Tumor Infiltrating Lymphocytes and Aldesleukin after Chemotherapy and Pembrolizumab in Treating Patients with Metastatic Cancers
Basic Trial Information
|Phase II||Treatment||Active||18 and over||10-C-0166|
NCI-2013-01461, 100166, 306343, P09567, NCT01174121
This phase II trial studies how well tumor infiltrating lymphocytes and aldesleukin work after chemotherapy and pembrolizumab in treating patients with cancers that has spread to other parts of the body (metastatic). Pembrolizumab may block cancer growth in different ways by targeting certain cells. Aldesleukin may stimulate lymphocytes to kill tumor cells. Treating lymphocytes with aldesleukin in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body after chemotherapy.
Further Study Information
I. To determine the rate of tumor regression in patients with metastatic digestive tract cancers who receive autologous, minimally cultured, cluster of differentiation 8 (CD8)+ enriched tumor infiltrating lymphocytes (TIL) plus aldesleukin following a lymphodepleting preparative regimen.
II. 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.
III. To determine the rate of tumor regression in patients in cohort 2 with metastatic digestive tract and urothelial cancers who receive autologous, minimally cultured tumor infiltrating lymphocytes (TIL) plus aldesleukin following a lymphodepleting preparative regimen.
IV. To determine the rate of tumor regression in patients in cohort 2 with metastatic digestive tract, urothelial, breast, and ovarian/endometrial cancers who receive autologous, minimally cultured tumor infiltrating lymphocytes (TIL) plus aldesleukin following a lymphodepleting preparative regimen.
V. To determine the rate of tumor regression in patients in cohort 3 with metastatic digestive tract, urothelial, breast, and ovarian/endometrial cancers who receive autologous, minimally cultured tumor infiltrating lymphocytes (TIL) plus aldesleukin following a lymphodepleting preparative regimen and anti-programmed cell death protein 1 (PD-1).
I. To determine the toxicity of this treatment regimen.
II. To evaluate the safety and efficacy of pembrolizumab in combination with the TIL therapy.
PREPARATIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6 and fludarabine phosphate intravenous piggyback (IVPB) over 30 minutes on days -7 to -3. Patients may also receive pembrolizumab IV over 30 minutes on days -2, 21, 42, and 63 at the discretion of the treating investigator.
TIL INFUSION: Patients receive autologous TIL IV over 20-30 minutes on day 0.
ALDESLEUKIN: Beginning within 24 hours of cell infusion, patients receive aldesleukin IV over 15 minutes every 8-24 hours on days 0-4. Patients also receive filgrastim subcutaneously (SC) on days 1-4 or until absolute neutrophil count begins to return to normal.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 6 weeks, 12 weeks, every 3 months for 9 months, every 6 months for 2 years, and then periodically thereafter.
Measurable metastatic (stage IV) gastric, gastroesophageal, pancreatic, hepatocellular carcinoma, cholangiocarcinoma, gallbladder, colorectal, urothelial, breast, and ovarian/endometrial 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, plus one other lesion that can be measured
All patients must be refractory to approved standard systemic therapy; specifically:
Metastatic colorectal patients must have received oxaliplatin or irinotecan
Hepatocellular carcinoma patients must have received sorafenib (Nexavar) since level 1 data support a survival benefit with this agent
Breast and ovarian cancer patients must be refractory to both first (1st) line and second (2nd) line treatments and must have received at least one second line chemotherapy regimen
Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible
Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
Life expectancy of greater than three months
Willing to practice birth control during treatment and for four months after receiving the treatment
Willing to sign a durable power of attorney
Able to understand and sign the informed consent document
Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim
Normal white blood cell (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)
Seronegative for human immunodeficiency virus (HIV) antibody
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 reverse transcriptase-polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative
Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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
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 or as specified
Six weeks must have elapsed since any prior anti-vascular endothelial growth factor (VEGF) or anti-tyrosine kinase receptors (TKR) therapy or anti-PD-1/programmed death-ligand 1 (PD-L1) agents to allow antibody levels to decline
Women of child-bearing potential who are pregnant or breastfeeding
Concurrent systemic steroid therapy
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
Advanced primary with impeding occlusion, perforation or bleeding, dependent on transfusion
Any form of primary immunodeficiency (such as severe combined immunodeficiency disease and acquired immune deficiency syndrome [AIDS])
History of major organ autoimmune disease
Grade 3 or 4 major organ immune-related adverse events (IRAEs) following treatment with anti-PD-1/PD-L1
Concurrent opportunistic infections
History of severe immediate hypersensitivity reaction to any of the agents used in this study
History of coronary revascularization or ischemic symptoms
Any patient known to have a left ventricular ejection fraction (LVEF) less than or equal to 45%
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 >= 60 years old
Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction
Trial Contact Information
Trial Lead Organizations / Sponsors / Collaborators
NCI - Center for Cancer Research
- National Cancer Institute
National Cancer Institute Surgery Branch
Steven A. Rosenberg
Steven A. Rosenberg
National Institutes of Health Clinical Center
Steven A. Rosenberg
Steven A. Rosenberg
Link to the current ClinicalTrials.gov record.
NLM Identifier NCT01174121
Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.