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

NCT03412877 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: 18004918-C-0049
• Study Type: interventional
• Target: 285
• Locations: 1 country
• Sites: 1

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:
• 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.
• Care at home over approximately 12 weeks.
• Stopping therapy for 4-6 weeks while their cells are changed in a lab.
• Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in the chest to administer drugs.
• 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.
• Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
• Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and urine tests.
• 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.

Conditions

Endocrine Tumors; Non-Small Cell Lung Cancer; Ovarian Cancer; Breast Cancer; Gastrointestinal/Genitourinary Cancers; Neuroendocrine Tumors; Multiple Myeloma

Keywords

Gene Therapy; Immunotherapy; Cell Therapy; Adoptive Cell Therapy

Outcome Measures

Primary Outcomes (1)

• Response rate

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

  6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion

Secondary Outcomes (1)

• Safety and tolerance

  6 weeks ( 2 weeks) following administration of the cell product or 30 days following the last dose of pembrolizumab

Study Arms (2)

1/iTCR

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high- or low-dose aldesleukin

Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin; Biological: Individual Patient TCR-Transduced PBL

2/iTCR + Pembro

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Aldesleukin; Biological: Individual Patient TCR-Transduced PBL; Drug: Pembrolizumab (KEYTRUDA(R))

Interventions

Cyclophosphamide DRUG

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.

1/iTCR; 2/iTCR + Pembro

Fludarabine DRUG

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

1/iTCR; 2/iTCR + Pembro

Aldesleukin DRUG

Aldesleukin 720,000 IU/kg IV (based on total body weight) 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.

1/iTCR; 2/iTCR + Pembro

Individual Patient TCR-Transduced PBL BIOLOGICAL

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).

1/iTCR; 2/iTCR + Pembro

Pembrolizumab (KEYTRUDA(R)) DRUG

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

2/iTCR + Pembro

Eligibility Criteria

• Age: 18 Years - 72 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Metastatic, solid cancer that can be measured, and falls into one of five cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); (4) endocrine tumors including neuroendocrine tumors; and, (5) multiple myeloma that includes measurable solid tumors (plasmacytomas). Participants with multiple myeloma are potentially eligible only if they have measurable multiple myeloma as defined in Section 16.7 after plasmacytoma resection.
• Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinomas.
• Documented diagnosis of cancer.
• 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 first- line treatment and refractory to or have refused 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 endocrine tumors including neuroendocrine tumors must be refractory to first-line therapy (e.g., lanreotide, octreotide) and must be refractory or have refused second-line treatments such as everolimus, sunitinib, or 177 Lu-Dotatate, if indicated.
• Participants with multiple myeloma must have received at least four prior lines of therapy that included at least one exposure to an immunomodulatory drug such as lenalidomide, a proteosome inhibitor, an anti-CD38 antibody treatment, and an autologous stem cell transplant.
• Participants with three (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 72 years.
• Clinical performance status of ECOG 0 or 1.
• Participants of both sexes must be willing to practice birth control from the time of enrollment on this study and for and 12 months after the last dose of combined chemotherapy for individuals of child-bearing potential (IOCBP) and four months after treatment for participants who can father a child.
• Individuals 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.
• NOTE: Certain malignancies may secrete hormones that produce false positive pregnancy tests. Serial blood testing (e.g. HCG measurements) and/ or ultrasound may be performed for clarification.

You may not qualify if:

• Participants who are pregnant or nursing 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).
• History of major organ autoimmune disease.
• 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, 4. or 5: 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (7)

• Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641-5. doi: 10.1126/science.1251102.

  PMID: 24812403 BACKGROUND

• Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C, Davis L, Dudley ME, Yang JC, Samuels Y, Rosenberg SA, Robbins PF. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014 Jul 1;20(13):3401-10. doi: 10.1158/1078-0432.CCR-14-0433.

  PMID: 24987109 BACKGROUND

• Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E, Samuels Y, Rosenberg SA. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013 Jun;19(6):747-52. doi: 10.1038/nm.3161. Epub 2013 May 5.

  PMID: 23644516 BACKGROUND

• Parkhurst M, Goff SL, Lowery FJ, Beyer RK, Halas H, Robbins PF, Prickett TD, Gartner JJ, Sindiri S, Krishna S, Zacharakis N, Ngo L, Ray S, Bera A, Shepherd R, Levin N, Kim SP, Copeland A, Nah S, Levi S, Parikh N, Kwong MLM, Klemen ND, Yang JC, Rosenberg SA. Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results. Nat Med. 2024 Sep;30(9):2586-2595. doi: 10.1038/s41591-024-03109-0. Epub 2024 Jul 11.

  PMID: 38992129 DERIVED

• Levin N, Kim SP, Marquardt CA, Vale NR, Yu Z, Sindiri S, Gartner JJ, Parkhurst M, Krishna S, Lowery FJ, Zacharakis N, Levy L, Prickett TD, Benzine T, Ray S, Masi RV, Gasmi B, Li Y, Islam R, Bera A, Goff SL, Robbins PF, Rosenberg SA. Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes. J Immunother Cancer. 2024 May 30;12(5):e008645. doi: 10.1136/jitc-2023-008645.

  PMID: 38816232 DERIVED

• Kooragayala K, Lou J, Hong YK. Current State of Cell Therapies for Gastrointestinal Cancers. Cancer J. 2022 Jul-Aug 01;28(4):310-321. doi: 10.1097/PPO.0000000000000611.

  PMID: 35880941 DERIVED

• Levy PL, Gros A. Fast track to personalized TCR T cell therapies. Cancer Cell. 2022 May 9;40(5):447-449. doi: 10.1016/j.ccell.2022.04.013. Epub 2022 May 9.

  PMID: 35537408 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Ovarian Neoplasms; Breast Neoplasms; Urogenital Neoplasms; Neuroendocrine Tumors; Multiple Myeloma

Interventions

Cyclophosphamide; fludarabine; aldesleukin; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Male Urogenital Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NCI SB Immunotherapy Recruitment Center

CONTACT

(866) 820-4505; IRC@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2018
• First Posted: January 29, 2018
• Study Start: September 6, 2018
• Primary Completion (Estimated): March 23, 2027
• Study Completion (Estimated): March 23, 2028
• Last Updated: April 24, 2026

Record last verified: 2026-03-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be 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.

Locations

US (1)