ongoing or active serious infections (e.g., pneumonia, sepsis) requiring systemic therapy Current diagnosis or previous history of immune-related (non-infectious) pneumonitis or interstitial lung disease that requires or required steroids Active autoimmune disease that required systemic treatment other than replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids) =< 2 years prior to registration Psychiatric illness/social situations that would limit compliance with study requirements Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. EXCEPTIONS: For patients with evidence of hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive), patients must have completed at least 4 weeks of hepatitis B virus (HBV) antiviral therapy and the HBV viral load must be undetectable at the time of registration Patients with a history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load. Patients must have completed curative anti-viral treatment >= 4 weeks prior to registration NOTE: Patients without symptoms or prior history do not require testing prior to registration Other active malignancy either requiring palliative systemic therapy =< 3 years prior to registration, or likely to require treatment in the next 2 years EXCEPTIONS: Patients with non-melanotic skin cancer, papillary thyroid cancer not requiring therapy or carcinoma-in-situ are eligible for this trial. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias NOTE: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone >10 mg/day or equivalent, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF]-alpha agents) =< 7 days prior to registration, or anticipation of need for systemic immunosuppressive medication during the course of the study NOTE: Patients who have received acute, low-dose systemic steroids (=< 10 mg/day oral prednisone or equivalent) prior to registration or a one-time pulse dose of systemic immunosuppressant medication (e.g., =< 48 hours of corticosteroids for a contrast allergy) are eligible for the study NOTE: The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed History of allogeneic stem cell transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (apheresis, FRalphaDC, pembrolizumab)<br>Patients undergo apheresis for multi-epitope folate receptor alpha-loaded dendritic cell vaccine manufacturing on study. Patients then receive multi-epitope folate receptor alpha-loaded dendritic cell vaccine ID and pembrolizumab IV on study. Patients also undergo CT and/or MRI as well as blood sample collection throughout the trial. Patients undergo biopsy on study. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Biological: Multi-epitope Folate Receptor Alpha-loaded Dendritic Cell Vaccine<br>* Given ID<br>* Other names: FRalphaDC Vaccine;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Procedure: Pheresis<br>* Undergo apheresis<br>* Other names: Hemapheresis;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine whether the combination of FRαDCs and pembrolizumab has an acceptable toxicity profile. | Three patients will be enrolled to starting dose (dose level 1) and enrollment will pause until each of the first 3 patients have completed cycle 1 of therapy. If zero or one of first 3 patients develops a dose limiting toxicity (DLT) during cycle 1, 3 more patients will be enrolled to dose level 1. If observe at most 1 DLT in the first 6 patients at dose level 1, it will be considered safe and will continue in phase II of trial. If 2 or more of the first 6 patients develop a DLT during cycle 1 for dose level 1, then enrollment will stop and dose level will be decreased. Additional patients will be enrolled in cohorts of 3 to that decreased dose level. If zero or one DLT in the first 6 patients at dose level -1, it will be considered safe and will continue in phase II of trial. Otherwise, if observe 2 or more DLTs in the first 6 patients of dose level -1, enrollment will stop until the Study Team adjusts the treatment plan with input from the Data Safety Monitoring Board. | Up to 21 days | 
| Confirm objective response rate (ORR) | Defined as the proportion of patients with a complete response (CR) or partial response (PR). If at least 7 confirmed responses are observed in the first 32 eligible patients (22%), the combination treatment will be considered worthy of further investigation. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | Duration of response (DoR) is defined as the time from the first disease assessment showing a complete response (CR) or partial response (PR) until the date of either disease progression or death of any cause. | Up to 5 years | 
| Progression free survival (PFS) | PFS will be estimated using the Kaplan-Meier method. The date of progression will be the date on which progressive disease is first detected, even if the patient does not immediately come off study. | Up to 5 years | 
| Overall survival (OS) | OS will be estimated using the Kaplan-Meier method. OS is defined as the time from study entry to death from any cause. | Up to 5 years | 
| Incidence of adverse events | The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. | Up to 5 years |