T-Cell Infusion, Aldesleukin, and Utomilumab in Treating Patients With Recurrent Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
This phase I/Ib trial studies the side effects and best dose of utomilumab and how well it works with CD8-positive T-lymphocyte (T-cell infusion) and aldesleukin in treating patients with ovarian cancer that has come back. Aldesleukin may stimulate white blood cells to kill ovarian cancer cells. Giving white blood cells (T-cells) that have been activated by a vaccine with aldesleukin may kill more tumor cells. Immunotherapy with utomilumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving T-cell infusion with aldesleukin and utomilumab may work better in treating patients with ovarian cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Assess the safety and toxicity of adoptively transferred central memory-type CTL targeting ovarian cancer antigens administered alone, and in combination with, utomilumab, an agonistic anti-CD137 antibody, in patients with platinum-resistant ovarian cancer. II. Evaluate the functional and numeric in vivo persistence of adoptively transferred central memory-type CTL with and without utomilumab. SECONDARY OBJECTIVES: I. Evaluate the anti tumor effect of adoptively transferred central memory-type CTL targeting ovarian cancer antigens as measured by best overall response rate (BORR) and progression free survival (PFS). OUTLINE: This is a dose escalation study of utomilumab. Patients undergo leukapheresis. Patients then receive cyclophosphamide intravenously (IV) on day -2, CD8-positive T-lymphocyte via infusion on day 0, and aldesleukin subcutaneously (SC) every 12 hours for 14 days. Beginning 24 hours after CD8-positive T-lymphocyte, patients also receive utomilumab IV over 90 minutes on days 1, 29, 57, 85, 113, and 141 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at days 3, 7, 14, 22, 28, 35, 43, 49, 56, 64, 70, 77, 84, 112, and 140.

Official Title
-----------------
Phase I/Ib Study of Adoptive Cellular Therapy Using Autologous IL-21-Primed CD8+ Tumor Antigen-Specific T Cells in Combination With Utomilumab (PF-05082566) in Patients With Platinum Resistant Ovarian Cancer

Conditions
-----------------
COL6A3 Positive, HLA-A*0201 Positive Cells Present, PRAME Positive, Recurrent Ovarian Carcinoma

Intervention / Treatment
-----------------
* Biological: Aldesleukin
* Drug: CD8-Positive T-Lymphocyte
* Drug: Cyclophosphamide
* Procedure: Leukapheresis
* Biological: Utomilumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histopathologic documentation (must be performed or reviewed at MD Anderson) of recurrent high grade epithelial ovarian cancer. At least one prior line of platinum-based chemotherapy (subjects are eligible for enrollment and leukapheresis while still platinum-sensitive, however, they must have developed platinum resistant disease for treatment (turnstile 2). Tumor expressing PRAME and/or COL6A3. Expression of HLA-A*0201. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Expected survival of greater than 16 weeks. Willing and able to give informed consent. Hemoglobin >= 9.0 g/dL. Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (>=1000 per mm^3). Platelet count >= 75 x 10^9/L (>=100,000 per mm^3). Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless diagnosed with Gilbert's syndrome. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN unless liver metastases are present, in which case it must be =< 5x ULN. Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance. Subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 50 years old and no menses for >=1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 1 month before start of therapy, and while women are on study for up to 3 months after T cell infusion, and at least 8 weeks after the study drug is stopped. {Turnstile 2} Subjects must have platinum resistant disease (progression on a platinum-containing regimen or recurrence within 180 days of last dose of platinum-containing chemotherapy). Subjects that are not platinum resistant but are deemed not to be candidates for platinum-based chemotherapy due to prior significant allergic reaction may participate with principal investigator (PI) approval. {Turnstile 2} Bi-dimensionally measurable disease by radiographic imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan). {Turnstile 2} At least 4 weeks must have elapsed since the last chemotherapy, immunotherapy, radiotherapy or major surgery. At least 6 weeks for bevacizumab. {Turnstile 2} Toxicity related to prior therapy must either have returned to =< grade 1, baseline, or been deemed irreversible. Exclusion Criteria: Clinically significant pulmonary dysfunction, as determined by medical history and physical exam. Patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in one second (FEV1) < 60% of normal or carbon monoxide diffusing capacity (DLco) (corrected [corr] for hemoglobin [Hgb]) < 55% will be excluded. Significant cardiovascular abnormalities including any one of the following: Congestive heart failure, Clinically significant hypotension, symptoms of coronary artery disease, presence of cardiac arrhythmias on electrocardiography (EKG) requiring drug therapy; or patients with a history of cardiovascular disease. (Patients with the above will undergo a cardiac evaluation which can include a stress test and/or echocardiography. Results of this evaluation will be considered before excluding patients on the basis of cardiovascular abnormalities). Subjects with evidence of stress-induced cardiac ischemia or ejection fraction less than 55% will be excluded. History of central nervous system (CNS) metastasis. Autoimmune disease: patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of autoimmune disease (e.g. systemic lupus erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the Investigator to be unacceptable. {Turnstile 2} Participation in another clinical study with an investigational product administered during the last 28 days. {Turnstile 2} Receipt of the last dose of previous chemotherapy, hormonal, or biologic treatment for ovarian, fallopian tube, or primary peritoneal cancer in the last 28 days (in the last 6 weeks for bevacizumab). {Turnstile 2} Current or prior use of immunosuppressive medication within 28 days before enrollment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. {Turnstile 2} Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1. History of allogeneic organ transplant. Unresolved partial or complete small or large bowel obstruction. {Turnstile 2} Receipt of live attenuated vaccination within 30 days prior to enrollment or within 30 days of planned lymphodepletion. Any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events. Active viral hepatitis. Confirmed human immunodeficiency virus (HIV) infection.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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 (T-cell infusion, aldesleukin, utomilumab)<br>Patients undergo leukapheresis. Patients then receive cyclophosphamide IV on day -2, CD8-positive T-lymphocyte via infusion on day 0, and aldesleukin SC every 12 hours for 14 days. Beginning 24 hours after CD8-positive T-lymphocyte, patients also receive utomilumab IV over 90 minutes on days 1, 29, 57, 85, 113, and 141 in the absence of disease progression or unacceptable toxicity. | Biological: Aldesleukin<br>* Given IV<br>* Other names: Recombinant Human Interleukin-2;Drug: CD8-Positive T-Lymphocyte<br>* Given IV<br>* Other names: T8 Lymphocytes;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Procedure: Leukapheresis<br>* Undergo leukapheresis<br>* Other names: Therapeutic Leukopheresis;Biological: Utomilumab<br>* Given IV<br>* Other names: PF-2566;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity Summary associated with Utomilumab Dose Escalation | Safety and toxicity of adoptively transferred central memory-type CTL targeting ovarian cancer antigens administered alone, and in combination with, an Utomilumab, an agonistic anti-CD137 antibody, in patients with platinum resistant ovarian cancer reported at each dose level. Safety and toxicity will be assessed using the latest version of Common Terminology Criteria for Adverse Events (CTCAE). | Up to 6-8 weeks | 
| Duration of in vivo persistence | To evaluate the functional and numeric in vivo persistence of adoptively transferred central memory-type CTL with and without Utomilumab, duration of in vivo persistence defined as the time between T cell infusion and last time point at which the transferred T cell DNA signature is detectable in peripheral blood. Transferred antigen-specific T cells will be tracked by tetramer analysis as well as by TCR tracking (Immunoseq assay, Adaptive Biotech), both assays, have been established in lab as reliable measures of T cell persistence. | Up to 6 months after the T cell infusion | 
| Maximum Tolerated Dose (MTD) of T Cells | Bayesian optimal interval (BOIN) design is used for dose escalation and finding the maximum tolerated dose (MTD). | 6 weeks | 
| Maximum Tolerated Dose (MTD) of T cells + Utomilumab | Bayesian optimal interval (BOIN) design is used for dose escalation and finding the maximum tolerated dose (MTD). | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response rate (BORR) | BORR is defined as the total number of participants who's BOR is complete response (CR) or partial response (PR), divided by the total number of participants. Radiographic imaging and clinical assessment of residual disease will be compared with pre-infusion baseline assessment according to modified RECIST 1.1 for response: complete response (CR) defined as total regression of all tumor, a partial response (PR) as 30% or greater decrease in sum of longest diameter of target lesions and progressive disease (PD) as 20% increase in sum of longest diameter of target lesions (modified world health organization criteria or mWHO). Assessment at 6 and 12 weeks following T cell infusion and then every 8 weeks (+/- 1 week) until disease progression or intervening therapy. The overall response rate (OR) will be after 1 cycle (12) weeks. | 12 weeks up to 1 year | 
| Progression free survival (PFS) | PFS is defined as the time between T cell infusion date and the date of progression or death. A participant who dies without reported prior progression will be considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS will be censored on the date of last tumor assessment. For participants who have PD prior to Week 12 and a subsequent assessment of SD, PR or CR, the date of PD following response (where available) will be used in the analysis of PFS; otherwise these participants will be censored on the date of their last tumor assessment. PFS is estimated for each arm using the Kaplan-Meier product limit method. | 6 months after the T cell infusion |