Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers
Study Details
Study Description
Brief Summary
Background:
In a new cancer therapy, researchers take a person s blood, select a certain white blood cell to grow in the lab, and then change the genes of these cells using a virus. The cells are then given back to the person. This is called gene transfer. For this study, researchers will modify the person s white blood cells with anti-CD70.
Objectives:
To see if a gene transfer with anti-CD70 cells can safely shrink tumors and to be certain the treatment is safe.
Eligibility:
Adults age 18 and older diagnosed with cancer that has the CD70-expressing cancer.
Design:
Participants will be screened with medical history, physical exam, scans, and other tests. They may by admitted to the hospital. Leukapheresis will be performed. For this, blood is removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm.
Eligible participants will have an intravenous catheter placed in their upper chest. Over several days, they will get chemotherapy drugs and the anti-CD70 cells. They will recover in the hospital.
Participants will take an antibiotic for 6 months after treatment. They will repeat leukapheresis.
Participants will visit the clinic every 1-3 months for the first year after treatment, every 6 months for the second year, and then as determined by their physician. Follow-up visits will take 1-2 days. At each visit, participants will have lab tests, imaging studies, and a physical exam.
Throughout the study, blood will be taken and participants will have many tests to determine the size and extent of their tumor and the treatment s impact.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
Background:
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We generated a chimeric antigen receptor (CAR) that engages CD70 using its natural ligand CD27, as the binding moiety. Transducing peripheral blood lymphocytes (PBL) with this CAR conveys major histocompatibility complex (MHC)-independent recognition of CD70-expressing target cells, which include renal cell carcinoma and other cancers.
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In co-cultures with CD70+ target cells, anti-hCD70 CAR transduced T cells secrete significant amounts of IFN-gamma with high specificity.
Objectives:
Primary objectives:
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Phase I: Determine the safety of administering PBL transduced with anti-hCD70 CAR in concert with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin).
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Phase II: Determine if anti-hCD70 CAR-transduced PBL can mediate the regression of CD70 expressing tumors.
Eligibility:
- Patients must be/have:
--Metastatic or unresectable CD70-expressing cancer which has progressed after standard therapy
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Patients may not have:
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Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or fludarabine.
Design:
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This is a phase I/II, single center study of PBL transduced with anti-hCD70 CAR in patients with measurable, unresectable cancer expressing CD70.
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PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
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Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-hCD70 CAR.
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All patients will receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine.
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On day 0, patients will receive PBL transduced with the anti-hCD70 CAR and will then begin high-dose aldesleukin.
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A complete evaluation of lesions will be conducted approximately 6 weeks (plus or minus two weeks) after treatment.
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The study will be conducted using a Phase I/II optimal design, with two separate cohorts for the Phase II component:Cohort 2a, patients with CD70-expressing clear cell renal cell carcinoma (RCC), and Cohort 2b, patients with a CD70-expressing non-RCC malignancy (solid tumors only).
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A total of up to 124 patients may be required; approximately 38 patients in the Phase I portion of the study and 43 (41, plus an allowance of up to 2 non-evaluable) patients in each cohort of the Phase II portion of the study.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: 1/Phase I Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-hCD70 CAR transduced PBL + high-dose aldesleukin |
Drug: Cyclophosphamide
For Phase I, Days -7 and -6:
Dose Level 1: 15 mg/kg/day x 2 days IV Dose Level 2: 15 mg/kg/day x 2 days IV Dose Level 3: 15 mg/kg/day x 2 days IV Dose Level 4: 15 mg/kg/day x 2 days IV Dose Level 5: 30 mg/kg/day x 2 days IV Dose Level 6: 60 mg/kg/day x 2 days IV
For Phase II, Days -7 and -6:
60 mg/kg/day x 2 days IV
Drug: Fludarabine
For Phase I, Days -7 to -5:
Dose Level 1: 25 mg/m(2)/day x 3 days IVPB Dose Level 2: 25 mg/m(2)/day x 3 days IVPB Dose Level 3: 25 mg/m(2)/day x 3 days IVPB Dose Level 4: 25 mg/m(2)/day x 3 days IVPB Dose Level 5: 25 mg/m(2)/day x 5 days IVPB Dose Level 6: 25 mg/m(2)/day x 5 days IVPB
For Phase II, Days -7 to -3:
25 mg/m(2)/day x 5 days IVPB
Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).
Biological: Anti-hCD70 CAR transduced PBL
Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes (2-5 days after the last dose of fludarabine).
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Experimental: 2/Phase II Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-hCD70 CAR transduced PBL + high-dose aldesleukin |
Drug: Cyclophosphamide
For Phase I, Days -7 and -6:
Dose Level 1: 15 mg/kg/day x 2 days IV Dose Level 2: 15 mg/kg/day x 2 days IV Dose Level 3: 15 mg/kg/day x 2 days IV Dose Level 4: 15 mg/kg/day x 2 days IV Dose Level 5: 30 mg/kg/day x 2 days IV Dose Level 6: 60 mg/kg/day x 2 days IV
For Phase II, Days -7 and -6:
60 mg/kg/day x 2 days IV
Drug: Fludarabine
For Phase I, Days -7 to -5:
Dose Level 1: 25 mg/m(2)/day x 3 days IVPB Dose Level 2: 25 mg/m(2)/day x 3 days IVPB Dose Level 3: 25 mg/m(2)/day x 3 days IVPB Dose Level 4: 25 mg/m(2)/day x 3 days IVPB Dose Level 5: 25 mg/m(2)/day x 5 days IVPB Dose Level 6: 25 mg/m(2)/day x 5 days IVPB
For Phase II, Days -7 to -3:
25 mg/m(2)/day x 5 days IVPB
Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).
Biological: Anti-hCD70 CAR transduced PBL
Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes (2-5 days after the last dose of fludarabine).
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Outcome Measures
Primary Outcome Measures
- Frequency and severity of treatment-related adverse events [From time of cell infusion to two weeks after cell infusion]
Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT
- Response rate [6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion]
Percentage of patients who have a clinical response (PR+CR) to treatment (objective tumor regression)
Secondary Outcome Measures
- Frequency and severity of treatment-related adverse events [6 weeks ( plus or minus 2 weeks) following administration of the cell product]
Aggregate of all adverse events, as well as their frequency and severity
Eligibility Criteria
Criteria
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INCLUSION CRITERIA:
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For Phase I: Evaluable, unresectable cancer expressing CD70 as assessed by immunohistochemistry of resected tissue (greater than or equal to 2+ CD70 positive on greater than or equal to 50% of cancer cells, or greater than or equal to 1+ CD70 positive on greater than or equal to 75% of cancer cells).
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For Phase II: Measurable (per RECIST v1.1 criteria), unresectable cancer expressing CD70 as assessed by immunohistochemistry of resected tissue (greater than or equal to 2+ CD70 positive on greater than or equal to 50% of cancer cells, or greater than or equal to 1+ CD70 positive on greater than or equal to 75% of cancer cells).
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Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
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Patients must have previously received at least one standard therapy for their cancer (if available) and have been either non-responders (progressive disease) or have recurred.
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Patients with 3 or fewer brain metastases that are less than or equal to 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
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Age greater than or equal to 18 years and less than or equal to 70 years.
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Clinical performance status of ECOG 0 or 1
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Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
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Women of child-bearing potential must be willing to undergo a pregnancy test prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.
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Serology
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Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may 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.
-Hematology
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ANC greater than 1000/mm(3) without the support of filgrastim
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WBC greater than or equal to 2500/mm(3)
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Platelet count greater than or equal to 80,000/mm(3)
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Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.
-Chemistry
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Serum ALT/AST less than or equal to 5.0 times ULN
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Serum creatinine less than or equal to 1.6 mg/dL
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Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dL.
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Patients must have completed any prior systemic therapy at the time of enrollment.
Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks prior to enrollment, as long as related major organ toxicities have recovered to grade 1 or less.
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Ability of subject to understand and the willingness to sign a written informed consent document.
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Willing to sign a durable power of attorney.
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Subjects must be co-enrolled on the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).
EXCLUSION CRITERIA:
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Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
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Concurrent systemic steroid therapy.
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Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
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Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
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History of major organ autoimmune disease.
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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).
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History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
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History of coronary revascularization or ischemic symptoms.
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For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
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For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50% predicted.
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Patients who are receiving any other investigational agents.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | National Institutes of Health Clinical Center | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: James C Yang, M.D., National Cancer Institute (NCI)
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Bowman MR, Crimmins MA, Yetz-Aldape J, Kriz R, Kelleher K, Herrmann S. The cloning of CD70 and its identification as the ligand for CD27. J Immunol. 1994 Feb 15;152(4):1756-61.
- Diegmann J, Junker K, Gerstmayer B, Bosio A, Hindermann W, Rosenhahn J, von Eggeling F. Identification of CD70 as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling, real-time RT-PCR and immunohistochemistry. Eur J Cancer. 2005 Aug;41(12):1794-801.
- Jilaveanu LB, Sznol J, Aziz SA, Duchen D, Kluger HM, Camp RL. CD70 expression patterns in renal cell carcinoma. Hum Pathol. 2012 Sep;43(9):1394-9. doi: 10.1016/j.humpath.2011.10.014. Epub 2012 Mar 7.
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