T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-DP0401 Positive

Phase 1

Completed

• Conditions: Melanoma; Cervical Cancer; Breast Cancer; Renal Cancer; Urothelial Cancer
• Interventions: Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL); Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin

• Registration Number: NCT02111850
• 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 metastatic 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 patient s white blood cells with a retrovirus that has the gene for anti-Melanoma antigen family A, 3 (MAGE-A3)-DP0401/0402 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-DP0401/0402 cells) cause tumors to shrink and to be certain the treatment is safe.

Eligibility:

- Adult's age 18-70 with metastatic 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-DP0401/0402 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-DP0401/0402 cells and aldesleukin. They will stay in the hospital for approximately 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.

Detailed Description

Background:

* We have constructed a single retroviral vector that contains both and $ \<= chains of a T cell receptor (TCR) that recognizes the DP0401/0402 restricted Melanoma antigen family A, 3 (MAGE-A3) tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.

* In co-cultures with HLA-DP0401/0402 and MAGE-A3 double positive tumors, the anti- MAGE-A3- DP0401/0402 restricted (anti-MAGE-A3-DP4) TCR transduced T cells secreted significant amounts of Interferon gamma (IFN-y) with high specificity.

Objectives:

Primary objectives:

* Determine a safe dose of the administration of autologous cluster of differentiation 4 (CD4) cells transduced with an anti-MAGE-A3-DP0401/0402 restricted (MAGE-A3-DP4) 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-DP4.

* Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are human leukocyte antigens (HLA)-DP0401/0402 positive and 18 years of age or older must have

* Metastatic cancer whose tumors express the MAGE-A3-DP4 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:

* PBMC obtained by leukapheresis will be enriched for CD4 cells and transduced with the retroviral vector supernatant encoding the anti-MAGE-A3-DP4 TCR.

* The study will begin in a standard phase 1 dose escalation. After the maximum tolerated dose (MTD) cell dose has been determined, patients will be enrolled into the phase 2 portion of the trial at the MTD established during the phase 1 portion of the study. In the phase 2 portion, patients will be entered into two cohorts: cohort 1 will include patients with metastatic melanoma; cohort 2 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 peripheral blood mononuclear cells (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 2 strata evaluated in the phase 2 portion, the study will be conducted using a phase 2 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 modest 20% partial response (PR) + complete response (CR) rate (p1=0.20).

Study Timeline

• Study Start: 2014-02-07
• Study First Submitted: 2014-04-09
• Study First Submitted QC: 2014-04-09
• Study First Posted: 2014-04-11
• Primary Completion: 2021-03-24
• Study Completion: 2021-03-24
• Results First Submitted: 2021-12-28
• Status Verified: 2022-03
• Results First Submitted QC: 2022-03-02
• Last Update Submitted: 2022-03-02
• Results First Posted: 2022-03-29
• Last Update Posted: 2022-03-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1/Phase I Experimental Therapy	Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL)	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
2/Phase II Experimental Therapy	Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL)	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
1/Phase I Experimental Therapy	Fludarabine	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
1/Phase I Experimental Therapy	Cyclophosphamide	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
2/Phase II Experimental Therapy	Cyclophosphamide	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
2/Phase II Experimental Therapy	Fludarabine	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
1/Phase I Experimental Therapy	Aldesleukin	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin
2/Phase II Experimental Therapy	Aldesleukin	Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Primary Outcome Measures

Name	Time	Method
Number of Adverse Events With Grades ≥1 That Are Possibly, Probably, and/or Definitely Related to Treatment	6 weeks after cell infusion	Aggregate of all adverse events with Grades ≥1 that are possibly, probably, and/or definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events.
Maximum Tolerated Cell Dose (MTD) of Cluster of Differentiation 4 (CD4) Cells Transduced With an Anti-MAGE-A3-DP0401/0402 Restricted (MAGE-A3-DP4) T Cell Receptor and Aldesleukin	Before progression to next-higher dose level, at least two weeks	Highest dose at which less than or equal to 1 of 6 patients experienced a dose-limiting toxicity (DLT) (all grade 3 and greater toxicities with the exception of myelosuppression and grade 3 fever, for example) or the highest dose level studied if DLTs are not observed at any of the dose levels.
Percentage of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression)	6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per principal investigator discretion, approximately 6 years	Percentage of participants who have a clinical response to treatment (objective tumor regression) measured by 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 of target lesions. Progression is at least a 20% increase in the sum of longest diameter of target lesions or the appearance of one or more new lesions. And stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

Secondary Outcome Measures

Name	Time	Method
Number of Engineered T Cell Receptor (TCR) Cells That Survived at 4 Weeks	4 weeks	T cell receptor (TCR) and vector presence was quantitated in peripheral blood mononuclear cells (PBMC) samples using flow cytometry. It is a process by which cells are suspended in a liquid so they can be counted.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike; 🇺🇸 Bethesda, Maryland, United States