Description:
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 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.
Title
- Brief Title: Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer
- Official Title: A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphodepleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumab
Clinical Trial IDs
- ORG STUDY ID:
100166
- SECONDARY ID:
10-C-0166
- NCT ID:
NCT01174121
Conditions
- Metastatic Colorectal Cancer
- Progressive Glioblastoma
- Metastatic Pancreatic Cancer
- Metastatic Ovarian Cancer
- Metastatic Breast Carcinoma
Interventions
| Drug | Synonyms | Arms |
|---|
| Young TIL | | 1/CD8+ Enriched TIL (CLOSED) |
| Aldesleukin | | 1/CD8+ Enriched TIL (CLOSED) |
| Cyclophosphamide | | 1/CD8+ Enriched TIL (CLOSED) |
| Fludarabine | | 1/CD8+ Enriched TIL (CLOSED) |
| Pembrolizumab (Keytruda) | | 3/Unselected TIL + Pembro Prior to Cells |
Purpose
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 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 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 upper or lower gastrointestinal, hepatobiliary, genitourinary, breast,
ovarian/endometrial cancer, or glioblastoma refractory to standard chemotherapy
- 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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| 1/CD8+ Enriched TIL (CLOSED) | Experimental | Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young CDS+ enriched TIL + high-dose aldesleukin (CLOSED) | - Young TIL
- Aldesleukin
- Cyclophosphamide
- Fludarabine
|
| 2/Unselected TIL (CLOSED) | Experimental | Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young unselected TIL + high-dose aldesleukin (CLOSED) | - Young TIL
- Aldesleukin
- Cyclophosphamide
- Fludarabine
|
| 3/Unselected TIL + Pembro Prior to Cells | Experimental | Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeks following cell infusion | - Young TIL
- Cyclophosphamide
- Fludarabine
- Pembrolizumab (Keytruda)
|
| 4/Unselected TIL + Pembro at POD | Experimental | Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin +pembrolizumab within 4 weeks of progressive disease for up to 8 doses every 3 weeks | - Young TIL
- Aldesleukin
- Cyclophosphamide
- Fludarabine
- Pembrolizumab (Keytruda)
|
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 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 completion of any prior systemic therapy
at the time the patient receives the preparative regimen, and major organ toxicities
must have recovered to grade 1 or less.
Note: Patients may have undergone minor surgical procedures or limited field radiotherapy
within the four weeks prior to enrollment, as long as related organ 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.
| Maximum Eligible Age: | 70 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Response rate |
| Time Frame: | 6 and 12 weeks after cell infusion, then every 3 months x 3, then every 6 months x 2 years, then per PI discretion |
| Safety Issue: | |
| Description: | Percentage of patients who have a clinical response to treatment (objective tumor regression) |
Secondary Outcome Measures
| Measure: | Frequency and severity of treatment-related to adverse events |
| Time Frame: | 30 days after end of treatment |
| Safety Issue: | |
| Description: | Aggregate of all adverse events, as well as their frequency and severity |
| Measure: | Safety and efficacy of pembrolizumab following TIL therapy |
| Time Frame: | Every 6 weeks (week 6, 12, 18, 24) within 24 hours prior to next scheduled pembrolizumab dose |
| Safety Issue: | |
| Description: | Response rate and evaluation of treatment-related adverseevents for patients who experience progressive disease and receivepembrolizumab |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Suspended |
| Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Digestive Tract Cancers
- Breast Cancer
- Glioblastoma
- Ovarian/Endometrial Cancer
- Genitourinary Cancer
Last Updated
August 16, 2021
