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Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

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ClinicalTrials.gov Identifier: NCT03745326
Recruitment Status : Suspended ((suspension))
First Posted : November 19, 2018
Last Update Posted : January 29, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE November 16, 2018
First Posted Date  ICMJE November 19, 2018
Last Update Posted Date January 29, 2021
Actual Study Start Date  ICMJE May 16, 2019
Estimated Primary Completion Date December 1, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • Frequency and severity of treatment-related adverse events [ Time Frame: From time of cell infusion to two weeks after cell infusion ]
    Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT
  • Response rate [ Time Frame: 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion ]
    Percentage of patients who have a clinical response (PR + CR) to treatment (objective tumor regression)
Original Primary Outcome Measures  ICMJE
 (submitted: November 16, 2018)
  • Frequency and severity of treatment-related adverse events [ Time Frame: 5 years following cell infusion ]
    Aggregate of all adverse events, as well as their frequency and severity
  • Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2018)
In vivo survival of mTCR geneengineered cells [ Time Frame: Batched and assayed at the conclusion of the study ]
TCR and vector presence will be quantified in PBMC samples using established PCR techniques
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients
Official Title  ICMJE A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients
Brief Summary

Background:

A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells.

Objective:

To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink.

Eligibility:

Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells

Design:

Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests.

An intravenous (IV) catheter will be placed in a large vein in the chest.

Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm.

A few weeks later, participants will have a hospital stay. They will:

  • Get 2 chemotherapy medicines by IV over 5 days.
  • Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells.
  • Recover in the hospital for up to 3 weeks. They will provide blood samples.

Participants will take an antibiotic for at least 6 months.

Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis.

Participants blood will be collected for several years.

Detailed Description

Background:

  • We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of KRAS (and other RAS family genes) expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into PBL.
  • In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR transduced T-cells lyse target cells and secrete IFN-y with high specificity.

Objectives:

-Primary objectives:

  • Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin).
  • Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation.

Eligibility:

  • Patients must be/have:

    • Age greater than or equal to 18 years and less than or eqaul to 70 years
    • HLA-A*11:01 positive
    • Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available).
  • Patients may not have:

    • Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or fludarabine.

Design:

  • This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS.
  • PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
  • Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR.
  • All patients will receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine.
  • On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin.
  • A complete evaluation of lesions will be conducted approximately 6 weeks (plus-minus 2 weeks) after treatment.
  • The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer.
  • A total of up to 70 patients may be required; approximately 24 patients in the Phase I portion of the study and 46 (21, plus an allowance of up to 2 non-evaluable per Phase II cohort) patients in the Phase II portion of the study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Gastrointestinal Cancer
  • Pancreatic Cancer
  • Gastric Cancer
  • Colon Cancer
  • Rectal Cancer
Intervention  ICMJE
  • 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 /m^2/day IVPB daily over 30 minutes for 5 days.
  • Drug: Aldesleukin
    Aldesleukin 720,000 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 3 days (maximum 9 doses).
  • Biological: anti-KRAS G12D mTCR 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).
Study Arms  ICMJE
  • Experimental: 1/Phase I
    Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Aldesleukin
    • Biological: anti-KRAS G12D mTCR PBL
  • Experimental: 2/Phase II
    Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Aldesleukin
    • Biological: anti-KRAS G12D mTCR PBL
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Actual Enrollment  ICMJE
 (submitted: January 8, 2021)
4
Original Estimated Enrollment  ICMJE
 (submitted: November 16, 2018)
70
Estimated Study Completion Date  ICMJE December 1, 2028
Estimated Primary Completion Date December 1, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-INCLUSION CRITIERIA:

  1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy expressing G12D mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on

    resected tissue. Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.

  2. Patients must be HLA-A*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.
  3. Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
  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 had at least two systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin, and irinotecan (or similar agents), or have contraindications to receiving those medications.
    • Patients with pancreatic cancer must have received gemcitabine, 5FU, and oxaliplatin (or similar agents), or have contraindications to receiving those medications.
    • Patients with non-small cell lung cancer (NSCLC) must have had appropriate targeted therapy as indicated by abnormalities in ALK, EGFR, or expression of PDL-1. Other patients must have had platinum-based chemotherapy.
    • Patients with ovarian cancer or prostate cancer must have had approved first-line chemotherapy.

    OR

    -have declined standard treatment

  5. 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.

  6. Age greater than or equal to 18 years and less than or equal to 70 years.
  7. Clinical performance status of ECOG 0 or 1
  8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  9. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  10. Serology

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

  11. Hematology

    • ANC > 1000/mm^3 without the support of filgrastim
    • WBC greater than or equal to 3000/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.
  12. 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 1.5 mg/dL, except in patients with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL.
  13. More than four weeks must have elapsed since completion of any prior systemic therapy an enrollment.

    Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks before enrollment, as long as related major organ toxicities have recovered to grade 1 or less

  14. Ability of subject to understand and the willingness to sign a written informed consent document.
  15. Willing to sign a durable power of attorney.
  16. Subjects must be co-enrolled on the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

EXCLUSION CRITERIA:

  1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  2. Concurrent systemic steroid therapy.
  3. Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
  4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  5. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible

    to its toxicities.)

  6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
  7. History of coronary revascularization or ischemic symptoms.
  8. 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.
  9. Documented FEV1 less than or equal to 50% predicted in patients with:

    • A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history, with cessation within the past two years).
    • Symptoms of respiratory dysfunction.
  10. Patients who are receiving any other investigational agents.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03745326
Other Study ID Numbers  ICMJE 190017
19-C-0017
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James C Yang, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP