Trial Title:
Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer
NCT ID:
NCT01174121
Condition:
Metastatic Colorectal Cancer
Metastatic Pancreatic Cancer
Metastatic Ovarian Cancer
Metastatic Breast Carcinoma
Metastatic Endocrine Tumors/ Neuroendocrine Tumors
Conditions: Official terms:
Neuroendocrine Tumors
Breast Neoplasms
Neoplasm Metastasis
Endocrine Gland Neoplasms
Aldesleukin
Cyclophosphamide
Pembrolizumab
Fludarabine
Conditions: Keywords:
Digestive Tract Cancers
Breast Cancer
Endocrine Tumors
Ovarian/Endometrial Cancer
Genitourinary Cancer
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Young TIL
Description:
Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30
minutes (one to four days after the last dose of fludarabine).
Arm group label:
1/CD8+ Enriched TIL (CLOSED)
Arm group label:
2/Unselected TIL (CLOSED)
Arm group label:
3/Unselected TIL + Pembro Prior to Cells
Arm group label:
4/Unselected TIL + Pembro at POD
Intervention type:
Drug
Intervention name:
Aldesleukin
Description:
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight
hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4
days (maximum 12 doses.)
Arm group label:
1/CD8+ Enriched TIL (CLOSED)
Arm group label:
2/Unselected TIL (CLOSED)
Arm group label:
3/Unselected TIL + Pembro Prior to Cells
Arm group label:
4/Unselected TIL + Pembro at POD
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15
mg/kg/day X2 days over 1 hr.
Arm group label:
1/CD8+ Enriched TIL (CLOSED)
Arm group label:
2/Unselected TIL (CLOSED)
Arm group label:
3/Unselected TIL + Pembro Prior to Cells
Arm group label:
4/Unselected TIL + Pembro at POD
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Arm group label:
1/CD8+ Enriched TIL (CLOSED)
Arm group label:
2/Unselected TIL (CLOSED)
Arm group label:
3/Unselected TIL + Pembro Prior to Cells
Arm group label:
4/Unselected TIL + Pembro at POD
Intervention type:
Drug
Intervention name:
Pembrolizumab (Keytruda)
Description:
Arm 3: Pembrolizumab 2mg/kg IV over approximately 30 minutes on Days -2, 21, 42, and 63
Arm 4: Pembrolizumab 2mg/kg IV over approximately 30 minutes (for patients who meet
progressive disease per RECIST criteria and have resolved major toxicities after cell
infusion or anytime during the post-treatment evaluation period; starting within 4 weeks
of progression; may receive up to 8 doses every 3 weeks).
Arm group label:
3/Unselected TIL + Pembro Prior to Cells
Arm group label:
4/Unselected TIL + Pembro at POD
Summary:
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 18-72 with upper or lower gastrointestinal, hepatobiliary, genitourinary,
breast, ovarian/endometrial cancer, or glioblastoma refractory to standard
chemotherapy.
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.
Detailed description:
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 led 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 72 years
- Metastatic upper or lower gastrointestinal, hepatobiliary, genitourinary, breast,
ovarian/endometrial cancer, or endocrine tumors including neuroendocrine tumors
refractory to standard chemotherapy
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.
Criteria for eligibility:
Criteria:
- INCLUSION CRITERIA:
- Measurable (per RECIST v1.0 criteria), metastatic cancer of one of the following
types: upper or lower gastrointestinal, hepatobiliary, genitourinary, breast,
ovarian/endometrial, or endocrine tumors including neuroendocrine tumors. 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 must have received sorafenib
(Nexavar(R)), 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 3 or fewer brain metastases that are < 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. Patients with surgically resected brain metastases are eligible.
- Age greater than or equal to 18 years and less than or equal to 72 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 12 months after the last dose of combined chemotherapy
for women and for four months after treatment for men.
- Women of child-bearing potential must be willing to undergo a pregnancy test prior
to the start of treatment 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/mm^3 without the support of filgrastim
- WBC greater than or equal to 2500/mm^3
- Platelet count greater than or equal to 80,000/mm^3
- 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 1.5 x ULN
- 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.
- Patients must have completed any prior systemic therapy at the time of enrollment.
Note: Patients may have undergone minor surgical procedures or limited field radiotherapy
within the four weeks prior to enrollment, as long as related major organ toxicities have
recovered to less than or equal to grade 1.
- 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.
- 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 clinically attributed to anti-PD-1/PD-L1 therapy.
- 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.
- For select patients with a clinical history prompting cardiac evaluation: last known
LVEF less than or equal to 45%.
- Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with
known underlying liver dysfunction.
- For select patients with a clinical history prompting pulmonary evaluation: known
FEV1 less than or equal to 50%.
- Patients who are receiving any other investigational agents.
Gender:
All
Minimum age:
18 Years
Maximum age:
72 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Recruiting
Start date:
August 26, 2010
Completion date:
December 27, 2024
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Institutes of Health Clinical Center (CC)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01174121
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2010-C-0166.html
