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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Metastatic Colorectal Cancer, Metastatic Gastric Cancer, Metastatic Pancreatic Cancer, Metastatic Hepatocellular Carcinoma, Metastatic Cholangiocarcinoma

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Trial Information

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


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.

Inclusion 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the ability of autologous CD8+-enriched TIL in conjunction with high dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen to meditate tumor regression in patients with metastatic digestive tract cancers...

Outcome Time Frame:

5 years

Safety Issue:

Yes

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

100166

NCT ID:

NCT01174121

Start Date:

July 2010

Completion Date:

July 2015

Related Keywords:

  • Metastatic Colorectal Cancer
  • Metastatic Gastric Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Hepatocellular Carcinoma
  • Metastatic Cholangiocarcinoma
  • Digestive Tract Cancers
  • Immunotherapy
  • Cell Therapy
  • Clinical Response
  • Carcinoma
  • Colorectal Neoplasms
  • Stomach Neoplasms
  • Pancreatic Neoplasms
  • Cholangiocarcinoma
  • Carcinoma, Hepatocellular

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892