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Treating Cancer With Anti-mesothelin Modified Lymphocytes

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 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: August 29, 2014
Last verified: August 2014

April 20, 2012
August 29, 2014
March 2012
March 2019   (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
 
Treating Cancer With Anti-mesothelin Modified Lymphocytes
Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes

Background:

- A possible new procedure for treating people with advanced cancer uses blood cells known as peripheral blood cells. Once these cells are modified and grown in a laboratory, they can be used to target and destroy cancer cells. Some cells can be modified to target a protein called mesothelin that is found on some types of cancer cells. By blocking mesothelin, it is expected that these cells will help shrink existing tumors. However, it is possible that the cells will not have this effect. Researchers want to try this therapy on people who have advanced cancer that has not responded to standard treatments.

Objectives:

- To test the safety and effectiveness of anti-mesothelin modified cells for advanced cancer.

Eligibility:

- Individuals at greater than or equal to 18 years of age and less than or equal to 66 years of age with advanced cancer that involves mesothelin and has not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam and medical history. They will also have imaging studies before starting treatment. Blood and urine samples will be collected.
  • Participants will have leukapheresis to collect peripheral blood cells. These cells will be modified for the treatment.
  • Participants will have chemotherapy to prepare the immune system to receive the modified cells. The chemotherapy will take place for 1 week before the cell infusion.
  • Participants will receive their modified cells as an infusion. They will also receive interleukin-2 to help boost their immune system response. The interleukin-2 will be given every 8 hours for up to 15 doses.
  • Participants will recover from the infusion treatment in the hospital for at least 2 weeks.
  • The results of the treatment will be monitored with frequent follow-up blood tests and imaging studies.

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
March 2019   (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 66 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)
August 2014

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