A Randomized Multicenter Phase II Trial to Evaluate the Safety and Immunogenicity of Two Doses of Vaccination With Folate Receptor Alpha Peptides With GM-CSF in Patients With Triple Negative Breast Cancer Defined as Primary Tumor That is Her2-neu and Low (< 10%) ER/PR Nuclear Staining
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 11
- 主要终点
- Immune response
研究概览
简要总结
This Phase II trial evaluates the safety and immunogenicity of two doses of the Folate Receptor Alpha (FRα) peptide vaccine mixed with GM-CSF as a vaccine adjuvant, with or without a immune priming with cyclophosphamide, as a consolidation therapy after neoadjuvant or adjuvant treatment of patients with Stage IIb-III triple negative breast cancer (TNBC).
详细描述
Triple negative breast cancers (TNBCs) occur in approximately 20-25% of all patients with breast cancer and are associated with a poor prognosis. Patients with TNBCs derive no benefit from targeted therapies. Excluding those patients who demonstrate a pathologic complete response following neoadjuvant chemotherapy, which is a minor fraction (i.e. 15%), overall survival is only 45% at 7 years.
Following standard of care, there are windows of opportunity to further and safely treat patients to prevent recurrence. Stimulating the immune system to produce T cells immunity specific for tumor antigens may significantly delay recurrence and cure patients.
The proposed vaccine is intended to induce T cells to survey for the reemergence of TNBCs and to prevent recurrence in the adjuvant setting. The vaccine strategy is antigen-specific and targets the Folate Receptor Alpha (FRα). FRα is an ideal target because of its limited expression in the healthy tissues and it high expression in 86% of TNBCs. Studies have shown that it is a biologically important marker that is associated with poorer clinical outcome and is retained in metastatic lesions.
The FRα vaccine include a pool of 5 peptides that are immunogenic epitopes and safely generate tissue-surveying CD4 T cell immune responses in patients tested in a recently completed phase I clinical trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female patient, age 18 years or older;
- •Completely resected unilateral or bilateral primary carcinoma of the breast
- •Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;
- •Primary tumor was negative for ER, PR (cut-off for positivity is >10% positive tumor cells with nuclear staining) and negative for Her2-neu (0 or 1+ on immunohistochemistry and/or normal gene copy number by in-situ hybridization); Central review is not required.
- •Completed primary treatment (surgery and radio/chemotherapy in adjuvant and/or neo-adjuvant setting) <360 days prior to first vaccination.
- •Completed last cycle of chemotherapy or radiation > 60 days prior to first vaccination
- •Either clinical or pathological Stage I (T1c), II, or III according to AJCC 7th edition
- •Note that patients with (i) non-invasive breast cancer (DCIS) alone, (ii) incidental (microscopic) nodal cancer without a primary tumor (pN1mi), or (iii) metastatic disease are excluded.
- •Resected tumor: No evidence of gross tumor at the surgical resection margin noted in the final surgery report. No evidence of gross residual adenopathy
- •Karnofsky index >= 70%;
- •Life expectancy of at least 5 years, disregarding the diagnosis of cancer;
- •Adequate Blood, renal and hepatic function, as determined within 28 days from registration:
- •ANC ≥ 1,500 / mm3
- •Platelet ≥ 100,000 / uL
- •Hgb > 9 g/dL
- •Creatinine ≤ 1.5 x ULN or 24-hour urine < Grade 2
- •Urinalysis with < 2+ proteinuria
- •Serum albumin ≥ 3 g/dL
- •SGOT (AST) ≤ 3 x ULN
- •Anti-nuclear antibody (ANA) negative or low-positive institutional range, as determined within 28 days from registration. Intermediate values (usually defined by a titer of ≤1:80, or as indicated by institutional range) are acceptable if there are, in the opinion of the Investigator, no early signs of an autoimmune disease.
- •Primary tumor is available for shipment to central laboratory for analysis of FRα expression by IHC.
- •Patients must be, in the opinion of the Investigator, available and compliant for treatment and follow-up.
排除标准
- •Clinical evidence of distant metastases per practice guidelines for breast cancer;
- •Inflammatory breast cancer or tumor with deep adherence or cutaneous invasion;
- •Known hypersensitivity reaction to the GM-CSF adjuvant; Any known contra-indication to GM-CSF or Cyclophosphamide treatment;
- •Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to registration and must implement adequate contraceptive measures during study treatment;
- •Active autoimmune disease requiring therapy within the past 2 years (Note: patients with vitiligo, Grave's disease or psoriasis not requiring systemic treatment within the past 2 years are not excluded);
- •Other uncontrolled illness or medical condition, such as active infection, symptomatic heart failure (New York Heart Association class III or IV; moderate to severe objective evidence of cardiovascular disease), unstable angina pectoris, myocardial infarction or stroke within last 6 months, psychiatric illness that may limit compliance with study requirement or interfere with the understanding and giving of informed consent;
- •Prior active secondary malignancy < 5 years prior to consent (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix) or currently receiving other specific treatment for this cancer (including monoclonal antibody or pathway inhibitor);
- •Completed treatment with systemic corticosteroid or immune-modulators < 30 days prior to registration;
- •Planned treatment with other experimental drugs or any other non-hormonal anti-cancer therapy;
- •Immunocompromised patients, including patients with known HIV infection;
- •Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor, TPO, thyroglobulin).
研究组 & 干预措施
Low dose FRα vaccine
FRα peptide vaccine with GM-CSF adjuvant - single ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: Low dose FRα vaccine (Biological)
High dose FRα vaccine
FRα peptide vaccine with GM-CSF adjuvant - triple ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: High dose FRα vaccine (Biological)
Low dose FRα vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRα peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: Low dose FRα vaccine (Biological)
Low dose FRα vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRα peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: Cyclophosphamide (Drug)
High dose FRα vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRα peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: Cyclophosphamide (Drug)
High dose FRα vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRα peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
干预措施: High dose FRα vaccine (Biological)
结局指标
主要结局
Immune response
时间窗: 3 years
Emergence of B and T cell immunity targeting the folate receptor alpha
次要结局
- Relapse Free Survival(3 years)
- Folate receptor alpha expression(Baseline)
- Safety and tolerability (treatment emergent adverse events and injection site reactions)(3 years)