SUPPORT HOTLINE (888) 901-2226
Donate Now

BRIEF TITLE: Phase I-II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01 Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin

A Phase I-II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01 Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin


  • Org Study ID: 140110
  • Secondary ID: 14-C-0110
  • NCT ID: NCT02153905
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Institutes of Health Clinical Center (CC)

Brief Summary

Background: The 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 patient s 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 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 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 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 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:

- 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 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 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% PR + 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.

Overal Status Start Date Phase Study Type
Recruiting July 3, 2014 Phase 1/Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Maximum tolerated cell dose (MTD)

Primary Outcome 1 - Time Frame: Before progression to next-higher dose level

Primary Outcome 2 - Measure: Response Rate

Primary Outcome 2 - Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then PI discretion

Primary Outcome 3 - Measure: Frequency of treatment related adverse events

Primary Outcome 3 - Time Frame: 30 days after end of treatment

Condition:

  • Breast Cancer
  • Cervical Cancer
  • Renal Cancer
  • Melanoma
  • Bladder Cancer

Eligibility

Criteria:
- INCLUSION CRITERIA:

1. Metastatic or locally advanced refractory/recurrent cancer that expresses MAGE-A3
as assessed by one of the following methods: RT-PCR on tumor tissue defined as
30,000 copies of MAGE-A3 per 106 GAPDH copies, or by immunohistochemistry of
resected tissue defined as 10% or greater of tumor cells being 2-3+ for MAGE-A3,
or serum antibody reactive with MAGE-A3. Metastatic cancer diagnosis will be
confirmed by the Laboratory of Pathology at the NCI.

2. Patients must have previously received prior first line standard therapy (or
effective salvage chemotherapy regimens) for their disease, if known to be
effective for that disease, and have been either non-responders (progressive
disease) or have recurred.

3. Patients must be HLA-A*01 positive.

4. Greater than or equal to 18 years of age and less than or equal to age 70.

5. Ability of subject to understand and the willingness to sign the Informed Consent
Document

6. Willing to sign a durable power of attorney

7. Clinical performance status of ECOG 0 or 1

8. 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.

9. 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.

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

11. 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 to 100,000/mm^3

- Hemoglobin > 8.0 g/dl

12. Chemistry:

- Serum ALT/AST less than or equal to to 2.5 times the upper limit of normal

- Serum creatinine less than or equal to to 1.6 mg/dl

- Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with
Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.

13. 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). Patients must have progressing disease after prior treatment. Note:
Patients who have previously received ipilimumab and have documented GI toxicity
must have a normal colonoscopy with normal colonic biopsies

14. Subjects must be co-enrolled in protocol 03-C-0277.

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. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation
disorders or any other active major medical illnesses.

3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
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 any cardiac events including coronary revascularization or ischemic
symptoms.

8. Documented LVEF of less than or equal to 45%; testing is required in patients who are:

- Age greater than or equal to 65 years old

- Clinically significant atrial and or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second or third degree
heart block or have a history of ischemic heart disease, or chest pain.

9. Patients with CNS metastases or symptomatic CNS involvement (including cranial
neuropathies or mass lesions).

10. Patients presenting with lesions that may harbor an occult infectious source.

11. 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

12. Patients who are receiving any other investigational agents.
Show More

Gender: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Healthy Volunteers: No

Official Information

Name: Steven A Rosenberg, M.D.

Role: Principal Investigator

Affiliation: National Cancer Institute (NCI)

Overall Contact

Name: Mary E. Link, R.N.

Phone: (866) 820-4505

Email: IRC@nih.gov

Link: NIH Clinical Center Detailed Web Page

Location

Facility Status Contact
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland 20892
United States
Recruiting For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center
866-820-4505
irc@nih.gov