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HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03354390
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : March 6, 2020
Sponsor:
Collaborator:
Loyola University Medical Center (LUMC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE November 23, 2017
First Posted Date  ICMJE November 28, 2017
Last Update Posted Date March 6, 2020
Actual Study Start Date  ICMJE July 20, 2018
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2018)
Toxicity [ Time Frame: 21 days ]
toxicity
Original Primary Outcome Measures  ICMJE
 (submitted: November 25, 2017)
Toxicity [ Time Frame: 21 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2017)
  • overall response rate [ Time Frame: ongoing ]
  • progression-free survival [ Time Frame: ongoing ]
  • overall survival [ Time Frame: ongoing ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma
Official Title  ICMJE A Phase I Study of HERV-E TCR Transduced Autologous T Cells in Patients With Metastatic Clear Cell Renal Cell Carcinoma
Brief Summary

Background:

Gene transfer is a new cancer therapy takes white blood cells from a person and grows them in a lab. The cells are changed with a virus to attack tumor cells, then returned to the person. Researchers want to see if this therapy fights kidney cancer cells.

Objective:

To see if gene transfer is safe and causes tumors to shrink.

Eligibility:

People at least 18 years old with certain kidney cancer

Design:

Participants will be screened with blood and urine tests. They may have:

  • Scans
  • Heart, lung, and eye tests
  • Lab tests
  • Tumor samples taken

Participants will have leukapheresis. Blood will be removed by a needle in an arm. It will go through a machine that removes white blood cells. Plasma and red cells will be returned through a needle in the participant s other arm.

Participants cells will be grown in the lab and genetically changed.

Participants will stay in the hospital 2 3 weeks. There they will:

  • Get 2 chemotherapy drugs by catheter (thin plastic tube) inserted into a vein in the chest.
  • Get the changed cells via catheter.
  • Get a drug to increase white blood cell count and one to make the cells active.
  • Recover for about a week.
  • Have lab and blood tests.

After leaving the hospital, participants will:

  • Take an antibiotic for several months.
  • Have leukapheresis.
  • Have one- or two-day clinic visits every few weeks for 2 years, and then as determined by their doctor. These will include blood and lab tests, imaging studies, and physical exam.

Participants will have follow-up checks for up to 15 years.

Sponsoring Institute: National Heart, Lung, and Blood Institute

...

Detailed Description

Metastatic renal cell carcinoma (RCC) is an incurable condition. Current therapy for this disease consists of the serial administration of agents such as VEGF, mTOR inhibitors and immunotherapy (high-dose (HD) IL-2 or immune-checkpoint inhibitors). Long-term survival can be achieved with high-doses IL-2 or immune-checkpoint inhibitors. However, of those patients treated with immunotherapy, three quarters will not respond at all and only 5-8% will achieve a complete and durable response.

Our team isolated a tumor-specific cytotoxic T lymphocyte (CTL) line from peripheral blood mononuclear cells (PBMCs) obtained after an allogeneic transplant from a patient who showed prolonged tumor regression. Using limiting dilution cloning, we identified an allogeneic (derived from the stem cell donor) CD8+ T-cell clone that killed ccRCC cells in an HLA A11 restricted fashion. Using cDNA expression cloning, we identified a HERV-E derived antigen expressed in the patient s ccRCC cells to be the target of this T-cell clone. Remarkably, we found this HERV-E was expressed in the majority of ccRCC cells with no expression in normal tissues. Based on the identification of the antigenicity of the HERV-E transcripts in ccRCC, our team in collaboration with Dr. Nishimura s laboratory (Loyola University Cardinal Bernardin Cancer Center) has cloned, expressed and characterized the TCR from this CD8+ T-cell clone that recognizes an HLA A11 restricted HERV-E antigen.

This research protocol is therefore designed to evaluate the safety and effectiveness of infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells in HLA-A*11:01 positive patients with metastatic clear cell RCC. Subjects will receive a novel non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide and fludarabine followed by an infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells. To mediate T cell survival and sustain function, moderate-doses of IL-2 (aldesleukin) will be administered intravenously twice a day for 14 doses.

The primary endpoint is safety by day 21. Secondary endpoints will include overall response rate, progressionfree survival and overall survival. We will also evaluate for the persistence of circulating HERV-E TCR transduced CD8+/CD34+ enriched T cells, changes in immune cell subsets and activation status of T cells, as well as, other immunologic determinants with clinical outcomes at baseline, at different time points during treatment and at the time of disease progression.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Cancer
Intervention  ICMJE Biological: cell infusion
This is a single-arm, phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLAA* 11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.
Study Arms  ICMJE
  • Experimental: 1
    1 x 10e6 HERV-E TCR transduced CD8/CD34 cells per kg body weight
    Intervention: Biological: cell infusion
  • Experimental: 2
    5 x 10e6 HERV-E TCR transduced CD8/CD34 cells per kg body weight
    Intervention: Biological: cell infusion
  • Experimental: 3
    1 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight
    Intervention: Biological: cell infusion
  • Experimental: 4
    5 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight
    Intervention: Biological: cell infusion
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 25, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed RCC with clear-cell component by the Laboratory of Pathology of 43T the NIH prior to entering this study.
  • Patients must be HLA-A 11:01 positive (confirmed by HLA typing at the NIH DTM)
  • Patients must have measurable disease and have disease progression during or after the last treatment regimen and within 6 months before study enrollment
  • Patients must have received at least one antiangiogenic drug and an immune-checkpoint inhibitor (i.e. nivolumab) unless the patient has contraindications to receiving these medications, the agents are not available to the patient, or the patient declines to receive these drugs due to personal preference.
  • Patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 180 days (female patients) or 90 days (male patients) after the end of the treatment if sexually active and able to bear or beget children. In addition, male patients must refrain from sperm donation for 90 days after the final dose of investigational product. Female patients must refrain from egg cell donation for 180 days after the final dose of investigational product
  • Patients must be between the ages of 18 and 70 years.
  • Patient must have an anticipated life expectancy of at least 3 months.
  • Patients must have a performance status of 0 or 1 ECOG performance status (PS) scale.
  • Patients must have a caregiver willing to stay with them during the first month of treatment (30 days +/- 7 days).
  • Patients receiving treatment with bisphosphonates or denosumab are eligible for enrollment if on a stable dose for greater than or equal to 4 weeks
  • Serology:

    • 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 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.
  • Organ Function

    • Hematology
    • Absolute neutrophil count greater than or equal to 500/ microL
    • WBC greater than or equal to 1500/microL
    • Platelet count greater than or equal to 75.000/microL (without transfusional support
    • Chemistry
    • Serum AST/ALT less than or equal to 2.5 x upper limit of normal (ULN)
    • Total bilirubin less than or equal to 1.5 mg/dl except for patients with Gilbert s syndrome who must have a total bilirubin less than or equal to 3 mg/dl
    • Calculated creatinine clearance by the method of CKI-EPI greater than or equal to 50 ml/min/1.73m2
    • INR < 1.5
    • Cardiology
    • Estimated left ventricular ejection fraction by echocardiography greater than or equal to 45%
    • Respiratory
    • Predicted DLCO / Alveolar Volume Adjusted by PFT > 45%
  • Patients must have the ability to provide written informed consent prior to study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time.

EXCLUSION CRITERIA:

  • Patients that require immediate therapy due to tumor mass effects or spinal cord compression.
  • Patients must not have had standard of care anti-VEGFR therapy (mean half-life around 30 hours), mTOR inhibitors (mean half-life around 30 hours), radiotherapy, or major surgery within the last 2 weeks prior to T-cell infusion. For PD-1/PD-L1 inhibitors or CTLA-4 inhibitors, a 4-week period must have elapsed before T-cell infusion. For recent experimental therapies a 28-day period must have elapsed before infusing expanded T-cells.
  • Patients with active CNS involvement by malignancy either by imaging or cerebrospinal fluid involvement or biopsy-proven (due to poor prognosis and potential for neurological dysfunction that would confound evaluation of neurological and other adverse events) except for:

    1. Patients with 3 or fewer brain metasteses of <1cm treated with either stereotactic or gamma knife radiotherapy and remained stable on MRI for 2 weeks are eligible.
    2. Patients with surgically resected brain metastases and no evidence of active disease in the CNS at the time of screening evaluation are eligible.
  • Patients with hypercalcemia (>10 mg/dL) of malignancy.
  • Any prior Grade (Bullet) 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA4 treatment that requires long-term immunosuppressive therapy. Note: Active or history of vitiligo or hypothyroidism will not be a basis for exclusion.
  • Patients with second malignancies in addition to their clear cell RCC are not eligible if the second malignancy has required systemic treatment within the past 4 years or is not in complete remission. There are exceptions to this criterion: successfully treated non-metastatic basal cell, squamous cell skin carcinoma, in situ non-invasive cervical cancer and in situ non-invasive breast cancer.
  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  • Active coagulation disorders or other major uncontrolled medical illnesses of the respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, uncontrolled systemic infection, active obstructive or restrictive pulmonary disease.
  • Patients who have recent history of cerebrovascular accident, transient ischemic attack should be cleared by the neurology consult service before enrolling this study.
  • Patients who have recent history of coronary artery disease or cardiac arrhythmia should be cleared by the cardiology consult service before enrolling this study.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus erythematosus that requires treatment with chronic immunosuppressive therapy.
  • Systemic corticosteroid steroid therapy of any dose is not allowed within 2 days prior to enrollment.

The following are exceptions to this criterion:

  • Intranasal, inhaled, and topical steroids
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent

    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

In the case of short-term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required washout period prior to starting the leukapheresis is 7 days.

  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Unable to understand the investigational nature of the study or give informed consent and does not have a legally authorized representative or surrogate that can provide informed consent.
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kristen E Wood (Gunn), R.N. (301) 827-2977 kristen.gunn@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03354390
Other Study ID Numbers  ICMJE 180012
18-H-0012
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Loyola University Medical Center (LUMC)
Investigators  ICMJE
Principal Investigator: Richard W Childs, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 3, 2020

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