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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2016 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01174121
First received: July 31, 2010
Last updated: September 27, 2016
Last verified: September 2016
  Purpose

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 metastatic digestive tract, urothelial, breast, or ovarian/endometrial cancer who have a tumor that can be safely removed.

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.


Condition Intervention Phase
Metastatic Colorectal Cancer
Metastatic Gastric Cancer
Metastatic Pancreatic Cancer
Metastatic Hepatocellular Carcinoma
Metastatic Cholangiocarcinoma
Biological: Young TIL
Drug: Aldesleukin
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Pembrolizumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumab

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine the rate of tumor regression in patients in cohort 3 with metastatic digestive tract, urothelial, breast, and ovarian/endometrial cancers who receive autologous, minimally cultured tumor infiltrating lymphocytes (TIL) plus aldesleuk... [ Time Frame: Approximately 8 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the toxicity of this treatment regimen. [ Time Frame: approximately 8 years ] [ Designated as safety issue: Yes ]
  • To evaluate the safety and efficacy of pembrolizumab in combination with the TIL therapy [ Time Frame: approximately 8 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 290
Study Start Date: July 2010
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Breast
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine, and anti-PD-1 followed by IV infusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.
Experimental: Gastric
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depleting preparative regimen of cyclophosphamide andfludarabine, and anti-PD-1 followed by IV infusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.
Experimental: Colorectal
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depletingpreparative regimen of cyclophosphamide and fludarabine, and anti-PD-1 followed by IVinfusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.
Experimental: Ovarian/Endometrial
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depletingpreparative regimen of cyclophosphamide andfludarabine, and anti-PD-1 followed by IV infusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.
Experimental: Pancreatic
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depletingpreparative regimen of cyclophosphamide andfludarabine, and anti-PD-1 followed by IV infusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.
Experimental: Bladder
Patients in cohort 3 will receive the standard SurgeryBranch nonmyeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine, and anti-PD-1 followed by IV infusion of young TIL PBL and aldesleukin.
Biological: Young TIL
On day 0, cells will be infused intravenously over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses.)
Drug: Cyclophosphamide
On day -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On day -5 to day -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Pembrolizumab
Day -2, day 21, day 42, and day 63, Pembrolizumab 2mg/kg IV over approximately 30 minutes.

  Hide Detailed Description

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 Surgery Branch and from the literature support that metastatic cancers are potentially immunogenic and that 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 but lymphodepleting chemotherapy 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 for metastatic cancers.

Objectives:

  • With Amendment Q, to determine the ability of autologous TIL infused after minimal in vitro culture in conjunction with high dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen and anti-PD-1 to mediate tumor regression in patients with metastatic cancers.
  • To determine the toxicity of this treatment regimen.
  • To evaluate the safety and efficacy of pembrolizumab in combination with TIL therapy.

Eligibility:

Patients who are 18 years of age or older must have:

  • Metastatic digestive tract, urothelial, breast, or ovarian/endometrial cancers refractory to standard chemotherapy, originating from a) gastric or gastroesophageal junction, or b) pancreas, liver or biliary tree, c) colon or rectum, d) bladder, e) breast, or f) ovarian/endometrial;
  • 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;
  • Contraindications for high dose aldesleukin administration.

Design:

  • Patients will 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 03-C-0277.
  • All patients in cohort 3 will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine, and pembrolizumab. On day 0 patients will receive the infusion of autologous TIL and then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 12 doses).
  • Pembrolizumab will be administered prior to TIL admiistration and continue for 3 additional cycles.
  • Clinical and immunologic response will be evaluated at the first follow-up evaluation following the last dose of pembrolizumab.
  • Twenty-one patients will be initially 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 (PR or CR), accrual will continue to 41 patients, targeting a 20% goal for objective response.
  • Up to 290 patients may be enrolled over 3-8 years
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic (stage IV) gastric, gastroesophageal, pancreatic, hepatocellular carcinoma, cholangiocarcinoma, gallbladder, colorectal, urothelial, breast, and ovarian/endometrial carcinomas with 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, plus one other lesion that can be measured.
  2. All patients must be refractory to approved standard systemic therapy.

    Specifically :

    • Metastatic colorectal patients must have received oxaliplatin or irinotecan.
    • Hepatocellular carcinoma patients must have received sorafenib (Nexavar ), since level 1 data support a survival benefit with this agent.
    • Breast and Ovarian cancer patients must be refractory to both 1st line and 2nd line treatments and must have received at least one second line chemotherapy regimen.
  3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible.
  4. Clinical performance status of ECOG 0 or 1.
  5. Life expectancy of greater than three months.
  6. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  7. Willing to practice birth control during treatment and for four months after receiving the treatment.
  8. Willing to sign a durable power of attorney.
  9. Able to understand and sign the Informed Consent Document.
  10. Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without support of filgrastim.
    • Normal WBC (> 3000/mm(3)).
    • Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.
    • Platelet count greater than 100,000/mm(3).
    • Normal prothrombin time (less than or equal to 15.2 seconds).
  11. Serology:

    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  12. Chemistry:

    • Serum ALT/AST less than five times the upper limit of normal.
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3 mg/dl.
  13. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures with the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.
  14. Six weeks must have elapsed since any prior anti-vascular endothelial growth factor (VEGF), anti-tyrosine kinase receptors (TKR) therapy or anti-PD-1/PD-L1 agents to allow antibody levels to decline.

EXCLUSION CRITERIA:

  1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  2. Concurrent systemic steroid therapy.
  3. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  4. Advanced primary with impeding occlusion, perforation or bleeding, dependant on transfusion.
  5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  6. History of major organ autoimmune disease.
  7. Grade 3 or 4 major organ Immune-Related Adverse Events (IRAEs) following treatment with anti-PD-1/PD-L1
  8. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
  9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  10. History of coronary revascularization or ischemic symptoms.
  11. Any patient known to have an LVEF less than or equal to 45%.
  12. Documented LVEF of less than or equal to 45% tested in patients with:

    • Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
    • Age greater than or equal to 60 years old
  13. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01174121

Contacts
Contact: Jessica G Yingling, R.N. (866) 820-4505 ncisbirc@mail.nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01174121     History of Changes
Other Study ID Numbers: 100166  10-C-0166 
Study First Received: July 31, 2010
Last Updated: September 27, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Digestive Tract Cancers
Breast Cancer
Cell Therapy
Ovarian/Endometrial Cancer
Urothelial Cancers

Additional relevant MeSH terms:
Colorectal Neoplasms
Pancreatic Neoplasms
Stomach Neoplasms
Carcinoma, Hepatocellular
Neoplasm Metastasis
Cholangiocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Stomach Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Liver Diseases
Neoplastic Processes
Pathologic Processes
Cyclophosphamide
Fludarabine phosphate

ClinicalTrials.gov processed this record on September 30, 2016