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

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ClinicalTrials.gov Identifier: NCT03412877
Recruitment Status : Suspended ((suspension))
First Posted : January 29, 2018
Last Update Posted : January 29, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

A person s tumor is studied for mutations. When cells are found that can attack the mutation in a person s tumor, the genes from those cells are studied to find the parts that make the attack possible. White blood cells are then taken from the person s body, and the gene transfer occurs in a laboratory. A type of virus is used to transfer the genes that make those white blood cells able to attack the mutation in the tumor. The gene transfer therapy is the return of those white blood cells back to the person.

Objective:

To see if gene transfer therapy of white blood cells can shrink tumors.

Eligibility:

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

Design:

Participants may complete screening under another protocol. Screening includes:

  • Getting tumor cells from a previous procedure
  • Medical history
  • Physical exam
  • Scans
  • Blood, urine, heart, and lung tests

The study has 8 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.
  2. Care at home over approximately 12 weeks.
  3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
  4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in the chest to administer drugs.
  5. Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the hospital. Three additional doses will be given after the cell infusion 3 weeks apart.
  6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
  7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and urine tests.
  8. 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
Endocrine Tumors Non-Small Cell Lung Cancer Ovarian Cancer Breast Cancer Gastrointestinal/Genitourinary Cancer Neuroendocrine Tumors Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Biological: Individual Patient TCR-Transduced PBL Drug: Pembrolizumab (KEYTRUDA ) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Using the Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer
Actual Study Start Date : September 6, 2018
Estimated Primary Completion Date : March 23, 2027
Estimated Study Completion Date : March 23, 2028


Arm Intervention/treatment
Experimental: 1/iTCR
Non-myeloablative lymphocyte depleting preparative 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 infused simultaneously 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 intravenously on the Patient Care Unit over 20-30 minutes (2-4 days after the last dose of fludarabine)..

Experimental: 2/iTCR + Pembro
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCRTransduced PBL + high- or low-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeksfollowing cell infusion
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 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 intravenously on the Patient Care Unit over 20-30 minutes (2-4 days after the last dose of fludarabine)..

Drug: Pembrolizumab (KEYTRUDA )
Arm 2: Pembrolizumab 2 mg /kg IV over approximately 30 minutes on Days -2, 21, 42, and 63.




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 receive pembrolizumab as part of the treatment regimen that have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. Safety and tolerance [ Time Frame: 6 weeks ( 2 weeks) following administration of the cell product or 30 days following the last dose of pembrolizumab ]
    Using standard CTCAE 5.0



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:
  • Metastatic, solid cancer that can be measured, that falls into one of four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) endocrine tumors including neuroendocrine tumors.

Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinomas.

  • Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology.
  • Refractory to approved standard systemic therapy. Specifically:

    • Participants with metastatic colorectal cancer must have received oxaliplatin or irinotecan.
    • Participants with breast and ovarian cancer must be refractory to both first- and second- line treatments.
    • Participants with NSCLC must have received at least one platinum-based chemotherapy regimen and at least one FDA-approved targeted treatment (when appropriate).
  • Participants 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 participant to be eligible. Participants 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.
  • Participants of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  • Women of child-bearing potential must be willing to undergo a pregnancy test prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.
  • Serology:

    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants 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 participant must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  • Hematology:

    • ANC > 1000/mm^3 without the support of filgrastim
    • WBC greater than or equal to 2500/mm^3
    • Platelet count greater than or equal to 80,000/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 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 participants with Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0 mg/dl.
  • Participants must have completed any prior systemic therapy at the time of enrollment.

Note: Participants 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.

  • 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.
  • 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.

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.

For Cohort 3: Any major bronchial occlusion or bleeding not amenable to palliation.

  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  • For Arm 2: History of major organ autoimmune disease.

Note: Participants with a history of major organ autoimmune disease may be enrolled on Arm 1 if all other eligibility criteria are met.

-For Arm 2: Grade 3 or 4 major organ irAEs following treatment with anti-PD-1/PD-L1, including but not limited to myocarditis and pneumonitis.

Note: Participants with grade 3 or 4 major organ irAEs may be enrolled on Arm 1 if all other eligibility criteria are met.

  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants 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.
  • For Cohorts 1, 2, or 4: Clinically significant participant history which in the judgment of the Principal Investigator (PI) would compromise the participants ability to tolerate high-dose aldesleukin.

Note: At the discretion of the PI, participants enrolled in Cohort 3 may receive low-dose aldesleukin.

  • History of coronary revascularization or ischemic symptoms.
  • For select participants with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
  • For select participants with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50% predicted.
  • Participants 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


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
Additional Information:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03412877    
Other Study ID Numbers: 180049
18-C-0049
First Posted: January 29, 2018    Key Record Dates
Last Update Posted: January 29, 2021
Last Verified: January 2021

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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) ):
Gene Therapy
Immunotherapy
Cell Therapy
Adoptive Cell Therapy
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neoplasm Metastasis
Endocrine Gland Neoplasms
Urogenital Neoplasms
Neoplasms
Neoplasms by Site
Endocrine System Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplastic Processes
Pathologic Processes
Aldesleukin
Cyclophosphamide
Pembrolizumab
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents