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Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers

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ClinicalTrials.gov Identifier: NCT02830724
Recruitment Status : Recruiting
First Posted : July 13, 2016
Last Update Posted : April 26, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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
Pancreatic Cancer Renal Cell Cancer Breast Cancer Melanoma Ovarian Cancer Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Biological: Anti-hCD70 CAR transduced PBL Phase 1 Phase 2

Detailed Description:

Background:

  • 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.
  • 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:

  • 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).
  • Phase II: Determine if anti-hCD70 CAR-transduced PBL can mediate the regression of CD70 expressing tumors.

Eligibility:

  • Patients must be/have:

    • Age greater than or equal to 18 years and less than or equal to 70 years
    • CD70-expressing tumors
    • Measurable metastatic disease that has progressed after standard therapy
  • Patients may not have:

    • Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or fludarabine.

Design:

  • This is a phase I/II, single center study of PBL transduced with anti-hCD70 CAR in patients with measurable, unresectable cancer expressing CD70.
  • PBMC obtained by leukapheresis 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 these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-hCD70 CAR.
  • All patients will receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine.
  • On day 0, patients will receive PBL transduced with the anti-hCD70 CAR and will then begin high-dose aldesleukin.
  • A complete evaluation of lesions will be conducted approximately 4-6 weeks after treatment.
  • The study will be conducted using a Phase I/II optimal design, with two separate cohorts for the Phase II component: Cohort 1 - clear cell renal cell carcinoma (RCC): Cohort 2 - non-RCC malignancies (solid tumors only).
  • A total of up to 113 patients may be required; approximately 27 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 113 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to Patients With CD70 Expressing Cancers
Actual Study Start Date : April 6, 2017
Estimated Primary Completion Date : January 1, 2027
Estimated Study Completion Date : January 1, 2028


Arm Intervention/treatment
Experimental: 1/Phase I
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-hCD70 CAR transduced PBL + high-dose aldesleukin
Drug: Cyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W infused simultaneously with Mesna 15 mg/kg /day over 1 hr x 2 days.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.

Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight 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.

Experimental: 2/Phase II
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-hCD70 CAR transduced PBL + high-dose aldesleukin
Drug: Cyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W infused simultaneously with Mesna 15 mg/kg /day over 1 hr x 2 days.

Drug: Fludarabine
Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.

Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight 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.




Primary Outcome Measures :
  1. Maximum tolerated cell dose (MTD) [ Time Frame: Before progression to next-higer dose level ]
    Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels

  2. Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. In vivo survival of anti-hCD70 CAR transduced cells [ Time Frame: 3 and 6 months, and 1 year post cell administration ]
    CAR and vector presence will be quantitated in PBMC samples using established PCR techniques

  2. Frequency and severity of treatment-related adverse events [ Time Frame: 5 years following cell infusion ]
    Aggregate of all adverse events, as well as their frequency and severity



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Measurable, unresectable cancer expressing CD70 as assessed by immunohistochemistry of resected tissue (> 2+ CD70 positive on > 50% of cancer cells, or >1+ CD70 positive on >75% of cancer cells).
  • Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
  • 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.
  • 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.
  • Age greater than or equal to 18 years and less than or equal to 70 years.
  • Clinical performance status of ECOG 0 or 1
  • 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.
  • Serology

    • 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

  • ANC 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. Subjects may be transfused to reach this cut-off.

    -Chemistry

  • Serum ALT/AST less than or equal to 2.5 times ULN
  • 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 or equal to 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). 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.

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

  • Ability of subject to understand and the willingness to sign a written informed consent document.
  • Willing to sign a durable power of attorney.
  • 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:

  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  • Concurrent systemic steroid therapy.
  • Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • History of major organ autoimmune 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).
  • History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
  • History of coronary revascularization or ischemic symptoms.
  • Documented LVEF less than or equal to 45% tested in patients:

    • Age greater than or equal to 65 years
    • With 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 and/or chest pain.
    • Who have had prior treatment with significant exposure to anthracyclines or cyclophosphamide.
  • Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history, with cessation within the past 2 years).
    • Symptoms of respiratory dysfunction
  • Patients who are receiving any other investigational agents.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02830724


Contacts
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Contact: Mary E. Link, R.N. (866) 820-4505 IRC@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James C Yang, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02830724     History of Changes
Other Study ID Numbers: 160131
16-C-0131
First Posted: July 13, 2016    Key Record Dates
Last Update Posted: April 26, 2019
Last Verified: March 20, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Metastatic Solid Cancers
Renal Cell Cancer
Cell Therapy
CAR T Cells

Additional relevant MeSH terms:
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Pancreatic Neoplasms
Carcinoma, Renal Cell
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action