Clinical trial NCT01273181
Conditions: Metastatic Cancer Metastatic Renal Cancer Metastatic Melanoma
Keywords: Immunotherapy Gene Therapy Metastatic Cancer Clinical Response Metastatic Melanoma Metastatic Renal Cell Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2010-12-01; Completion date: 2012-12-01
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- MAGE-A3/12 is a type of protein commonly found on certain types of cancer cells, particularly in metastatic cancer. Researchers have developed a process to take lymphocytes (white blood cells) from cancer patients, modify them in the laboratory to target cancer cells that contain MAGE-A3/12, and return them to the patient to help attack and kill the cancer cells. These modified white blood cells are an experimental treatment, but researchers are interested in determining their safety and effectiveness as a possible treatment for cancers that involve MAGE-A3/12.

Objectives:

\- To evaluate the safety and effectiveness of anti-MAGE-A3/12 lymphocytes as a treatment for metastatic cancers that have not responded to standard treatment.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with metastatic melanoma, renal cell cancer, or another type of metastatic cancer that has not responded to standard treatment.

Design:

* Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, tumor samples, and imaging studies.
* Participants will have leukapheresis to collect enough white blood cells for modification in the laboratory.
* Seven days before the start of anti-MAGE-A3/12 treatment, participants will have chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the treatment.
* After the last dose of chemotherapy, participants will receive the anti-MAGE-A3/12 cells as an infusion for 20 to 30 minutes, followed by a dose of interleukin-2 to keep the anti-MAGE-A3/12 cells alive and active as long as possible. Participants will also receive filgrastim to encourage the production of blood cells.
* Participants will remain in the hospital to be monitored for possible side effects, and after release from the hospital will have regular followup exams with blood samples and imaging studies to evaluate the effectiveness of the treatment....

Detailed description:
Background

We have constructed a single retroviral vector that contains both alpha and beta chains of a T cell receptor (TCR) that recognizes the MAGE-A3/12 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency (\> 30%) without the need to perform any selection.

In co-cultures with human leukocyte antigen serotype within HLA-A serotype group (HLA-A2) and MAGE-A3/12 double positive tumors, anti-MAGE-A3/12 TCR transduced T cells secreted significant amounts of Interferon (IFN)-gamma with high specificity.

Objectives:

Primary objectives:

* Determine if the administration of anti-MAGE-A3/12 engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer that expresses the MAGE-A3/12 antigen.
* Determine the toxicity profile of this treatment regimen

Secondary objectives:

-Determine the in vivo survival of TCR gene-engineered cells.

Eligibility:

Patients who are human leukocyte antigen (HLA)-A\*0201 positive and 18 years of age or older must have:

* metastatic cancer whose tumors express the MAGE-A3/12 antigen;
* previously received and have been a non-responder to or recurred following standard care for metastatic disease;

Patients may not have:

-contraindications for high dose aldesleukin administration.

Design:

PBMC obtained by leukapheresis (approximately 10\^10) cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.

Transduction is initiated by exposure of approximately 10\^7 to 5 X 10\^8 cells to retroviral vector supernatant containing the anti-MAGE-A3/12 TCR genes.

The study will begin by evaluating the safety of two ranges of cells, 5 x 10\^9 - 3 x 10\^10, and greater than 3 x 10\^10- 1 x 10\^11 in a standard phase I dose escalation fashion using a 3+3 design. Once this safety has been confirmed, patients will be enrolled into the phase 2 portion of the trial using up to 1 x 10\^11 cells. In the phase 2 portion, patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer.

Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced peripheral blood mononuclear cells (PBMC) plus intravenous (IV) aldesleukin (720,000 IU/kg every (q)8h for a maximum of 15 doses).

Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (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.

For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, 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 in that stratum.

For both strata, the objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-MAGE-A3/12 TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% partial response (PR) + complete response (CR) rate (p1=0.20).

Arms: arm 1: Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10\^9-3x10\^10, and greater than 3x10\^10-1x10\^11 in a standard phase I dose escalation fashion using a 3+3 design. arm 2: Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10\^9-3x10\^10, and greater than 3x10\^10-1x10\^11 in a standard phase I dose escalation fashion using a 3+3 design. arm 3: Phase II:Anti-MAGE A3/12 TCR PBL MTD + HD IL-2, Melanoma, RCC

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer. arm 4: Phase II: Anti-MAGE A3/12 TCR PBL MTD + HD-IL2 Other Cancer

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer.
Interventions: intervention 1: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes intervention 2: Aldesleukin intervention 3: Cyclophosphamide intervention 4: Fludarabine
Intervention descriptions: intervention 1: None intervention 2: 720,000 IU/kg every 8 hours for a maximum of 15 doses intervention 3: 60 mg/kg/day x 2 days intravenous (IV)over 1 hour. intervention 4: 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Protocol documents: