NCT01174121

Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer

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

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 332 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 72 Years
• Healthy volunteers: Not accepted

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 18-72 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 led 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 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.

Conditions

• Metastatic Colorectal Cancer
• Metastatic Pancreatic Cancer
• Metastatic Ovarian Cancer
• Metastatic Breast Carcinoma
• Metastatic Endocrine Tumors/ Neuroendocrine Tumors

Interventions

Type	Name	Description
DRUG	Pembrolizumab (Keytruda)	Arm 3 or 5: 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).
DRUG	Fludarabine	Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
DRUG	Cyclophosphamide	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.
DRUG	Aldesleukin	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.)
BIOLOGICAL	Young TIL	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).

Timeline

• Start date: 2010-08-26
• Primary completion: 2028-12-27
• Completion: 2029-12-27
• First posted: 2010-08-03
• Last updated: 2026-03-04

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study