Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer

Study Overview
=================
Brief Summary
-----------------
Background: The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. Researchers want to know if TIL shrink s tumors in people with digestive tract, urothelial, breast, or ovarian/endometrial cancers. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells. Objective: The purpose of this study is to see if these specifically selected tumor fighting cells can cause digestive tract, urothelial, breast, or ovarian/endometrial tumors to shrink and to see if this treatment is safe. Eligibility: - Adults age 18-70 with upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial cancer, or glioblastoma refractory to standard chemotherapy. Design: Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed. Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product. Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Detailed Description
-----------------
Background: Metastatic digestive tract cancers, in particular esophageal, gastric, pancreatic and hepatobiliary carcinomas, are associated with poor survival beyond five years and poor response to existing therapies. Data from the National Cancer Institute Surgery Branch (NCI-SB) and from the literature support that metastatic cancers are potentially immunogenic and that tumor-infiltrating lymphocytes (TIL) can be grown and expanded from these tumors. In metastatic melanoma, TIL can mediate the regression of bulky disease at any site when administered to an autologous patient with high-dose aldesleukin (IL-2) following a nonmyeloablative, lymphodepleting preparative regimen. The recent young-TIL approach, in which TIL are minimally cultured in vitro, not selected for tumor recognition, before rapid expansion and infusion to metastatic melanoma patients, has lead to objective response rates comparable to previous trials relying on TIL screened for tumor recognition, with no added toxicities. In pre-clinical models, the administration of an anti-PD-1 antibody enhances the anti-tumor activity of transferred T-cells. We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer therapy in combination with pembrolizumab, administered either prior to cell administration or at the time of progressive disease, for metastatic cancers. Objectives: -Primary objective: --With Amendment BB, to determine the rate of tumor regression in patients with metastatic cancer who receive autologous, minimally cultured TIL in conjunction with a non-myeloablative, lymphodepleting preparative regimen, high-dose aldesleukin, and anti-PD-1. Eligibility: Patients must be/have: Age greater than or equal to 18 years and less than or equal to 72 years Metastatic upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial cancer, or endocrine tumors including neuroendocrine tumors refractory to standard chemotherapy Normal basic laboratory values Patients may not have: Concurrent major medical illnesses Severe hepatic function impairment due to liver metastatic burden Unpalliated biliary or bowel occlusion, cholangitis, or digestive tract bleeding Any form of immunodeficiency Severe hypersensitivity to any of the agents used in this study Design: Patients may undergo resection or biopsy to obtain tumor for generation of autologous TIL cultures and autologous cancer cell lines, and for frozen tissue archive. Lymph nodes, ascites,peritoneal implants, and normal tissue adjacent to metastatic deposit will also be obtained when possible for ongoing and future research as described in the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols). With the approval of Amendment BB, patients will be enrolled on Arm 3 or Arm 4. All patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the infusion of autologous TIL and high-dose aldesleukin. Patients enrolled on Arm 3 will receive pembrolizumab prior to cell administration and three additional doses every three weeks following the cell infusion. Patients enrolled on Arm 4 will receive pembrolizumab within four weeks after meeting progressive disease by RECIST criteria, continuing for up to 8 doses every 3 weeks. Clinical and immunologic response will be evaluated about 6 weeks after cell infusion and periodically thereafter. Twenty-one patients will initially be enrolled in each group to assess toxicity and tumor responses. If two or more of the first 21 patients per groups shows a clinical response (partial response or complete response), accrual will continue to 41 patients, targeting a 20% goal for objective response. Up to 332 patients may be enrolled.

Official Title
-----------------
A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphodepleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumab

Conditions
-----------------
Metastatic Colorectal Cancer, Metastatic Pancreatic Cancer, Metastatic Ovarian Cancer, Metastatic Breast Carcinoma, Metastatic Endocrine Tumors/ Neuroendocrine Tumors

Intervention / Treatment
-----------------
* Biological: Young TIL
* Drug: Aldesleukin
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Pembrolizumab (Keytruda)


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Measurable (per RECIST v1.0 criteria), metastatic cancer of one of the following types: upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial, or endocrine tumors including neuroendocrine tumors. Patients must have at least one lesion that is resectable for TIL generation with minimal morbidity, preferentially using minimal invasive laparoscopic or thoracoscopic surgery for removal of superficial tumor deposit. Confirmation of diagnosis of metastatic cancer by the NCI Laboratory of Pathology. Refractory to approved standard systemic therapy. Specifically: Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan. Patients with Hepatocellular carcinoma patients must have received sorafenib (Nexavar ), since level 1 data support a survival benefit with this agent. Patients with breast and ovarian cancer must be refractory to both first and second line treatments and must have received at least one second-line chemotherapy regimen. Patients with glioblastoma must have received standard surgery, radiation therapy, and chemotherapy for their primary tumors and require resection of their tumors for palliative or other clinical indications. These patients will not undergo surgery solely for treatment on this protocol. Patients with 3 or fewer brain metastases that are less than or equal to 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Age greater than or equal to 18 years and less than or equal to 72 years. Clinical performance status of ECOG 0 or 1. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment. Women of child-bearing potential must be willing to undergo a pregnancy test prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus. Serology Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative. Hematology ANC > 1000/mm3 without the support of filgrastim WBC greater than or equal to 2500/mm3 Platelet count greater than or equal to 80,000/mm3 Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off. Chemistry Serum ALT/AST less than or equal to 5.0 x ULN Serum creatinine less than or equal to 1.6 mg/dL Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL. Patients must have completed any prior systemic therapy at the time of enrollment. Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks prior to enrollment, as long as related organ toxicities have recovered to grade 1 or less. Ability of subject to understand and the willingness to sign a written informed consent document. Willing to sign a durable power of attorney. Subjects must be co-enrolled on protocol 03-C-0277. Exclusion Criteria: Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Concurrent systemic steroid therapy, except for patients with recurrent glioblastoma who require steroids for clinical indications. Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses. Advanced primary with impeding occlusion, perforation or bleeding, dependent on transfusion. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS). History of major organ autoimmune disease. Grade 3 or 4 major organ irAEs clinically attributed to anti-PD-1/PD-L1 therapy. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible to its toxicities.) History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin. History of coronary revascularization or ischemic symptoms. For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction. For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50%. Patients who are receiving any other investigational agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/CD8+ Enriched TIL (CLOSED)<br>Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young CD8+ enriched TIL + high-dose aldesleukin (CLOSED) | Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes (one to four days after the last dose of fludarabine).<br>Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses.)<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X2 days over 1 hr.<br>Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.<br>|
| Experimental: 2/Unselected TIL (CLOSED)<br>Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin (CLOSED) | Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes (one to four days after the last dose of fludarabine).<br>Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses.)<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X2 days over 1 hr.<br>Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.<br>|
| Experimental: 3/Unselected TIL + Pembro Prior to Cells<br>Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeks following cell infusion | Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes (one to four days after the last dose of fludarabine).<br>Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses.)<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X2 days over 1 hr.<br>Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.<br>Drug: Pembrolizumab (Keytruda)<br>* Arm 3: Pembrolizumab 2mg/kg IV over approximately 30 minutes on Days -2, 21, 42, and 63 Arm 4: Pembrolizumab 2mg/kg IV over approximately 30 minutes (for patients who meet progressive disease per RECIST criteria and have resolved major toxicities after cell infusion or anytime during the post-treatment evaluation period; starting within 4 weeks of progression; may receive up to 8 doses every 3 weeks).<br>|
| Experimental: 4/Unselected TIL + Pembro at POD<br>Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab within 4 weeks of progressive disease for up to 8 doses every 3 weeks | Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes (one to four days after the last dose of fludarabine).<br>Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses.)<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X2 days over 1 hr.<br>Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.<br>Drug: Pembrolizumab (Keytruda)<br>* Arm 3: Pembrolizumab 2mg/kg IV over approximately 30 minutes on Days -2, 21, 42, and 63 Arm 4: Pembrolizumab 2mg/kg IV over approximately 30 minutes (for patients who meet progressive disease per RECIST criteria and have resolved major toxicities after cell infusion or anytime during the post-treatment evaluation period; starting within 4 weeks of progression; may receive up to 8 doses every 3 weeks).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Percentage of patients who have a clinical response to treatment (objective tumor regression) | 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and efficacy of pembrolizumab in combination with TIL therapy | Response rate and evaluation of treatment-related adverse events for patients who receive pembrolizumab | Every 6 weeks (week 6, 12, 18, 24) within 24 hours prior to next scheduled pembrolizumab dose | 
| Frequency and severity of treatment-related adverse events | Aggregate of all adverse events, as well as their frequency and severity | 30 days after end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Digestive Tract Cancers, Breast Cancer, Endocrine Tumors, Ovarian/Endometrial Cancer, Genitourinary Cancer