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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT06253520
Recruitment Status : Recruiting
First Posted : February 12, 2024
Last Update Posted : February 22, 2024
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


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.


To test a cancer treatment that uses a person s own modified white blood cells along with a vaccine that targets a specific protein.


Adults aged 18 to 72 years with certain solid tumors that have spread after treatment.


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.


Condition or disease Intervention/treatment Phase
Metastatic Solid Cancers Colorectal Cancer Breast Cancer Non-Small Cell Lung Cancer Gastrointestinal Cancer Ovarian Cancer Genitourinary Cancer Drug: Aldesleukin Drug: Fludarabine Drug: Cyclophosphamide Biological: KRAS TCR-Transduced PBL Biological: GRT-C903/GRT-R904 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Clinical Trial to Evaluate the Administration of 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
Estimated Study Start Date : March 15, 2024
Estimated Primary Completion Date : June 15, 2031
Estimated Study Completion Date : June 15, 2033

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vaccines

Arm Intervention/treatment
Experimental: 1/ KRAS TCR + vaccine
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
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.

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

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.

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

Biological: GRT-C903/GRT-R904
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

Primary Outcome Measures :
  1. Complete response (CR) and/ or partial response (PR) [ Time Frame: Response assessed at 4, 8, 12 and 20 weeks post-cell infusion, every 3 months x3, every 6 months x 2 years ]
    Clinical response rate ([PR+CR]/evaluable participants) will be determined and reported along with the corresponding 95% two-sided confidence interval.

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

Secondary Outcome Measures :
  1. Safety [ Time Frame: From study treatment initiation up to 4 weeks after the last study treatment ]
    The number of participants with toxicity of grade 3 or higher related to the KRAS-TCR transduced cells or vaccine, according to type of toxicity. Adverse events assessed per CTCAE version 5.

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 72 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • 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 (see Appendix A).
  • Women of child-bearing potential (WOCBP) 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

Men 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 men with female partners of childbearing potential to ask female partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization).

NOTE: WOCBP is defined as any female 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:

    • Seronegative for HIV antibody.
    • 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.
  • Adequate organ and marrow function as defined below:


    • ANC > 1000/mm^3 without growth factor support
    • WBC >= 2500/mm^3
    • Platelet count (Bullet) 80,000/mm3
    • Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.
  • Chemistry:
  • Serum ALT/AST <= 5.0 x ULN
  • Serum creatinine <= 1.6 mg/dL
  • Total bilirubin <= 2.0 mg/dL, except in participants with Gilbert s Syndrome, who must have a total bilirubin < 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 participants with NSCLC or lung metastases, 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.
  • Participants must be co-enrolled on protocol 03-C-0277.


  • Women who are pregnant or breastfeeding 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.

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 identifier (NCT number): NCT06253520

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Contact: NCI SB Immunotherapy Recruitment Center (866) 820-4505
Contact: Steven A Rosenberg, M.D. (240) 858-3080

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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: NCI/Surgery Branch Recruitment Center    866-820-4505   
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT06253520    
Other Study ID Numbers: 10001662
First Posted: February 12, 2024    Key Record Dates
Last Update Posted: February 22, 2024
Last Verified: February 20, 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All collected IPD will be shared. All IPD recorded in the medical record will be shared with intramural investigators upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (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.

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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) ):
KRAS Mutations
Gene Therapy
Cell Therapy
Additional relevant MeSH terms:
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Neoplasm Metastasis
Gastrointestinal Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Neoplastic Processes
Pathologic Processes
Male Urogenital Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents