Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

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 at least 18 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....

Further Study Information

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 digestive tract 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 non-myeloablative but lymphodepleting chemotherapy preparative regimen.

• The recent young-TIL approach, in which TIL are minimally cultured in vitro, not selected for tumor recognition, and enriched in CD8+ cells 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 a CD8+young-TIL adoptive transfer therapy for metastatic digestive tract cancers.

• With approval of amendment D, we propose to investigate the feasibility, safety, and efficacy of young-TIL adoptive transfer therapy for metastatic digestive tract cancers.

Objectives:

• To determine the ability of autologous CD8+-enriched 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 digestive tract cancers.

• With approval of amendment D, to determine the rate of tumor regression in patients in cohort 2 with metastatic digestive tract cancers who receive autologous, minimally cultured tumor infiltrating lymphocytes (TIL) plus aldesleukin following a lymphodepleting preparative regimen.

• To determine the phenotypic and functional characteristics of TIL derived from digestive tract cancers.

• To determine the toxicity of this treatment regimen.

Eligibility:

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

• Metastatic digestive tract cancers refractory to standard chemotherapy, originating from a) gastric or gastroesophageal junction, or b) pancreas, liver or biliary tree, or c) colon or rectum;

• 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 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 cancers.

• Prior to amendment D, TIL will be expanded according to current TIL-lab standard operating procedures, minimally cultured and enriched in CD8+ T cells using the Miltenyi Biotec CliniMACS apparatus prior to rapid expansion for clinical scale infusion.

• With approval of amendment D, cohort 1 will be closed and cohort 2 will be opened in which young TIL will not undergo CD8 enrichment. At this time, unselected young tumor infiltrating lymphocytes (TIL) cultures will be grown from fragments of patient's tumor.

• All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m(2)/day IV) on days -5 through -1.

• On day 0 patients will receive the infusion of autologous CD8+ 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.

• For both cohorts 1 and 2, using a Phase II design for three groups of tumors: a) gastric and gastroesophageal carcinomas, b) pancreatic and hepatobiliary carcinomas, and c) colorectal carcinomas, 21 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.

Eligibility Criteria

-INCLUSION CRITERIA:

1. Measurable metastatic (stage IV) gastric, gastroesophageal, pancreatic, hepatocellular carcinoma, cholangiocarcinoma, gallbladder, and colorectal 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(Registered Trademark)), since level 1 data support a survival benefit with this agent.

3. Clinical performance status of ECOG 0 or 1.

4. Life expectancy of greater than three months.

5. Greater than or equal to 18 years of age.

6. Willing to practice birth control during treatment and for four months after receiving the preparative regimen.

7. Willing to sign a durable power of attorney.

8. Able to understand and sign the Informed Consent Document.

9. 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).

10. 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.

11. 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.

12. 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.

13. 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 preparative chemotherapy 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 FEV1 less than or equal to 60% predicted tested in patients with:

• A prolonged history of cigarette smoking.

• Symptoms of respiratory dysfunction.

12. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Steven A. Rosenberg

Principal Investigator

June Kryk, R.N.		Ph: (301) 451-1929
		Email: ncisbirc@mail.nih.gov

U.S.A.
Maryland
	Bethesda
	NIH - Warren Grant Magnuson Clinical Center
		For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center	Ph: 866-820-4505
			Email: ncisbirc@mail.nih.gov

See All Trial Sites

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01174121
Information obtained from ClinicalTrials.gov on May 16, 2013

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