Description:
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.
Title
- Brief Title: Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers
- 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
Clinical Trial IDs
- ORG STUDY ID:
160131
- SECONDARY ID:
16-C-0131
- NCT ID:
NCT02830724
Conditions
- Pancreatic Cancer
- Renal Cell Cancer
- Breast Cancer
- Melanoma
- Ovarian Cancer
Interventions
Drug | Synonyms | Arms |
---|
Cyclophosphamide | | 1/Phase I |
Fludarabine | | 1/Phase I |
Aldesleukin | | 1/Phase I |
Anti-hCD70 CAR transduced PBL | | 1/Phase I |
Purpose
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.
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:
--Metastatic or unresectable CD70-expressing cancer which 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 6 weeks (plus or minus
two 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 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).
- 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.
Trial Arms
Name | Type | Description | Interventions |
---|
1/Phase I | Experimental | Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-hCD70 CAR transduced PBL + high-dose aldesleukin | - Cyclophosphamide
- Fludarabine
- Aldesleukin
- Anti-hCD70 CAR transduced PBL
|
2/Phase II | Experimental | Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-hCD70 CAR transduced PBL + high-dose aldesleukin | - Cyclophosphamide
- Fludarabine
- Aldesleukin
- Anti-hCD70 CAR transduced PBL
|
Eligibility Criteria
- INCLUSION CRITERIA:
- 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).
- 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).
- 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 5.0 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 3.0 mg/dL.
- More than four weeks must have elapsed since completion of 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.
- 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.
Maximum Eligible Age: | 70 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Frequency and severity of treatment-related adverse events |
Time Frame: | From time of cell infusion to two weeks after cell infusion |
Safety Issue: | |
Description: | 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 |
Secondary Outcome Measures
Measure: | Frequency and severity of treatment-related adverse events |
Time Frame: | 6 weeks ( plus or minus 2 weeks) following administration of the cell product |
Safety Issue: | |
Description: | Aggregate of all adverse events, as well as their frequency and severity |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Suspended |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Metastatic Solid Cancers
- Renal Cell Cancer
- Cell Therapy
- CAR T Cells
Last Updated
January 29, 2021