Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations in Conjunction With a Vaccine Directed Against These Antigens in Participants With Metastatic Cancer

NCT06253520 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001662001662-C
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Many cancer cells produce substances called antigens that are unique to each cancer. These antigens stimulate the body s immune responses. One approach to treating these cancers is to take disease-fighting white blood cells from a person, change those cells so they will target the specific proteins (called antigens) from the cancer cells, and return them to that person s blood. The use of the white blood cells in this manner is one form of gene therapy. A vaccine may help these modified white cells work better. Objective: To test a cancer treatment that uses a person s own modified white blood cells along with a vaccine that targets a specific protein. Eligibility: Adults aged 18 to 72 years with certain solid tumors that have spread after treatment. Design: Participants will undergo leukapheresis: Blood is removed from the body through a tube attached to a needle inserted into a vein. The blood passes through a machine that separates out the white blood cells. The remaining blood is returned to the body through a second needle. Participants will stay in the hospital for 3 or 4 weeks. They will take chemotherapy drugs for 1 week to prepare for the treatment. Then their modified white cells will be infused through a needle in the arm. They will take other drugs to prevent infections after the infusion. The vaccine is injected into a muscle; participants will receive their first dose of the vaccine on the same day as their cell infusion. Participants will have follow-up visits 4, 8, and 12 weeks after the cell infusions. They will receive 2 or 3 additional doses of the boost vaccine during these visits. Follow-up will continue for 5 years, but participants will need to stay in touch with the gene therapy team for 15 years. ...

Conditions

Metastatic Solid Cancers; Colorectal Cancer; Breast Cancer; Non-Small Cell Lung Cancer; Gastrointestinal Cancer; Ovarian Cancer; Genitourinary Cancer

Keywords

KRAS Mutations; Gene Therapy; Cell Therapy; Immunotherapy; Vaccine

Outcome Measures

Primary Outcomes (2)

• Complete response (CR) and/ or partial response (PR)

  Clinical response rate (\[PR+CR\]/evaluable participants) will be determined and reported along with the corresponding 95% two-sided confidence interval.

  Response assessed at 4, 8, 12 and 20 weeks post-cell infusion, every 3 months x3, every 6 months x 2 years

• Safety

  Safety and tolerability will be analyzed by reporting the number of patients experiencing toxicity, classified by type and grade to the experimental regimen. Adverse events assessed per CTCAE version 5.

  All adverse Events (AE) per CTCAE v5.0, by type and grade of toxicity, from first dose through 4 weeks after the last treatment

Secondary Outcomes (1)

• Safety

  From study treatment initiation up to 4 weeks after the last study treatment

Study Arms (1)

1/ KRAS TCR + vaccine

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + KRAS TCR-Transduced PBL + high-dose aldesleukin + vaccine (Day 0, weeks 4 and 8 and at week 12 (if no progression)

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: KRAS TCR-Transduced PBL; Biological: GRT-C903/GRT-R904

Interventions

Aldesleukin DRUG

Aldesleukin 600,000 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/ KRAS TCR + vaccine

Fludarabine DRUG

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

1/ KRAS TCR + vaccine

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/ KRAS TCR + vaccine

KRAS TCR-Transduced PBL BIOLOGICAL

Day 0: Cells will be infused intravenously (IV) over 20-30 minutes (2-4 days after the last dose of fludarabine).

1/ KRAS TCR + vaccine

GRT-C903/GRT-R904 BIOLOGICAL

Day 0 (GRT-C903): Injection of 1.0 mL at each of 2 bilateral vaccine injections. Weeks 4, 8 and 12 (as applicable, GRT-R904): Injection of 0.25 mL of diluted GRT-R904 at each of 2 bilateral vaccine injections

1/ KRAS TCR + vaccine

Eligibility Criteria

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

You may qualify if:

• Participants with an appropriate HLA match for available Surgery Branch KRAS TCRs with evaluable metastatic solid cancer (e.g., gastrointestinal, genitourinary, breast, ovarian, non-small cell lung cancer (NSCLC) and other solid cancers) with known KRAS G12V or G12D mutation.
• Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology.
• Refractory to standard systemic therapy. Specifically:
• Participants with metastatic colorectal cancer must have received oxaliplatin and/or irinotecan.
• Participants with breast and ovarian cancer must have received at least two systemic 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 other solid tumors must have received at least one prior line of systemic treatment or have declined standard treatment.
• Participants with three (3) or fewer brain metastases that are \< 1 cm in diameter each 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 \>= 18 years and \<= 72 years.
• Clinical performance status of ECOG 0 or 1.
• Individuals of child-bearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device \[IUD, abstinence, surgical sterilization starting at the time of study entry, for the duration of study therapy, and 12 months after the last dose of combined chemotherapy
• Participants who can father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment and for 4 months after the last dose of combined chemotherapy. We also will recommend participants that can father children with partners of childbearing potential to ask their partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization).
• NOTE: IOCBP is defined as any person who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
• 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.
• Participants must have serology results as follows:

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.
• Any form of secondary immunosuppression.
• Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
• For participants with NSCLC or lung metastases, 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.
• 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, aldesleukin or vaccines.
• Clinically significant participant history which in the judgment of the Principal Investigator (PI) would compromise the participants ability to tolerate high-dose aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• For select participants with a clinical history prompting cardiac evaluation: last known LVEF \<= 45%.
• For select participants with a clinical history prompting pulmonary evaluation: known FEV1 \<= 50% predicted.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Gastrointestinal Neoplasms; Ovarian Neoplasms; Urogenital Neoplasms

Interventions

aldesleukin; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic 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; Male Urogenital 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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 9, 2024
• First Posted: February 12, 2024
• Study Start: May 16, 2024
• Primary Completion (Estimated): June 15, 2031
• Study Completion (Estimated): June 15, 2033
• Last Updated: March 31, 2026

Record last verified: 2026-03-27

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)