Clinical trial NCT01993719: Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Melanoma
Keywords: Melanoma
Adoptive Cell Therapy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2013-11-25
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

* The National Cancer Institute (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-programmed cell death-1 (PD-1) 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 Gray (Gy) or 12 Gy total body irradiation (TBI) objective response rates using Response Evaluation Criteria In Solid Tumors (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 tumor infiltrating lymphocytes (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.

Eligibility criteria: -INCLUSION CRITERIA:

1. Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation and at least one other lesion that can be measured by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of National Cancer Institute (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 Eastern Cooperative Oncology Group (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 human immunodeficiency virus (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 reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (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
    * White blood cell (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 alanine aminotransferase (ALT)/aspartate aminotransferase (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 left ventricular ejection fraction (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 forced expiratory volume (FEV1) less than or equal to 60% predicted tested in patients with:

    * A prolonged history of cigarette smoking (20 pack (pk)/year of smoking within the past 2 years).
    * Symptoms of respiratory dysfunction

Primary outcomes:
measure: Number of Participants With Treatment-related Grade 3-5 Adverse Events in Arm 1N and Arm 1P
timeFrame: 30 days after end of treatment
measure: Number of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression)
timeFrame: 4 weeks after cell infusion, then every 3 months x 3 and then every 6 months for 5 years, then per Principal Investigator (PI) discretion up to 5 years or disease progression
measure: Overall Response Rate (ORR)
timeFrame: Date of cells until time of disease progression, up to approximately 67.2 months.
Secondary outcomes:
measure: Number of Treatment-related Adverse Events for Participants Who Received Pembrolizumab
timeFrame: Date treatment consent signed until approximately 4 weeks following last dose of Pembrolizumab, up to 4 weeks
measure: Progression-free Survival (PFS)
timeFrame: Date of cells until time of disease progression up to approximately 67.2 months.
measure: Overall Survival
timeFrame: Date of cells until time to death, up until 90.1 months.
measure: Overall Survival
timeFrame: An average of 25.6 months.
measure: Overall Progression Free Survival (PFS)
timeFrame: Time to progression and time to death, approximately up to 67.2 months.
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 102 months and 9 days, 92 months and 19 days, 86 months and 9 days, 99 months and 16 days, and 86 months and 26 days for each group respectively.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Stephanie L Goff, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008 Nov 10;26(32):5233-9. doi: 10.1200/JCO.2008.16.5449. Epub 2008 Sep 22.
citation: O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, Lerner S, Keating M. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001 Mar 1;19(5):1414-20. doi: 10.1200/JCO.2001.19.5.1414.