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: September 20, 2014
Last verified: June 2014

July 31, 2010
September 20, 2014
July 2010
July 2016   (final data collection date for primary outcome measure)
To determine the rate of tumor regression in patients with metastatic digestive tract cancers [ Time Frame: approximately 5 years ] [ Designated as safety issue: Yes ]
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Complete list of historical versions of study NCT01174121 on ClinicalTrials.gov Archive Site
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A Phase II Study Using Short-Term Cultured, CD8+-Enriched Autologous Tumor-infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Digestive Tract Cancers
A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Cancers

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:

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.

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....

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.
  • We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer therapy for metastatic cancers.

Objectives:

  • 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 to mediate tumor regression in patients with metastatic cancers.
  • To determine the phenotypic and functional characteristics of TIL derived from digestive tract, urothelial, breast, and ovarian/endometrial cancers.
  • To determine the toxicity of this treatment regimen.

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 assessing phenotypic and functional characteristics of TIL derived from digestive tract, urothelial, breast, or ovarian/endometrial cancers.
  • All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabineOn 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 15 doses).
  • Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.
  • 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 260 patients may be enrolled over 3-8 years
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Metastatic Colorectal Cancer
  • Metastatic Gastric Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Hepatocellular Carcinoma
  • Metastatic Cholangiocarcinoma
  • 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: Breast
    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.
    Interventions:
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • 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.
    Interventions:
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • 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.
    Interventions:
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • 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.
    Interventions:
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • Experimental: Ovarian/Endometrial
    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.
    Interventions:
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
260
July 2016
July 2016   (final data collection date for primary outcome measure)

-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 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 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) 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.
Both
18 Years to 66 Years
No
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
United States
 
NCT01174121
100166, 10-C-0166
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP