Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer
| Status: | Recruiting |
|---|---|
| Conditions: | Breast Cancer, Colorectal Cancer, Liver Cancer, Cancer, Cancer, Brain Cancer, Gastrointestinal |
| Therapuetic Areas: | Gastroenterology, Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 3/16/2019 |
| Start Date: | August 26, 2010 |
| End Date: | December 27, 2024 |
| Contact: | Margaret Shovlin, R.N. |
| Email: | IRC@nih.gov |
| Phone: | (866) 820-4505 |
A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumabat Time of Progression
Background:
The NCI Surgery Branch has developed an experimental therapy that involves taking white blood
cells from patients' tumors, growing them in the laboratory in large numbers, and then giving
the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 200 patients with melanoma. Researchers want
to know if TIL shrink s tumors in people with digestive tract, urothelial, breast, or
ovarian/endometrial cancers. In this study, we are selecting a specific subset of white blood
cells from the tumor that we think are the most effective in fighting tumors and will use
only these cells in making the tumor fighting cells.
Objective:
The purpose of this study is to see if these specifically selected tumor fighting cells can
cause digestive tract, urothelial, breast, or ovarian/endometrial tumors to shrink and to see
if this treatment is safe.
Eligibility:
- Adults age 18-70 with metastatic digestive tract, urothelial, breast, or
ovarian/endometrial cancer who have a tumor that can be safely removed.
Design:
Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo
a history and physical examination, scans, x-rays, lab tests, and other tests as needed.
Surgery: If the patients meet all of the requirements for the study they will undergo surgery
to remove a tumor that can be used to grow the TIL product.
Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells.
{Leukapheresis is a common procedure, which removes only the white blood cells from the
patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for
about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
The NCI Surgery Branch has developed an experimental therapy that involves taking white blood
cells from patients' tumors, growing them in the laboratory in large numbers, and then giving
the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 200 patients with melanoma. Researchers want
to know if TIL shrink s tumors in people with digestive tract, urothelial, breast, or
ovarian/endometrial cancers. In this study, we are selecting a specific subset of white blood
cells from the tumor that we think are the most effective in fighting tumors and will use
only these cells in making the tumor fighting cells.
Objective:
The purpose of this study is to see if these specifically selected tumor fighting cells can
cause digestive tract, urothelial, breast, or ovarian/endometrial tumors to shrink and to see
if this treatment is safe.
Eligibility:
- Adults age 18-70 with metastatic digestive tract, urothelial, breast, or
ovarian/endometrial cancer who have a tumor that can be safely removed.
Design:
Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo
a history and physical examination, scans, x-rays, lab tests, and other tests as needed.
Surgery: If the patients meet all of the requirements for the study they will undergo surgery
to remove a tumor that can be used to grow the TIL product.
Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells.
{Leukapheresis is a common procedure, which removes only the white blood cells from the
patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for
about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
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 National Cancer Institute Surgery Branch (NCI-SB) and from the literature
support that metastatic cancers are potentially immunogenic and that tumor-infiltrating
lymphocytes (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, lymphodepleting 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.
- In pre-clinical models, the administration of an anti-PD-1 antibody enhances the
anti-tumor activity of transferred T-cells.
- We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer
therapy in combination with pembrolizumab, administered either prior to cell
administration or at the time of progressive disease, for metastatic cancers.
Objectives:
-Primary objective:
--With Amendment BB, to determine the rate of tumor regression in patients with metastatic
cancer who receive autologous, minimally cultured TIL in conjunction with a
non-myeloablative, lymphodepleting preparative regimen, high-dose aldesleukin, and anti-PD-1.
Eligibility:
Patients must be/have:
- Age greater than or equal to 18 years and less than or equal to 70 years
- Metastatic digestive tract, urothelial, breast, ovarian/endometrial cancer, or
glioblastoma refractory to standard chemotherapy, originating from the (a) gastric,
gastroesophageal junction; (b) pancreas, liver, or biliary tree; (c) colon or rectum;
(d) bladder; (e) breast; or (f) ovarian/endometrium; or, (g) brain.
- 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
Design:
- Patients may 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 ongoing and future research as described in the
NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch
Adoptive Cell Therapy Protocols).
- With the approval of Amendment BB, patients will be enrolled on Arm 3 or Arm 4. All
patients will receive a non-myeloablative, lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by the infusion of autologous
TIL and high-dose aldesleukin. Patients enrolled on Arm 3 will receive pembrolizumab
prior to cell administration and three additional doses every three weeks following the
cell infusion. Patients enrolled on Arm 4 will receive pembrolizumab within four weeks
after meeting progressive disease by RECIST criteria, continuing for up to 8 doses every
3 weeks.
- Clinical and immunologic response will be evaluated about 6 weeks after cell infusion
and periodically thereafter.
- Twenty-one patients will initially be 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 (partial response or complete response), accrual will continue to 41 patients,
targeting a 20% goal for objective response.
- Up to 332 patients may be enrolled.
- 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 National Cancer Institute Surgery Branch (NCI-SB) and from the literature
support that metastatic cancers are potentially immunogenic and that tumor-infiltrating
lymphocytes (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, lymphodepleting 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.
- In pre-clinical models, the administration of an anti-PD-1 antibody enhances the
anti-tumor activity of transferred T-cells.
- We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer
therapy in combination with pembrolizumab, administered either prior to cell
administration or at the time of progressive disease, for metastatic cancers.
Objectives:
-Primary objective:
--With Amendment BB, to determine the rate of tumor regression in patients with metastatic
cancer who receive autologous, minimally cultured TIL in conjunction with a
non-myeloablative, lymphodepleting preparative regimen, high-dose aldesleukin, and anti-PD-1.
Eligibility:
Patients must be/have:
- Age greater than or equal to 18 years and less than or equal to 70 years
- Metastatic digestive tract, urothelial, breast, ovarian/endometrial cancer, or
glioblastoma refractory to standard chemotherapy, originating from the (a) gastric,
gastroesophageal junction; (b) pancreas, liver, or biliary tree; (c) colon or rectum;
(d) bladder; (e) breast; or (f) ovarian/endometrium; or, (g) brain.
- 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
Design:
- Patients may 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 ongoing and future research as described in the
NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch
Adoptive Cell Therapy Protocols).
- With the approval of Amendment BB, patients will be enrolled on Arm 3 or Arm 4. All
patients will receive a non-myeloablative, lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by the infusion of autologous
TIL and high-dose aldesleukin. Patients enrolled on Arm 3 will receive pembrolizumab
prior to cell administration and three additional doses every three weeks following the
cell infusion. Patients enrolled on Arm 4 will receive pembrolizumab within four weeks
after meeting progressive disease by RECIST criteria, continuing for up to 8 doses every
3 weeks.
- Clinical and immunologic response will be evaluated about 6 weeks after cell infusion
and periodically thereafter.
- Twenty-one patients will initially be 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 (partial response or complete response), accrual will continue to 41 patients,
targeting a 20% goal for objective response.
- Up to 332 patients may be enrolled.
- INCLUSION CRITERIA:
- Measurable (per RECIST v1.0 criteria), metastatic cancer of one of the following
types: gastric, gastroesophageal, pancreatic, hepatocellular, cholangiocarcinoma,
gallbladder, colorectal, urothelial, breast, ovarian/endometrial, or glioblastoma.
Patients must have 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.
- Confirmation of diagnosis of metastatic cancer by the NCI Laboratory of Pathology.
- Refractory to approved standard systemic therapy. Specifically:
- Patients with metastatic colorectal cancer must have received oxaliplatin or
irinotecan.
- Patients with Hepatocellular carcinoma patients must have received sorafenib
(Nexavar ), since level 1 data support a survival benefit with this agent.
- Patients with breast and ovarian cancer must be refractory to both first and
second line treatments and must have received at least one second-line
chemotherapy regimen.
- Patients with glioblastoma must have received standard surgery, radiation
therapy, and chemotherapy for their primary tumors and require resection of their
tumors for palliative or other clinical indications. These patients will not
undergo surgery solely for treatment on this protocol.
- Patients with 3 or fewer brain metastases that are less than or equal to 1 cm in
diameter and asymptomatic are eligible. Lesions that have been treated with
stereotactic radiosurgery must be clinically stable for one month after treatment for
the patient to be eligible.
- Age greater than or equal to 18 years and less than or equal to 70 years.
- Clinical performance status of ECOG 0 or 1.
- Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for four months after treatment.
- Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the treatment on the fetus.
Serology
- Seronegative for HIV antibody. (The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who are HIV seropositive may
have decreased immune-competence and thus may be less responsive to the experimental
treatment and more susceptible to its toxicities.)
- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If
hepatitis C antibody test is positive, then the patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
Hematology
- ANC > 1000/mm3 without the support of filgrastim
- WBC greater than or equal to 3000/mm3
- Platelet count greater than or equal to 100,000/mm3
- Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.
Chemistry
- Serum ALT/AST less than or equal to 5.0 x ULN
- Serum creatinine less than or equal to 1.6 mg/dL
- Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert s
Syndrome, who must have a total bilirubin < 3.0 mg/dL.
- 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.
Note: Patients may have undergone minor surgical procedures within the past three weeks, as
long as all toxicities have recovered to grade 1 or less.
- Ability of subject to understand and the willingness to sign a written informed
consent document.
- Willing to sign a durable power of attorney.
- Subjects must be co-enrolled on protocol 03-C-0277.
Exclusion Criteria:
- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
- Concurrent systemic steroid therapy, except for patients with recurrent glioblastoma
who require steroids for clinical indications.
- Active systemic infections requiring anti-infective treatment, coagulation disorders,
or any other active or uncompensated major medical illnesses.
- Advanced primary with impeding occlusion, perforation or bleeding, dependent on
transfusion.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease
and AIDS).
- History of major organ autoimmune disease.
- Grade 3 or 4 major organ irAEs following treatment with anti-PD-1/PD-L1.
- Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased
immunecompetence may be less responsive to the experimental treatment and more
susceptible
to its toxicities.)
- History of severe immediate hypersensitivity reaction to cyclophosphamide,
fludarabine, or aldesleukin.
- History of coronary revascularization or ischemic symptoms.
- Documented LVEF less than or equal to 45% tested in patients:
- Age greater than or equal to 65 years
- With clinically significant atrial and/or ventricular arrhythmias, including but
not imited to: atrial fibrillation, ventricular tachycardia, second- or
third-degree heart block, or have a history of ischemic heart disease and/or
chest pain.
- Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known
underlying liver dysfunction.
- Documented FEV1 less than or equal to 60% predicted tested in patients with:
- A prolonged history of cigarette smoking (greater than or equal to 20 pack-year
smoking history within the past two years).
- Symptoms of respiratory dysfunction
- Patients who are receiving any other investigational agents.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 866-820-4505
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