| City: |
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Bethesda |
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State:
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MD |
| Zip Code: |
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20892 |
| Conditions: |
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Metastatic Colorectal Cancer - Metastatic Gastric Cancer - Metastatic Pancreatic Cancer - Metastatic Hepatocellular Carcinoma - Metastatic Cholangiocarcinoma |
| Purpose: |
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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....
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| Study summary: |
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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.
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.
- 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.
- 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.
- 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.
- 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. |
| Criteria: |
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-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. |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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October 23, 2010 |
Modifications to
this listing: |
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above to view all information about this clinical trial. |
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