Metastatic CancerPhase 1/2NCT01273181
MAGE-A3/12 Metastatic Cancer Treatment With Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes
A Phase 1/2 study testing PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Aldesleukin and Cyclophosphamide in people with Metastatic Cancer and Metastatic Renal Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Cancer, Metastatic Renal Cancer, Metastatic Melanoma
- What is being tested?
- PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Aldesleukin and Cyclophosphamide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2010to Dec 2012
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Metastatic cancer that expresses MAGE-A3/12 as assessed by one of the following methods: reverse transcription polymerase chain reaction (RT-PCR) on tumor tissue defined as 30,000 copies of MAGE-A3/12 per 106 GAPDH copies, or by immunohistochemistry of resected tissue defined as 10% or greater of cells being 2-3+, or serum antibody reactive with MAGE-A3/12. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI).
- Patients with melanoma or renal cell cancer must have previously received high dose aldesleukin and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
- 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 Eastern Cooperative Oncology Group (ECOG) 0 or 1.
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- Life expectancy of greater than three months.
- Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
- Patients must be human leukocyte antigen (HLA)-A0201 positive
- Serology:
- Seronegative for human immunodeficiency virus (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 hepatitis C antibody unless antigen negative.
- Hematology:
- Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
- White blood cell (WBC) (> 3000/mm^3).
- Platelet count greater than 100,000/mm^3.
- Hemoglobin greater than 8.0 g/dl.
- Chemistry:
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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).
Who cannot join
- 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.
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- History of coronary revascularization or ischemic symptoms
- Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.
- Documented LVEF of less than or equal to 45% tested in patients with:
- History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
- Age greater than or equal to 60 years old
- Documented forced expiratory volume 1 (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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Phase I/II Study of Metastatic Cancer That Expresses MAGE-A3/12 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes
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.
Read more
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....
Read the 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).
- Being tested
- PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Aldesleukin, Cyclophosphamide, Fludarabine
- Keywords
- Immunotherapy, Gene Therapy, Metastatic Cancer, Clinical Response, Metastatic Melanoma, Metastatic Renal Cell Cancer
- Medical subject headings
- Neoplasm Metastasis, Kidney Neoplasms, Melanoma, Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood LymphocytesBiological
AldesleukinDrug
Also called IL-2
720,000 IU/kg every 8 hours for a maximum of 15 doses
CyclophosphamideDrug
60 mg/kg/day x 2 days intravenous (IV)over 1 hour.
FludarabineDrug
25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.
| Study group | Role | What they receive |
|---|---|---|
| Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9 | Experimental | 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. Receives: Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes; Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine |
| Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10 | Experimental | 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. Receives: Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes; Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine |
| Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 | Experimental | 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. Receives: Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes; Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine |
| Ph II:Anti-MAGE A3/12 TCR PBL MTD | Experimental | 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. Receives: Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes; Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Toxicity Profile
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Measured: 2 years
Clinical Tumor Regression (Complete Response (CR) + Partial Response (PR)) in Patients With Metastatic Cancer
Tumor regression response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2011 (estimated)
- Study startDec 2010
- Primary completionDec 2012
- Study completionDec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Metastatic CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Steven A Rosenberg, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01273181
- Sponsor's protocol ID
- 110062
- Other IDs
- 11-C-0062
- Status last verified
- Oct 2015
- First submitted
- 7 Jan 2011
- Last updated
- 28 Oct 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4. doi: 10.1038/35077246.
PubMed 11357146Berendt MJ, North RJ. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J Exp Med. 1980 Jan 1;151(1):69-80. doi: 10.1084/jem.151.1.69.
PubMed 6444236Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006 May;6(5):383-93. doi: 10.1038/nri1842.
PubMed 16622476Abate-Daga D, Hanada K, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood. 2013 Aug 22;122(8):1399-410. doi: 10.1182/blood-2013-04-495531. Epub 2013 Jul 16.
PubMed 23861247Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, Phan GQ, Hughes MS, Kammula US, Miller AD, Hessman CJ, Stewart AA, Restifo NP, Quezado MM, Alimchandani M, Rosenberg AZ, Nath A, Wang T, Bielekova B, Wuest SC, Akula N, McMahon FJ, Wilde S, Mosetter B, Schendel DJ, Laurencot CM, Rosenberg SA. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013 Feb;36(2):133-51. doi: 10.1097/CJI.0b013e3182829903.
PubMed 23377668
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of Metastatic Cancer That Expresses MAGE-A3/12 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes
- ClinicalTrials.gov ID
- NCT01273181
- Acronym / sponsor ID
- 110062
- Keywords
- Immunotherapy, Gene Therapy, Metastatic Cancer, Clinical Response, Metastatic Melanoma, Metastatic Renal Cell Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 9 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Dec 2010
- Primary completion
- Dec 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 10 Jan 2011 (estimated)
- Results
- Posted 27 Mar 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9 | Experimental | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Drug: Aldesleukin, Drug: Cyclophosphamide, Drug: FludarabineCyclophosphamide : 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. |
| Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10 | Experimental | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Drug: Aldesleukin, Drug: Cyclophosphamide, Drug: FludarabineCyclophosphamide : 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. |
| Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 | Experimental | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Drug: Aldesleukin, Drug: Cyclophosphamide, Drug: FludarabinePhase 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. |
| Ph II:Anti-MAGE A3/12 TCR PBL MTD | Experimental | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Drug: Aldesleukin, Drug: Cyclophosphamide, Drug: FludarabinePhase 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Metastatic cancer that expresses MAGE-A3/12 as assessed by one of the following methods: reverse transcription polymerase chain reaction (RT-PCR) on tumor tissue defined as 30,000 copies of MAGE-A3/12 per 106 GAPDH copies, or by immunohistochemistry of resected tissue defined as 10% or greater of cells being 2-3+, or serum antibody reactive with MAGE-A3/12. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI).
- Patients with melanoma or renal cell cancer must have previously received high dose aldesleukin and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes | Biological | Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10, Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9, Ph II:Anti-MAGE A3/12 TCR PBL MTD, Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 |
| AldesleukinAlso: IL-2720,000 IU/kg every 8 hours for a maximum of 15 doses | Drug | Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10, Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9, Ph II:Anti-MAGE A3/12 TCR PBL MTD, Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 |
| Cyclophosphamide60 mg/kg/day x 2 days intravenous (IV)over 1 hour. | Drug | Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10, Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9, Ph II:Anti-MAGE A3/12 TCR PBL MTD, Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 |
| Fludarabine25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. | Drug | Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10, Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9, Ph II:Anti-MAGE A3/12 TCR PBL MTD, Ph II:Anti-MAGE TCR PBL MTD+HD IL-2 |
Primary outcome
Toxicity Profile
Time frame: 2 years
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Clinical Tumor Regression (Complete Response (CR) + Partial Response (PR)) in Patients With Metastatic Cancer
Time frame: 2 years
Tumor regression response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11357146Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4. doi: 10.1038/35077246.
- Background: PubMed 6444236Berendt MJ, North RJ. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J Exp Med. 1980 Jan 1;151(1):69-80. doi: 10.1084/jem.151.1.69.
- Background: PubMed 16622476Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006 May;6(5):383-93. doi: 10.1038/nri1842.
- Derived from this study: PubMed 23861247Abate-Daga D, Hanada K, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood. 2013 Aug 22;122(8):1399-410. doi: 10.1182/blood-2013-04-495531. Epub 2013 Jul 16.
- Derived from this study: PubMed 23377668Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, Phan GQ, Hughes MS, Kammula US, Miller AD, Hessman CJ, Stewart AA, Restifo NP, Quezado MM, Alimchandani M, Rosenberg AZ, Nath A, Wang T, Bielekova B, Wuest SC, Akula N, McMahon FJ, Wilde S, Mosetter B, Schendel DJ, Laurencot CM, Rosenberg SA. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013 Feb;36(2):133-51. doi: 10.1097/CJI.0b013e3182829903.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven A Rosenberg, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes, Aldesleukin and Cyclophosphamide in people with Metastatic Cancer and Metastatic Renal Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Mar 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Toxicity Profile (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01273181, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2015.