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Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer

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ClinicalTrials.gov Identifier: NCT03412877
Recruitment Status : Recruiting
First Posted : January 29, 2018
Last Update Posted : June 21, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

In gene transfer therapy, cells are taken from a person s tumor to isolate mutations. White blood cells are then taken from the person's body, changed with a type of virus to attack the tumor cells, and returned to the person.

Objective:

To see if gene transfer therapy shrinks tumors.

Eligibility:

People with certain metastatic cancer for which standard treatments have not worked

Design:

Participants will complete screening and stages 1-3 under another protocol. Screening includes:

Undergoing a biopsy or surgery at the NIH to obtain pieces of tumor in order to grow tumor cells

Medical history

Physical exam

Scans

Blood, urine, heart, and lung tests

The study has 7 stages:

  1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. An IV catheter will be placed in the chest.
  2. Care at home over 6-12 weeks.
  3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
  4. Hospital stay for 1 week to get chemotherapy by IV.
  5. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
  6. Recover in the hospital for 1 2 weeks. Participants will get drugs and have blood and urine tests.
  7. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined.


Condition or disease Intervention/treatment Phase
Glioblastoma Non-Small Cell Lung Cancer Ovarian Cancer Breast Cancer Gastrointestinal/Genitourinary Cancer Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Biological: Individual Patient TCR-Transduced PBL Phase 2

Expanded Access : National Cancer Institute (NCI) has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer
Estimated Study Start Date : June 26, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : March 23, 2028


Arm Intervention/treatment
Experimental: 1-Experimental Therapy
non-myeloablative lymphocyte depleting chemotherapy regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high or low-dose aldesleukin
Drug: Cyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W with mesna 15 mg/kg/day over 1 hour x 2 days.

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

Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses). Patients in cohort 3 may receive 72,000 IU/kg IV.

Biological: Individual Patient TCR-Transduced PBL
Day 0: Cells will be infused at a dose not to exceed 1.5E11 in 400 mL intravenously over 20-30 minutes or as clinically determined by an investigator for patient safety via non-filtered tubing, gently agitating the bag during infusion to prevent cell clumping.




Primary Outcome Measures :
  1. Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment



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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 solid cancer with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured that falls into one of four cohorts:

    1. gastrointestinal and genitourinary cancers
    2. breast and ovarian, and other solid cancers
    3. non-small cell lung cancer (NSCLC)
    4. glioblastoma

      • Note: Metastatic disease is required for cohorts 1-3, but not required for cohort 4.
      • Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas. Neuroendocrine tumors are not eligible.
  • Refractory to approved standard systemic therapy. Specifically:

    • Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan.
    • Patients with breast and ovarian cancer must be refractory to both 1st line and 2nd line treatments.
    • Patients with NSCLC must have received at least one platinum-based chemotherapy regimen and at least one FDA approved targeted treatment (when appropriate).
    • Patients with glioblastoma must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered NED). This includes recurrent GBM after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy.
  • For cohorts 1-3, patients with 3 or fewer brain metastases that are less than 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.
  • For cohorts 1-3, clinical performance status of ECOG 0 or 1.
  • For cohort 4, (glioblastoma), patients must have Karnofsky performance status of greater than or equal to 60.
  • For cohort 4 only (glioblastoma), patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • Age greater than or equal to 18 years and less than or equal to 70 years.
  • Willing to sign a durable power of attorney.
  • Patients of both genders must be willing to practice birth control during treatment and for four months after treatment.
  • Able to understand and sign a written informed consent document.
  • 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 may be less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for active hepatitis B, 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:

    • Absolute neutrophil count > 1000/mm^3 without support of filgrastim
    • Normal WBC (> 3000/mm^3).
    • Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.
    • Platelet count > 100,000/mm^3
  • Chemistry:

    • Serum ALT/AST < 5.0 x ULN
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • 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 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. Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to grade 1 or less.
  • For cohort 3, more than two weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding at the time the patient receives the preparative regimen, and patient s toxicities must have recovered to a grade 1 or less.
  • For cohort 4, patients must be at least four weeks from radiation therapy. Additionally, patients must be at least six weeks from nitrosoureas, four weeks from temozolomide, three weeks from procarbazine, two weeks from vincristine and four weeks from last bevacizumab administration. Patients must be at least four weeks from other cytotoxic therapies not listed above and two weeks for non-cytotoxic agents (e.g., interferon) including investigative agents.
  • Subjects must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

  • Women of child-bearing potential who are pregnant or breastfeeding because of the potential effects of the treatment on the fetus or infant.
  • Systemic steroid therapy required, except for patients with glioblastoma (cohort 4).
  • Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active or uncompensated major medical illnesses.
  • For cohort 3, any major bronchial occlusion or bleeding not amenable to palliation.
  • For cohort 4, clinically significant hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; however, patients with a history of prior intratumoral bleeding, will need to undergo a non-contrast head CT to exclude acute bleeding.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  • 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.
  • Any patient known to have an LVEF less than or equal to 45%.
  • 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
  • Clinically significant patient history which in the judgment of the PI would compromise the patients' ability to tolerate high-dose aldesleukin. (Note: At the discretion of the PI, patients enrolled in cohort 3 may receive low-dose aldesleukin.)
  • Documented FEV1 less than or equal to 50% predicted tested in patients with:

    • A prolonged history of cigarette smoking (approximately 20 packs/year within the past two 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): NCT03412877


Contacts
Contact: Ellen Bodurian (866) 820-4505 IRC@nih.gov

Locations
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
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03412877     History of Changes
Other Study ID Numbers: 180049
18-C-0049
First Posted: January 29, 2018    Key Record Dates
Last Update Posted: June 21, 2018
Last Verified: April 4, 2018

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) ):
Gene Therapy
Immunotherapy
Cell Therapy
Adoptive Cell Therapy

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Glioblastoma
Neoplasm Metastasis
Urogenital Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplastic Processes
Pathologic Processes
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs