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Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients

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ClinicalTrials.gov Identifier: NCT03190941
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : December 2, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells.

Objective:

To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors.

Eligibility:

Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors.

Design:

In another protocol, participants will:

Be screened

Have cells harvested and grown

Have leukapheresis

In this protocol, participants will have the procedures below.

Participants will be admitted to the hospital.

Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest.

A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter.

For up to 3 days, participants will get a drug to make the cells active.

A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin.

Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests.

Participants will take an antibiotic for at least 6 months.

Participants will have visits every few months for 2 years, and then as determined by their doctor.

Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn.

Participants will have blood collected over several years.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Gastric Cancer Gastrointestinal Cancer Colon Cancer Rectal Cancer Drug: Cyclophosphamide Drug: Fludarabine Biological: anti-KRAS G12V mTCR Drug: Aldesleukin Phase 1 Phase 2

Detailed Description:

Background:

  • We generated an HLA-A*11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12V-mutated variant of KRAS (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains its alpha and beta chains that confers recognition of this antigen when transduced into PBL.
  • In co-cultures with HLA-A*11:01+ target cells expressing this mutated oncogene, mTCR transduced T cells lyse target cells and secrete IFN-gamma with high specificity.

Objectives:

Primary objectives:

  • Phase I: determine the safety of administering PBL transduced with anti-KRAS G12V mTCR in concert with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin).
  • Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12V mutation.

Eligibility:

Patients must be/have:

  • Age greater than or equal to 18 years and less than or equal to 70 years
  • HLA-A*11:01 positive
  • Metastatic or unresectable RAS G12V-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 G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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 G12V mTCR.
  • All patients will receive a non-myeloablative, lympho-depleting preparative regimen of cyclophosphamide and fludarabine.
  • On day 0 patients will receive their PBL transduced with the anti-KRAS G12V mTCR and will then begin high-dose aldesleukin.
  • A complete evaluation of lesions will be conducted approximately 6 weeks (+/- 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 G12V pancreatic

cancer, and Cohort 2b, patients with RAS G12V non-pancreatic cancer.

-A total of 110 patients may be required; approximately 24 patients in the phase I portion of the study and 86 (41, plus an allowance of up to 2 non-evaluable per phase II cohort) patients in the phase II portion of the study.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
Actual Study Start Date : September 21, 2017
Estimated Primary Completion Date : June 29, 2027
Estimated Study Completion Date : June 29, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/Phase I
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-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.

Biological: anti-KRAS G12V mTCR
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: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).

Experimental: 2/Phase II
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-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.

Biological: anti-KRAS G12V mTCR
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: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).




Primary Outcome Measures :
  1. Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, every 6 months x2 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)

  2. Frequency and severity of treatment-related adverse events [ Time Frame: 6 weeks ( 2 weeks) following administration of the cellproduct ]
    Aggregate of all adverse events, as well as their frequency and severity


Secondary Outcome Measures :
  1. In vivo survival of mTCR gene engineered cells [ Time Frame: Batched and assayed at the conclusion of the study ]
    TCR and vector presence will be quantitated in PBMC samples using established PCR techniques



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:
  • Measurable metatstatic unresectable malignancy expressing G12V 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 G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.
  • Patients must be HLA-A*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.
  • Confirmation of the diagnosis of cancer by the Laboratory of Pathology of the NCI.
  • Patients must:
  • have previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred. Specifically:

    • For patients with metastatic colorectal cancer, they 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
  • Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients

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
  • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
  • Serology:
  • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus may 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.
  • Hematology:
  • ANC greater than or equal to 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
  • Chemistry:

    • Serum ALT/AST less than or equal to 5.0 x ULN
    • Total bilirubin less tha or equal to 1.5 mg/dL, except in patients with Gilbert s Syndrome who must have a total bilirubin less than or equal to 3.0 mg/dL.
  • Patients must have either an eGFR > 60 mL/m (based on serum creatinine and lab nomogram) or a formal 6-24h CrCl > 60 mL/m.
  • More than four weeks must have elapsed since completion of any prior systemic therapy and 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.

  • 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 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 immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  6. History of severe immediate hypersensitivity reaction to cyclophosphamide, aldesleukin, or fludarabine.
  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 tested in patients with:

    • A prolonged history of cigarette smoking (approximately 20 packs/year within the past two years).
    • Symptoms of respiratory dysfunction
  10. Patients 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): NCT03190941


Contacts
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Contact: Ellen Bodurian (866) 820-4505 IRC@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James C Yang, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03190941     History of Changes
Other Study ID Numbers: 170113
17-C-0113
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: December 2, 2019
Last Verified: November 26, 2019

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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
HRAS
NRAS
Cell Therapy
Immunotherapy
Additional relevant MeSH terms:
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Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Vidarabine
Aldesleukin
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Anti-Retroviral Agents