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

• ClinicalTrials.gov Identifier: NCT02621021
• Recruitment Status: Recruiting
• First Posted: December 3, 2015
• Last Update Posted: February 15, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

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 OF THE SKIN

Design:

Participants will be screened with:

Physical exam

CT, MRI, or PET scans

X-rays

Heart and lung function tests if indicated

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

Filgrastim injections to help restore your blood counts

Recovery for 1-3 weeks

After treatment, participants will:

Take an antibiotic and an antiviral for at least 6 months, as applicable

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: Aldesleukin; Drug: Pembrolizumab; Biological: young TIL	Phase 2

Detailed Description:

Background:

- Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered along with highdose aldesleukin (IL-2) following a non-myeloablative lymphodepleting

preparative regimen consisting of cyclophosphamide and fludarabine.

- Pembrolizumab, a monoclonal antibody that binds to PD-1 and blocks the PD-1/PD-L1 axis, facilitates the activity of anti-tumor lymphocytes in the tumor micro environment. Pembrolizumab administration can result in objective tumor responses in patients with

metastatic melanoma and is approved for use by the FDA for the treatment of these patients.

• Administered TIL express low levels of PD-1, though PD-1 can be re-expressed on TIL in vivo following TIL administration
• In pre-clinical models, the administration of an anti-PD1 antibody enhances the anti-tumor activity of transferred T-cells.

Objectives:

Primary Objectives:

• Determine in a prospective randomized trial whether the addition of pembrolizumab to the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 can improve complete response rates in patients with metastatic melanoma who have received prior anti PD-1/PD-L1 therapy (Cohort 1)
• Determine the complete response rate to the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 in combination with pembrolizumab in patients with metastatic melanoma who have not received prior anti-PD-1/PD-L1 therapy (Cohort 2)

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 allergies or hypersensitivity to high-dose aldesleukin administration
• No concurrent major medical illnesses or any form of immunodeficiency

Design:

• Patients with metastatic melanoma will have lesions resected for TIL

• Patients will be assigned one of 2 cohorts: (1)

  • patients who are refractory to prior anti PD-1/PD-L1
  • patients who have not received prior anti PD-1/PD-L1

• After TIL growth is established:

  • Patients assigned to Cohort 1 will be randomized to either receive or not receive pembrolizumab in combination with the standard non-myeloablative conditioning regimen, TIL and high dose IL-2
  • All patients assigned to Cohort 2 will receive the standard nonmyeloablative conditioning regimen, TIL, and high-dose IL-2ACT in combination with pembrolizumab.
• For those patients receiving pembrolizumab- Pembrolizumab will be administered immediately prior to TIL administration and continue for an additional three cycles following the cell infusion.
• Up to 170 patients may be enrolled over 3-4 years.

Study Design

• 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 II Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor-Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
• Actual Study Start Date: December 4, 2015
• Estimated Primary Completion Date: June 16, 2025
• Estimated Study Completion Date: June 16, 2026

Arms and Interventions

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: Aldesleukin; 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: Cells will be administered intravenously (IV) on the Patient Care Unit 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: Aldesleukin; 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. (Cohort 1, Arm 1 Retreatment) 4 doses every 3 weeks (+/- 2 days): Pembrolizumab 2mg/kg IV over approximately 30 minutes.; Biological: young TIL; Day 0: Cells will be administered intravenously (IV) on the Patient Care Unit over 20-30 minutes.

Outcome Measures

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 5 years, then per PI discretion ]
   Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (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.

Contacts and Locations

Contacts

Contact: NCI/Surgery Branch Recruitment Center; (866) 820-4505; IRC@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephanie L Goff, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15.

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.

Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, Ohayon D, Shalmon B, Markel G, Yerushalmi R, Apter S, Ben-Nun A, Ben-Ami E, Shimoni A, Nagler A, Schachter J. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res. 2013 Sep 1;19(17):4792-800. doi: 10.1158/1078-0432.CCR-13-0380. Epub 2013 May 20.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02621021
• Other Study ID Numbers: 160027; 16-C-0027
• First Posted: December 3, 2015
• Last Update Posted: February 15, 2023
• Last Verified: January 24, 2023

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.

• 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) ):

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; 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; Immune Checkpoint Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents