T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Melanoma

Metastatic Cancer Clinical Trial

Official title:

Phase II Study of CD62L+-Derived T Lymphocytes Transduced With a T Cell Receptor Recognizing the NY-ESO-1 Antigen and Aldesleukin Following Lymphodepletion in Patients With NY-ESO-1 Expressing Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02062359
• Other study ID #: 140058
• Secondary ID: 14-C-0058
• Status: Completed
• Phase: Phase 2
• First received: February 12, 2014
• Last updated: February 26, 2016
• Start date: February 2014
• Est. completion date: February 2016

Study information

• Verified date: October 2015
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Background:

The NCI Surgery Branch has developed an experimental therapy for treating patients with melanoma that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying them, and then giving the cells back to the patient. In a previous study, the NCI Surgery Branch used the anti-ESO-1 gene and a type of virus (retrovirus) to make these tumor-fighting cells (anti-ESO-1 cells). About half of the patients who received this treatment experienced shrinking of their tumors. In this study, we are using a slightly different method of producing the anti-ESO-1 cells selected for a specific cell type, which we hope, will be better in making the tumors shrink.

Objectives:

The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their surface can cause melanoma tumors to shrink and to see if this treatment is safe.

Eligibility:

-Adults 18 and older with cancer that has the ESO-1 molecule on tumor surfaces

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

• Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti ESO-1 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 anti-ESO 1 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 take up to 2 days.

Description:

Background:

• A T cell receptor (TCR) that recognizes the NY-ESO-1 (ESO) tumor/testes antigen has been cloned into a retrovirus and can be used to genetically modify human peripheral blood lymphocytes (PBL) so they recognize HLA-A2+, ESO+ tumors

• PBL expressing the anti-ESO TCR have been administered with aldesleukin with or without ALVAC vaccine to 21 patients with melanoma following lymphodepleting chemotherapy at the Surgery Branch, resulting in objective tumor regression (complete or partial regression) in ten patients (47%).

• In animal models using murine cells and in experiments with human T cells in vitro, T cell subsets expressing the lymphoid homing and differentiation marker CD62L, including na(SqrRoot) ve T cells (TNaive), stem cell memory T cells (TSCM), and central memory T cells (TCM), were shown to have superior attributes compared to whole PBL and CD62L- PBL for adoptive cell therapy, including superior persistence following transfer in vivo.

Objectives:

Primary objective:

• To determine whether the administration of anti-ESO TCR engineered CD62L+-derived lymphocytes plus high-dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen can result in an objective regression rate (PR + CR) of melanoma tumors.

Secondary objectives:

• Determine the persistence of genetically engineered, adoptively transferred CD62L+ derived lymphocytes.

• Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are:

• HLA-A*0201 positive

• 18 years of age or older

• Have metastatic melanoma that expresses the ESO antigen

Patients may not have:

• Contraindications for high dose aldesleukin administration.

Design:

• PBMC will be obtained by leukapheresis and will undergo positive selection for CD62L using a CliniMACS magnetic cell separation apparatus to enrich for the less differentiated TNaive, TSCM, and TCM subsets.

• The enriched CD62L+ lymphocytes will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth, then transduced with the anti-ESO TCR.

• All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.

• On day 0 patients will receive anti-ESO TCR gene-transduced CD62L+ -derived lymphocytes and then begin high dose aldesleukin.

• A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks) following the administration of the cell product.

• The primary objective will be efficacy. The study will be conducted using a phase II optimal design (Simon R, Controlled Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low 40% overall response rate (p0=0.40) in favor of an improved response rate of 65% (p1=0.65). This study will initially enroll 11 evaluable patients, and if 0 to 5 of the 11 have a response, then no further patients will be accrued. If 6 or more of the first 11 patients have a response, then accrual would continue until a total of 20 patients have been enrolled. If there were 11 or more responses in 20 patients (55%), this would be sufficiently interesting to warrant further study in later trials. To allow for a very small number of inevaluable patients, the accrual ceiling will be set at 22 patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

-INCLUSION CRITERIA:

1. Measurable metastatic melanoma that expresses ESO as assessed by one of the following methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue, or serum antibody reactive with ESO.

2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of the 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. Willing to sign a durable power of attorney

6. Able to understand and sign the Informed Consent Document

7. Clinical performance status of ECOG 0 or 1

8. Life expectancy of greater than three months

9. Patients must be HLA-A*0201 positive

10. 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

11. 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 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 patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

12. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.

13. 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 100,000/mm(3)

• Hemoglobin > 8.0 g/dl

14. 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.

15. 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 or as specified in the eligibility criteria in Section 2.1.

16. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, toat the time the patient receives the preparative regimen to allow antibody levels to decline.

Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

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. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

4. 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).

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. Documented LVEF of less than or equal to 45%. Testing is required in patients with:

• Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block

• Age greater than or equal to 60 years old

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Metastatic Cancer
• Metastatic Melanoma
• Neoplasm Metastasis

Intervention

Biological:
• Anti-NY ESO-1 TCR CD62L+ cells
Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of anti-NY ESO-1 TCR CD62L+ cells and high dose aldesleukin. On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Drug:
• Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
• Cyclophosphamide
On days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.
• Fludarabine
On days -5 to -1: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	National Institutes of Health Clinical Center (CC)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9571-6. Epub 2005 Jun 24. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determine whether administration of the anti-ESO TCR engineered CD62L+ cells can result in an objective regression of melanoma tumors		approximately 3 years	Yes

External Links

•   NIH Clinical Center Detailed Web Page