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Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Skin Cancer, Metastatic Melanoma

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Trial Information

Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12


Background:

- Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed
a retroviral vector that contains an inducible single chain IL-12 driven by an NFAT
responsive promoter which can be used to mediate transfer of this gene into anti-tumor
lymphocytes. This construct enables the secretion of IL-12 following stimulation of the
T cell receptor.

- Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound
increase in the ability of these lymphocytes to mediate tumor regression following
administration to tumor bearing mice. These cells have a profound advantage in inducing
anti-tumor responses because very few cells are needed and there is no requirement for
the concomitant administration of interleukin-2 (IL-2) as is the case for conventional
cell transfer immunotherapies.

- Based on these murine studies we have now constructed a similar retrovirus that
contains an inducible human single chain IL-12 driven by an NFAT responsive promoter.
This retrovirus can be used to transduce tumor infiltrating lymphocytes (TIL) suitable
for the therapy of patients with metastatic melanoma.

Objectives:

Primary objectives:

- To evaluate the safety of the administration of IL-12 engineered TIL in patients
receiving a non-myeloablative conditioning regimen.

- Determine if the administration of IL-12 engineered TIL to patients following a
non-myeloablative but lymphoid depleting preparative regimen will result in clinical
tumor regression in patients with metastatic cancer.

Secondary objective:

-Determine the in vivo survival of IL-12 gene-engineered cells.

Eligibility:

Patients who are 18 years of age or older must have:

- metastatic melanoma;

- ECOG performance status 0 or 1;

Design:

- TIL will be resected from metastatic deposits and grown in IL-2 using standard
techniques.

- Prior to approval of amendment A, after about 2 weeks TIL will undergo CD8 enrichment
on a Miltenyi column and then undergo a rapid expansion by exposure to OKT-3 an IL-2 in
the presence irradiated feeder cells. Four to five days later, transduction is
initiated by addition of retroviral vector supernatant containing the IL-12 gene.

With approval of amendment A, TIL will not undergo CD8 enrichment. Starting with cohort 5,
after initial growth, TIL undergo a rapid expansion by exposure to OKT-3 and IL-2 in the
presence irradiated feeder cells. Four to five days later, transduction is initiated by
addition of retroviral vector supernatant containing the IL-12 gene.

- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of
IL-12 gene-transduced TIL. Cohorts of 3 patients each will receive increasing cell
doses.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after
treatment. If the patient has SD or tumor shrinkage, repeat complete evaluations will
be performed every 1-3 months. After the first year, patients continuing to respond
will continue to be followed with this evaluation every 3-4 months until off study
criteria are met.

- The study will be conducted using a Phase I/II optimal design. The protocol will
proceed in a phase 1 dose escalation design.

- Prior to approval of amendment A, the protocol enrolled 1 patient in each of the first
3 dose cohorts. Cohort 4 proceeded in a phase 1 dose escalation design, with of n=3.
Should a single patient experience a dose limiting toxicity due to the cell transfer at
a particular dose level, additional patients would be treated at that dose to confirm
that no greater than 1/6 patients have a DLT prior to proceeding to the next higher
level. If a level with 2 or more DLTs in 3-6 patients has been identified, three
additional patients will be accrued at the next- lowest dose, for a total of 6, in
order to further characterize the safety of the maximum tolerated dose.

- With approval of amendment A, no additional patients will be enrolled in cohort 4, and
the protocol will enroll 1 patient in cohort 5 with a dose of 1 X 10(7) bulk young TIL
cells. Cohorts 6-12 will proceeded in a phase 1 dose escalation design, with an n=3.
Should a single patient experience a dose limiting toxicity due to the cell transfer at
a particular dose level, additional patients would be treated at that dose to confirm
that no greater than 1/6 patients have a DLT prior to proceeding to the next higher
level. If a level with 2 or more DLTs in 3-6 patients has been identified, three
additional patients will be accrued at the next-lowest dose, for a total of 6, in order
to further characterize the safety of the maximum tolerated dose prior to starting the
pahse II portion. If a dose limiting toxicity occurs in the cohort 4, that cohort will
be expanded to 6 patients. If 2 DLTs are encountered in this cohort, the study will be
terminated.

- Once the MTD has been determined, the study then would proceed to the phase II portion
using a phase II optimal design where initially 21 evaluable patients will be enrolled.
If 0 or 1 of the 21 patients experiences a clinical response, then no further patients
will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a
clinical response, then accrual will continue until a total of 41 evaluable patients
have been enrolled.

- The objective will be to determine if the combination of lymphocyte depleting
chemotherapy, and IL-12 gene engineered lymphocytes is associated with a clinical
response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate
(p1=0.20).

Inclusion Criteria


- INCLUSION CRITERIA:

- Metastatic melanoma with evaluable disease.

- Greater than or equal to 18 years of age.

- Willing to sign a durable power of attorney

- Able to understand and sign the Informed Consent Document

- Clinical performance status of ECOG 0 or 1

- Life expectancy of greater than three months

- 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 receiving the preparative
regimen.

- 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.

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

- Hematology:

- Absolute neutrophil count greater than 1000/mm(3) without the support of
filgrastim.

- WBC (> 3000/mm(3)).

- Platelet count greater than 100,000/mm(3).

- Hemoglobin greater than 8.0 g/dl.

- Chemistry:

- Serum ALT/AST less 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.

- 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).

EXCLUSION CRITERIA:

- Previous treatment with IL-12.

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

- 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.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- 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).

- Concurrent systemic steroid therapy.

- History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

- 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

- In patients > 60 years old, documented LVEF of less than or equal to 45%.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To evaluate the safety of the administration of IL-12 engineered TIL in patients receiving a non-myeloablative conditioning regimen, and to determine if its administration will result in clinical tumor regression in patients with metastatic canc...

Outcome Time Frame:

3 years

Safety Issue:

No

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110011

NCT ID:

NCT01236573

Start Date:

October 2010

Completion Date:

October 2013

Related Keywords:

  • Skin Cancer
  • Metastatic Melanoma
  • Clinical Response
  • Metastatic Melanoma
  • Immunotherapy
  • Adoptive Cell Therapy
  • Skin Neoplasms
  • Melanoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892