A Phase II Study Using Short-Term Cultured, CD8+-Enriched Autologous Tumor-infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Digestive Tract Cancers

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 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: July 26, 2014
Last verified: June 2014
  Purpose

Background:

- Metastatic digestive tract cancers, in particular esophageal, gastric, pancreatic, and liver carcinomas, have poor 5-year survival rates and respond poorly to existing therapies. Research has suggested that digestive tract cancers can be treated with white blood cells provided by the patient and modified in a laboratory to specifically attack cancer cells. These cells are called tumor infiltrating lymphocytes (TIL). Researchers are interested in determining whether a combination of TIL and aldesleukin (to stimulate cell growth) is a safe and effective treatment for these kinds of cancer.

Objectives:

- To evaluate the safety and effectiveness of using donated and modified white blood cells to treat metastatic digestive tract cancers.

Eligibility:

- Individuals greater than or equal to 18 years and less than or equal to 66 years of age who have a digestive tract cancer that has not responded to standard chemotherapy.

Design:

  • Participants will be screened with a complete medical history, blood and urine samples, and tumor studies.
  • Participants will have leukapheresis to collect white blood cells for the TIL procedure.
  • Within 1 to 2 weeks after leukapheresis, participants will have inpatient chemotherapy with cyclophosphamide and fludarabine for 7 days to prepare for TIL infusion.
  • Participants will receive TIL and aldesleukin within 1 to 4 days after the end of chemotherapy, and will also receive filgrastim to stimulate white blood cell production.
  • After the last dose of aldesleukin (a maximum of 8 days after the start of TIL), participants will recover in the hospital for monitoring and further tests until they have recovered from the treatment.
  • Participants will return for follow-up visits 4 to 6 weeks after the end of treatment, with additional visits on a regular basis as required by the study researchers.
  • Participants whose tumors respond to the treatment (either by shrinking or not growing) may be eligible for an additional treatment that will start within 12 to 24 weeks after the last dose of aldesleukin....

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
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 Digestive Tract and Urothelial Cancers

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 with metastatic digestive tract cancers [ Time Frame: approximately 5 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 136
Study Start Date: July 2010
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gastric
Patients will receive the standard Surgery Branch non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine 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.
Experimental: Pancreatic
Patients will receive the standard Surgery Branch non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine 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.
Experimental: Colorectal
Patients will receive the standard Surgery Branch non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine 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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 66 Years
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, and urothelial 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.
  2. All patients must be refractory to approved standard systemic therapy.

    Specifically :

    • Metastatic colorectal patients must have received 5-FU and leucovorin in combination with either oxaliplatin and/or irinotecan, since level 1 evidence support increase survival with these regimens, compared to 5-FU and leucovorin alone.
    • Hepatocellular carcinoma patients must have received sorafenib (Nexavar ), since level 1 data support a survival benefit with this agent.
  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 66 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) or anti-tyrosine kinase receptors (TKR) therapy 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. Systemic steroid therapy required.
  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. 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.)
  7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  8. History of coronary revascularization or ischemic symptoms.
  9. Any patient known to have an LVEF less than or equal to 45%.
  10. 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
  11. 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: June Kryk, R.N. (301) 451-1929 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
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( 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: July 26, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Digestive Tract Cancers
Immunotherapy
Cell Therapy
Clinical Response

Additional relevant MeSH terms:
Cholangiocarcinoma
Carcinoma
Colorectal Neoplasms
Stomach Neoplasms
Pancreatic Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Stomach Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Adenocarcinoma
Liver Neoplasms
Liver Diseases
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Aldesleukin
Immunosuppressive Agents

ClinicalTrials.gov processed this record on July 29, 2014