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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01993719
Recruitment Status : Active, not recruiting
First Posted : November 25, 2013
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE November 22, 2013
First Posted Date  ICMJE November 25, 2013
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE December 12, 2013
Estimated Primary Completion Date October 27, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
  • 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
  • Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x5 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)
Original Primary Outcome Measures  ICMJE
 (submitted: November 22, 2013)
Determine whether patients receiving TIL plus a lower dose chemotherapy preparative regimen followed by aldesleukin are able to attain a response rate equivalent to TIL plus our standard chemotherapy regimen followed by aldesleukin. [ Time Frame: 5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
  • Progression-free and overall survival [ Time Frame: Time to progression and time to death ]
    Time to disease progression following the start of treatment, and time to death following the start of treatment
  • Safety and efficacy of pembrolizumab + TIL therapy [ Time Frame: 6 and 12 weeks after cellinfusion, then every 3 months x3, then every 6 months x5 years, then per PI discretion ]
    Response rate and evaluation of treatment-related adverse events for patients who received pembrolizumab
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2013)
To evaluate the relative platelet and red cell transfusion requirements on the two arms [ Time Frame: 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
Official Title  ICMJE A Phase II Study for Metastatic Melanoma Using High Dose Chemotherapy Preparative Regimen Followed by Cell Transfer Therapy Using Tumor Infiltrating Lymphocytes Plus IL-2 With the Administration of Pembrolizumab in the Retreatment Arm
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 400 patients with melanoma.
  • In this trial, we are determining if there is a difference in the response between patients who have received prior anti-PD1 treatment to those who have not received this prior ant-PD1 treatment.

Objectives:

- To determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not.

Eligibility:

- Individuals at least 18 years and less than or equal to 70 years of age who have metastatic melanoma.

Design:

  • Work up stage: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
  • Surgery: Surgery or biopsy will be performed to obtain tumor from which to grow white blood cells. White blood cells will be grown from the tumor in the laboratory.
  • Leukapheresis: Participants will have leukapheresis to collect additional white blood cells. (Leukapheresis is a common procedure which removes only the white blood cells from the patient.)
  • Treatment: Participants will receive standard dose chemotherapy to prepare their immune system to accept the white blood cells. Participants will receive an infusion of their own white blood cells grown from tumor. They will also receive aldesleukin for up to five days to boost the immune system s response to the white blood cells. 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 take up to 2 days.
Detailed Description

Background:

  • Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
  • In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months.
  • The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia.

Objectives:

  • With amendment D, to determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not; both groups will receive non-myeloablative lymphoid depleting preparative regimen followed by autologous young TIL and administration of high dose aldesleukin.
  • To determine the toxicity of the treatment.

Eligibility:

  • Age greater than or equal to 18 and less than or equal to 70 years
  • Evaluable metastatic melanoma
  • Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
  • No contraindications to high-dose aldesleukin administration
  • No concurrent major medical illnesses or any form of immunodeficiency

Design:

  • Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will receive ACT with TIL plus aldesleukin following high dose chemotherapy preparative regimen.
  • Up to 64 patients may be enrolled over 4-5 years.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Melanoma
Intervention  ICMJE
  • Drug: Aldesleukin
    720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).
  • Drug: Fludarabine
    25 mg/m2/day IVPB daily for 5 days or 30 mg/m2 IV once
  • Drug: Cyclophosphamide
    60 mg/kg/day X 2 days IV or 30 mg/kg/day X 2 days IV. Days -5 to -3 (low- dose arm-CLOSED): Cyclophosphamide 300 mg/m2 IV over 60 minutes.
  • Biological: Young TIL
    Day 0: Cells will be infused intravenously (IV)
  • Drug: Pembrolizumab (Keytruda)
    2 mg/kg IV on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days).
Study Arms  ICMJE
  • Experimental: 1/ Arm 1P
    Standard preparative regimen + Young TIL Cells + possible retreatment with standard preparative regimen + Young TIL Cells +pembrolizumab
    Interventions:
    • Drug: Aldesleukin
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Biological: Young TIL
    • Drug: Pembrolizumab (Keytruda)
  • Experimental: 1/Arm 1 (CLOSED)
    Standard preparative regimen + Young TIL Cells
    Interventions:
    • Drug: Aldesleukin
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Biological: Young TIL
  • Experimental: 2/Arm 2 (CLOSED)
    Lower dose preparative regimen + Young TIL Cells
    Interventions:
    • Drug: Aldesleukin
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Biological: Young TIL
  • Experimental: 3/ Arm 1N
    Standard preparative regimen + Young TIL Cells
    Interventions:
    • Drug: Aldesleukin
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Biological: Young TIL
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 19, 2019)
33
Original Estimated Enrollment  ICMJE
 (submitted: November 22, 2013)
120
Estimated Study Completion Date  ICMJE September 28, 2029
Estimated Primary Completion Date October 27, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation and at least one other lesion that can be measured by RECIST criteria.
  2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI.
  3. 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. Patients with surgically resected brain metastases are eligible.
  4. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  5. Ability of subject to understand and the willingness to sign the Informed Consent Document
  6. Willing to sign a durable power of attorney.
  7. Clinical performance status of ECOG 0, 1 or 2.
  8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
  9. Serology:

    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus are 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 patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  10. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim
    • WBC greater than or equal to 3000/mm(3)
    • Platelet count greater than or equal to 100,000/mm(3)
    • Hemoglobin > 8.0 g/dl
  12. Chemistry:

    • Serum ALT/AST less than or equal to 2.5 times the upper limit of normal
    • Serum Creatinine less than or equal to 1.6 mg/dl
    • Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.
  13. 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 (except for toxicities such as alopecia or vitiligo). Patients must have progressive disease after prior treatment.

    Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

  14. Subjects must be co-enrolled in 03-C-0277

EXCLUSION CRITERIA:

  1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  3. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  4. Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses.
  5. Concurrent systemic steroid therapy.
  6. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  7. History of coronary revascularization or ischemic symptoms.
  8. Any patient known to have an LVEF less than or equal to 45%
  9. Documented LVEF of less than or equal to 45%, note: testing is required in patients with:

    • Age greater than or equal to 65 years old
    • Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or history of ischemic heart disease or chest pain.
  10. Patients who are receiving other investigational agents
  11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
    • Symptoms of respiratory dysfunction
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01993719
Other Study ID Numbers  ICMJE 140022
14-C-0022
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stephanie L Goff, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 29, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP