Non-Viral TCR Gene Therapy
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|ClinicalTrials.gov Identifier: NCT04102436|
Recruitment Status : Recruiting
First Posted : September 25, 2019
Last Update Posted : June 2, 2023
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A person s white blood cells can be modified in a lab to recognize certain changes in their tumor. Many of these cells are collected from the person, modified, then given back to the person. This may help treat some cancers.
To learn if a person s white blood cells modified with T-cell receptors can cause solid tumors to shrink.
People ages 18-70 who have cancer of the gastrointestinal tract, genitourinary tract, ovary, breast, or lung that has spread, or who have glioblastoma.
Participants will be screened and have their cells prepared for treatment in another protocol.
Participants will be hospitalized one week before treatment. They will stay approximately 3 - 4 weeks after treatment.
Participants will get the modified white blood cells and chemotherapy through an IV catheter, which is a small plastic tube inserted in a vein.
Participants will take drugs by mouth to prevent infection. They will receive filgrastim as a shot or injection under the skin.
Participants will have tests before, during, and after treatment:
Heart, blood, and urine tests
Scans: They will lie in a machine that takes pictures of the body.
Possible apheresis: The participant s blood is removed through a needle in an arm. The blood goes through a machine that removes the white blood cells. The rest of the blood is returned through a needle in the other arm.
Participants will have visits about 6 and 12 weeks after treatment. If they are responding to treatment, they will then have visits every 3-6 months for 3 years. Then they will join another study and be followed about 12 more years.
|Condition or disease||Intervention/treatment||Phase|
|Endocrine/Neuroendocrine Non-Small Cell Lung Cancer Breast Cancer Gastrointestinal/Genitourinary Cancers Ovarian Cancer||Drug: Fludarabine Drug: Cyclophosphamide Drug: Aldesleukin Biological: Sleeping Beauty Transposed PBL||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||210 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study Using the Administration of Autologous T-Cells Engineered Using the Sleeping Beauty Transposon/Transposase System to Express T-Cell Receptors Reactive Against Mutated Neoantigens in Patients With Metastatic Cancer|
|Estimated Study Start Date :||June 7, 2023|
|Estimated Primary Completion Date :||December 31, 2028|
|Estimated Study Completion Date :||December 31, 2029|
Experimental: 1/Sleeping Beauty
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.
Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
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 hour x 2 days.
Aldesleukin 720,000 IU/kg or 72,000 IU/kg (based on total body weight) 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).
Biological: Sleeping Beauty Transposed PBL
Day 0: Cells are to be infused at a dose not to exceed 1.5e11 in 400 mL intravenously on the Patient Care Unit over 20-30 minutes or as clinically determined by an investigator for patient safety (between 2-4 days after the last dose of fludarabine).
- 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 (objective tumor regression)
- Phenotypic and functional characteristics of PBL [ Time Frame: 2-4 years post cell infusion ]Patient PBL will be obtained from whole blood and then evaluated for function and phenotype.
- Safety and tolerance [ Time Frame: 6 weeks (+/- 2 weeks) following administration of the cell product ]Using standard CTCAE 5.0
- Immune monitoring [ Time Frame: 6 weeks (+/-2 weeks) following administration of the cell product ]Will consist of quantifying T-cells reactive with HLA-matched tumor cells using established techniques such as intracellular FACS, cytokine release assays, and ELISpot assays.
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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|
- INCLUSION CRITERIA:
Patients with histologically confirmed solid cancer that falls into one of four cohorts:
- Gastrointestinal and genitourinary (Cohort 1),
- Breast and ovarian (Cohort 2),
- Non-small cell lung cancer (NSCLC), NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas (Cohort 3),
- Glioblastoma (Cohort 4)
- Patients must have evaluable or measurable disease per RECIST 1.1 with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured. Metastatic disease is required for Cohorts 1-3 but is not required for Cohort 4.
Patients must have:
previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred, specifically:
- Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan (or similar agents)
- Patients with breast and ovarian cancer must be refractory to first-line treatments
- Patients with lung cancer 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. OR
- declined standard treatment
- For Cohorts 1-3: Patients with 3 or fewer brain metastases that are < 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
- For Cohort 3: Patients must have documented FEV1 > 60% predicted.
- Age greater than or equal to 18 years and less than or equal to 70 years.
- For Cohorts 1-3: Clinical performance status of ECOG 0 or 1.
- For Cohort 4: Patients must have Karnofsky performance status of greater than or equal to 60.
- The effects of study treatment on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at time of study entry, for the duration of treatment and up to 4 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- 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.
- ANC > 1,000/mm^3 without the support of filgrastim
- WBC greater than or equal to 3,000/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.
- Serum ALTlAST less than or equal to 5.0 x ULN
- Serum creatinine less than or equal to 1.6 mgldL
- Total bilirubin less than or equal to 1.5 mg/dL, except in patients with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL.
- More than four weeks must have elapsed since completion of any prior systemic therapy and enrollment.
Note: Patients may have undergone minor surgical procedures or limited field radiotherapy (with the exception of patients with glioblastoma) within the four weeks before enrollment, as long as any related major organ toxicities have recovered to less than or equal to grade 1.
- For Cohort 3: More than two weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding and enrollment, and patient s toxicities must have recovered to less than or equal to grade 1.
- 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. Patient s toxicities must have recovered to less than or equal to grade 1.
- 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 protocol 03-C-0277.
- Pregnant women are excluded from this study because study treatment s potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated on this trial.
- Concurrent systemic steroid therapy, 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 six months that were not related to glioma surgery.
Note: 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).
- 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.
Documented FEVl less than or equal to 50% predicted tested in patients with:
- A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history within the past two years).
- Symptoms of respiratory dysfunction.
- Clinically significant patient history which in the judgment of the Principal Investigator (PI) would compromise the patients ability to tolerate high-dose aldesleukin.
- Patients who are receiving any other investigational agents.
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): NCT04102436
|Contact: NCI/Surgery Branch Recruitment Center||(866) firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator:||Steven A Rosenberg, M.D.||National Cancer Institute (NCI)|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
|First Posted:||September 25, 2019 Key Record Dates|
|Last Update Posted:||June 2, 2023|
|Last Verified:||May 5, 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||.All IPD recorded in the medical record will be shared with intramural investigators upon request.|
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
|Time Frame:||Clinical data available during the study and indefinitely.|
|Access Criteria:||Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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