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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01174121
Recruitment Status : Recruiting
First Posted : August 3, 2010
Last Update Posted : June 27, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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 18-70 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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Metastatic Pancreatic Cancer Metastatic Ovarian Cancer Metastatic Breast Carcinoma Neuroendocrine Tumors Metastatic Endocrine Tumors Biological: Young TIL Drug: Aldesleukin Drug: Cyclophosphamide Drug: Fludarabine Drug: Pembrolizumab (Keytruda) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 332 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 26, 2010
Estimated Primary Completion Date : December 29, 2023
Estimated Study Completion Date : December 27, 2024


Arm Intervention/treatment
Experimental: 1/CD8+ Enriched TIL (CLOSED)
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young CD8+ enriched TIL + high-dose aldesleukin (CLOSED)
Biological: Young TIL
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).

Drug: Aldesleukin
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.)

Drug: Cyclophosphamide
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.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25mg/m2/day IVPB daily over 30 minutes for 5 days.

Experimental: 2/Unselected TIL (CLOSED)
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin (CLOSED)
Biological: Young TIL
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).

Drug: Aldesleukin
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.)

Drug: Cyclophosphamide
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.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25mg/m2/day IVPB daily over 30 minutes for 5 days.

Experimental: 3/Unselected TIL + Pembro Prior to Cells
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
Biological: Young TIL
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).

Drug: Aldesleukin
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.)

Drug: Cyclophosphamide
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.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25mg/m2/day IVPB daily over 30 minutes for 5 days.

Drug: Pembrolizumab (Keytruda)
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).

Experimental: 4/Unselected TIL + Pembro at POD
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
Biological: Young TIL
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).

Drug: Aldesleukin
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.)

Drug: Cyclophosphamide
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.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25mg/m2/day IVPB daily over 30 minutes for 5 days.

Drug: Pembrolizumab (Keytruda)
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).




Primary Outcome Measures :
  1. Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. Safety and efficacy of pembrolizumab in combination with TIL therapy [ Time Frame: Every 6 weeks (week 6, 12, 18, 24) within 24 hours prior to next scheduled pembrolizumab dose ]
    Response rate and evaluation of treatment-related adverse events for patients who receive pembrolizumab

  2. Frequency and severity of treatment-related adverse events [ Time Frame: 30 days after end of treatment ]
    Aggregate of all adverse events, as well as their frequency and severity



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 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/mm3 without the support of filgrastim
  • WBC greater than or equal to 2500/mm3
  • Platelet count greater than or equal to 80,000/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.
  • 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 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01174121


Contacts
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Contact: For more information NCI/Surgery Branch Recruitment Center (866) 820-4505 IRC@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01174121    
Other Study ID Numbers: 100166
10-C-0166
First Posted: August 3, 2010    Key Record Dates
Last Update Posted: June 27, 2022
Last Verified: June 13, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data will be available during the study and indefinitely.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Digestive Tract Cancers
Breast Cancer
Endocrine Tumors
Ovarian/Endometrial Cancer
Genitourinary Cancer
Additional relevant MeSH terms:
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Neoplasms
Neuroendocrine Tumors
Breast Neoplasms
Neoplasm Metastasis
Endocrine Gland Neoplasms
Neoplasms by Site
Endocrine System Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Aldesleukin
Cyclophosphamide
Pembrolizumab
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Anti-HIV Agents