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
概览
- 阶段
- 1 期
- 干预措施
- Cyclophosphamide
- 疾病 / 适应症
- Pancreatic Cancer
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Response rate
- 状态
- 招募中
- 最后更新
- 8天前
概览
简要总结
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.
详细描述
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 alpha and beta chains that confer 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: 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 72 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, lymphodepleting 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 up to 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.
研究者
入排标准
入选标准
- •INCLUSION CRITERIA:
- •Measurable (per RECIST V1.1 criteria, metastatic, or 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 NCI Laboratory of Pathology.
- •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-
- •Other patients must have had platinum-based chemotherapy.
排除标准
- •Large volume pulmonary irradiation.
- •Women of child-bearing potential who are pregnant or breastfeeding 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.
- •Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
- •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.)
- •History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
- •History of coronary revascularization or ischemic symptoms
- •For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
- •For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50% or DLCO less than 60%.
研究组 & 干预措施
1/Phase I
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Cyclophosphamide
1/Phase I
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Anti-KRAS G12V mTCR PBL
1/Phase I
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Aldesleukin
2/Phase II
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Cyclophosphamide
2/Phase II
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Fludarabine
2/Phase II
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Anti-KRAS G12V mTCR PBL
2/Phase II
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Aldesleukin
1/Phase I
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
干预措施: Fludarabine
结局指标
主要结局
Response rate
时间窗: 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)
Frequency and severity of treatment-related adverse events
时间窗: 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