T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 Positive
- Conditions
- Cervical CancerMelanomaBreast CancerBladder CancerRenal Cancer
- Interventions
- Biological: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)
- Registration Number
- NCT02153905
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-MAGE-A3 incorporated in the retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-MAGE A3 cells) cause tumors to shrink and to be certain the treatment is safe
Eligibility:
- Adults age 18-66 with cancer expressing the MAGE-A3 molecule.
Design:
* Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (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 MAGE-A3 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 MAGE-A3 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.
- 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 human leukocyte antigen serotype within HLA-A "A" serotype group (HLA-A 01) restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
* In co-cultures with human leukocyte antigen serotype within HLA-A A serotype group (HLA-A 01) and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01 restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of Interferon (IFN)- \>= with high specificity.
Objectives:
Primary objectives:
* Determine a safe dose of administration of autologous T cells transduced with an anti- MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) TCR and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen.
* Determine if this approach will result in objective tumor regression in patients with metastatic cancer expressing MAGE-A3.
* Determine the toxicity profile of this treatment regimen.
Eligibility:
Patients who are HLA-A 01 positive and 18 years of age or older must have
* Metastatic cancer whose tumors express the MAGE-A3 antigen
* Previously received and have been a non-responder to or recurred following at least one first line treatment for metastatic disease
Patients may not have:
- Contraindications for high dose aldesleukin administration.
Design:
* Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be transduced with the retroviral vector supernatant encoding the anti-MAGE-A3 HLA-A 01-restricted TCR.
* The study will begin with a phase I dose escalation. After the maximum tolerated dose (MTD) cell dose has been determined, patients will be enrolled into the phase II portion of the trial at the MTD established during the phase I portion of the study. In the phase II portion, patients will be entered into two cohorts: cohort 2a will include patients with metastatic melanoma; cohort 2b will include patients with renal cancer and 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 PBMC plus intravenous (IV) aldesleukin.
* Patients will undergo complete evaluation of tumor response every 1-6 months until off study criteria are met.
* For each of the two 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 treatment regimen is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modes 20% partial response (PR) + complete response (CR) rate (p1=0.20).
* In order to complete the dose escalation phase and both phase II cohorts, a total of up to 20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up to 6 patients enrolled at the MTD will count towards the accrual in the appropriate phase II strata if they are evaluable for response and if they would be fully eligible for enrollment in the phase II portion of the trial. Provided that about 4-5 patients per month will be able to be enrolled onto this trial, approximately 2 to 3 years may be needed to accrue the maximum number of required patients.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 3
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1 - Dose Escalation/De-Escalation Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR) Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase II - Maximum Tolerated Dose Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR) Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase 1 - Dose Escalation/De-Escalation Fludarabine Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase II - Maximum Tolerated Dose Cyclophosphamide Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase 1 - Dose Escalation/De-Escalation Cyclophosphamide Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase II - Maximum Tolerated Dose Fludarabine Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase 1 - Dose Escalation/De-Escalation Aldesleukin Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin Phase II - Maximum Tolerated Dose Aldesleukin Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
- Primary Outcome Measures
Name Time Method Number of Treatment Related Adverse Events Related to T-Cell Receptor (TCR) Gene-Engineered Cells Date treatment consent signed to end of treatment, approximately 30 days Aggregate of all Grade ≥3 adverse events and their frequency possibly, probably or definitely related to the research. Adverse Events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL). Grade 4 is life-threatening consequences; urgent intervention indicated. Grade 5 is death related to adverse event.
Number of Participants With Serious and Non-Serious Adverse Events Date treatment consent signed to date off study, approximately 53 days for the Anti-MAGE-A3 A1 TCR PBL 1x10^9 Cells + Interleukin-2 (IL-2) Arm/Group, and 1 year and 4 months for the Anti-MAGE-A3 A1 TCR PBL 1x10^8 Cells + Interleukin-2 (IL-2) Arm/Group. Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Number of Patients With Objective Tumor Regression 6 and 12 weeks after cell infusion on up to 2 years Objective tumor regression is defined as the number of participants with a complete or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Maximum Tolerated Cell Dose (MTD) Within 30 days of study cell infusion, before progression to next-higher dose level Highest dose at which less than or equal to 1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels. DLT is defined as follows: Grade 3-5 allergic reactions related to the study cell infusion. Grade 3 and greater autoimmune reactions. Grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study cell infusion and does not resolve within 72 hours. Treatment-related death within 8 weeks of the study cell infusion.
- Secondary Outcome Measures
Name Time Method In Vivo Survival of T-Cell Receptor (TCR) Cells Up to 3 years after study cell infusion In vivo survival of gene-engineered lymphocytes derived from the infused cells will be analyzed by tetramer analysis and staining for the T-cell receptor (TCR). Tetramer analysis is measured by % of peripheral blood.
Number of Participants With Dose-Limiting Toxicity (DLT) Within 30 days of study cell infusion DLT is defined as follows: Grade 3-5 allergic reactions related to the study cell infusion. Grade 3 and greater autoimmune reactions. Grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study cell infusion and does not resolve within 72 hours. Treatment-related death within 8 weeks of the study cell infusion.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States