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A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab

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ClinicalTrials.gov Identifier: NCT02621021
Recruitment Status : Recruiting
First Posted : December 3, 2015
Last Update Posted : August 3, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to the person. Researchers think adding the drug pembrolizumab might make the therapy more effective.

Objective:

To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma tumors.

Eligibility:

People ages 18 70 years with metastatic melanoma

Design:

Participants will be screened with:

Physical exam

CT, MRI, or PET scans

X-rays

Heart and lung function tests

Blood and urine tests

Before treatment, participants will have:

A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells

Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white blood cells.

The rest of the blood returns through a needle in the other arm.

An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if assigned)

Participants will stay in the hospital for treatment. This includes:

Daily chemotherapy for 1 week

For some participants, pembrolizumab infusion 1 day after chemotherapy

TIL cell infusion 2 4 days after chemotherapy, then aldesleukin infusion every 8 hours for up to 12 doses

Possible filgrastim injection

Recovery for 1 2 weeks

After treatment, participants will:

Take an antibiotic and antiviral for at least 6 months

If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have another round.

Have 2-day follow-up visits every 1 3 months for 1 year and then every 6 months


Condition or disease Intervention/treatment Phase
Melanoma Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldeslaukin Drug: Pembrolizumab Biological: young TIL Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
Study Start Date : December 2, 2015
Estimated Primary Completion Date : June 16, 2025
Estimated Study Completion Date : June 16, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: 1/ACT TIL
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2)
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 over 1 hour X 2 days.

Drug: Fludarabine
Days -7 to -3, Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.

Drug: Aldeslaukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).

Biological: young TIL
Day 0, young TIL will be administered intravenously over 20-30 minutes.

Experimental: 2/ACT TIL+Pembro
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2) + pembrolizumab
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 over 1 hour X 2 days.

Drug: Fludarabine
Days -7 to -3, Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.

Drug: Aldeslaukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).

Drug: Pembrolizumab
Cohort 1, Arm 2 and Cohort 2) On day -2, and days 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days) following cell infusion: Pembrolizumab 2mg/kg IV over approximately 30 minutes.

Biological: young TIL
Day 0, young TIL will be administered intravenously over 20-30 minutes.

Experimental: 3/Retreatment
Standard dose pembrolizumab
Drug: Pembrolizumab
Cohort 1, Arm 2 and Cohort 2) On day -2, and days 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days) following cell infusion: Pembrolizumab 2mg/kg IV over approximately 30 minutes.




Primary Outcome Measures :
  1. Response Rates [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x5 years, then PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. Frequency of treatment related adverse events [ Time Frame: 30 days after end of treatment ]
    Aggregate of all adverse events as well as their events

  2. Overall survival [ Time Frame: Time of death ]
    Time from start of treatment to death from any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation.
  2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI.
  3. Patients must have received at least one prior therapy for metastatic melanoma.
  4. 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.
  5. Greater than or equal to 16 years of age and less than or equal to 70 years of age.
  6. All participants and/or their parents or legally authorized representatives must sign a written informed consent. Assent will be obtained for all participants under the age of 18 years.
  7. All participants greater than or equal to 18 years of age or older must be willing to sign a durable power of attorney
  8. Clinical performance status of ECOG 0 or 1.
  9. 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.
  10. 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.
  11. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  12. Hematology

    • Absolute neutrophil count greater than 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
  13. 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 musthave a total bilirubin less than 3.0 mg/dl.
  14. 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). (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)

  15. Patients must demonstrate progressive disease at the time of treatment. (Note: Patients who have received tyrosine kinase inhibitors (e.g. vemurafinib) may be treated if they present with stable disease at the time of treatment).
  16. Subjects must be co-enrolled in protocol 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. History of major organ autoimmune disease
  6. Concurrent systemic steroid therapy.
  7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  8. Grade 3 or 4 Major organ Immune-related Adverse Events (IRAEs) following treatment with anti PD-1/PD-L1.
  9. History of coronary revascularization or ischemic symptoms.
  10. 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 have a history of ischemic heart disease, chest pain.
  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
  12. 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): NCT02621021


Contacts
Contact: Mary E. Link, R.N. (866) 820-4505 IRC@nih.gov

Locations
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
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02621021     History of Changes
Other Study ID Numbers: 160027
16-C-0027
First Posted: December 3, 2015    Key Record Dates
Last Update Posted: August 3, 2018
Last Verified: August 1, 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Melanoma
Skin Cancer
Immunotherapy
Cell Therapy

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cyclophosphamide
Fludarabine phosphate
Pembrolizumab
Fludarabine
Aldesleukin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Anti-Retroviral Agents