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CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01583686
First received: April 20, 2012
Last updated: January 23, 2015
Last verified: December 2014

April 20, 2012
January 23, 2015
March 2012
December 2018   (final data collection date for primary outcome measure)
Determine a safe dose of administration and determine if this approach will result in an objective tumor regression. [ Time Frame: approximately 6 years ] [ Designated as safety issue: Yes ]
  • Determine if anti-mesothelin CAR engineered PBL and aldesleukin to patients following the protocol regimen will result in clinical tumor regression.
  • Evaluate safety of anti-mesothelin CAR engineered PBL in patients receiving the protocol regimen.
Complete list of historical versions of study NCT01583686 on ClinicalTrials.gov Archive Site
Not Provided
Determine the in vivo survival of CAR gene engineered cells.
Not Provided
Not Provided
 
CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer
Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes

Background:

The 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-mesothelin 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 tumor fighting cells (anti-mesothelin cells) cause metastatic cancer tumors to shrink.

Eligibility:

- Adults age 18-70 with metastatic cancer expressing the mesothelin 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-mesothelin 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-mesothelin 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 will take up to 2 days.

...

Background:

  • We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this CAR with high efficiency (> 50%) without the need to perform any selection.
  • In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells secreted significant amounts of IFN-gamma with high specificity.

Objectives:

Primary Objectives:

  • To evaluate the safety of the administration of anti-mesothelin CAR engineered peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning regimen, and aldesleukin.
  • Determine if the administration anti-mesothelin CAR 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.

Secondary Objective:

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

Eligibility:

Patients who are 18 years of age or older must have

  • Metastatic or unresectable cancer that expresses mesothelin;
  • Previously received and have been a non-responder to or recurred after standard care;

Patients may not have:

-Contraindications for low dose aldesleukin administration.

Design:

  • PBMC obtained by leukapheresis will be cultured in order to stimulate T-cell growth.
  • Transduction is initiated by exposure of approximately 108 to 5 X 108 cells to retroviral vector supernatant containing the anti-mesothelin CAR.
  • Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo CAR gene-transduced PBMC plus low dose IV aldesleukin
  • Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has 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.
  • The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design. Once the MTD has been determined, the study then would proceed to the phase II portion. Patients will be entered into two cohorts based on histology: cohort 1 will include patients with mesothelioma, and cohort 2 will include patients with other types of cancer that express mesothelin.
  • For each of the 2 strata evaluated, 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.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Metastatic Cancer
  • Pancreatic Cancer
  • Mesothelioma
  • Ovarian
  • Drug: Fludarabine
    Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
  • Biological: Anti-mesothelin CAR
    Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-mesothelin CAR engineered PBL. On day 0, cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).
  • Drug: Cycolphosphamide
    Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
  • Drug: Aldesleukin
    Aldesleukin (based on total body weight) 72,000 IU/kg IV over a period of 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
Experimental: Single Arm
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-mesothelin CAR engineered PBL plus low dose IV aldesleukin.
Interventions:
  • Drug: Fludarabine
  • Biological: Anti-mesothelin CAR
  • Drug: Cycolphosphamide
  • Drug: Aldesleukin

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
136
December 2019
December 2018   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:

    1. Metastatic or unresectable measurable cancers that express mesothelin. As in other protocols conducted by Dr. Hassan in the NCI, epitheial mesotheliomas and pancreatic cancers do not need to be assessed for mesothelin expression since all of these tumors have been shown to express mesothelin. Other metastatic or unresectable cancers must be shown to expresses mesothelin as assessed by RT-PCR or immunohistochemistry on tumor tissue. Bi-phasic mesotheliomas must express mesothelin on greater than 50% of the cells in the epithelial component. Diagnosis will be confirmed by the Laboratory of Pathology, NCI.
    2. Patients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
    3. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
    4. Willing to sign a durable power of attorney
    5. Able to understand and sign the Informed Consent Document
    6. Clinical performance status of ECOG 0 or 1.
    7. Life expectancy of greater than three months.
    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:

      1. 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 immunecompetence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
      2. 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:

      1. Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim.
      2. WBC (> 3000/mm(3)).
      3. Platelet count greater than 100,000/mm(3).
      4. Hemoglobin greater than 8.0 g/dl.
    12. Chemistry:

      1. Serum ALT/AST less or equal to 2.5 times the upper limit of normal.
      2. Serum creatinine less than or equal to 1.6 mg/dl.
      3. 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.
    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).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

EXCLUSION CRITERIA:

  1. Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of mesothelioma.
  2. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  3. Patients with known brain metastases.
  4. Patients receiving full dose anticoagulative therapy.
  5. 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.
  6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  7. 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).
  8. Patients with diabetic retinopathy.
  9. Concurrent Systemic steroid therapy.
  10. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  11. History of coronary revascularization or ischemic symptoms.
  12. Documented LVEF of less than or equal to 45% tested in patients with:

    • 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
Both
18 Years to 70 Years
No
Contact: June Kryk, R.N. (301) 451-1929 ncisbirc@mail.nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.nih.gov
United States
 
NCT01583686
120111, 12-C-0111
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP