Phase I/II Study of Peptide Vaccination Associated With GM-CT-01, a Galactomannan Oligomer That Inhibits Galectin-3, in Patients With Advanced Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- Response rate in both arms
研究概览
简要总结
The purpose of this study is to determine whether the intravenous and/or GM-CT-01 administration can correct Tumor Infiltrating Lymphocytes (TIL) anergy and induce a more efficient and long-lasting anti-tumoral immune response following peptide vaccination.
详细描述
Human cancers express tumor antigens that can be targeted by cytolytic T lymphocytes (CTL). These antigens consist of a small peptide, derived from endogenous proteins, that is presented at the cancer cell's surface by an HLA class I molecule. Such antigenic peptides, including MAGE-3.A1 and NA17.A2, have been tested in experimental therapeutic vaccines to elicit CTL responses in cancer patients, mainly with metastatic melanoma. Up to now, only rare tumor responses have been observed.
Tumor resistance to CTL killing is the most likely explanation for the poor effectiveness of cancer vaccines. This resistance is probably acquired by the tumor during its development and selected by its repetitive challenge with spontaneous anti-tumoral immune responses. Recently, we have identified a novel mechanism causing anergy of tumor-associated T lymphocytes, and established new approaches to correct this anergy in vitro. Galectin-3, secreted by tumor cells, appears to inhibit CTL function the co-localization of the T cell receptor and the cluster of differentiation 8 coreceptor. Importantly, this functional defect is restored when anergic T cells are incubated with galectin-3 inhibitors such as the disaccharides lactose and N-acetyllactosamine, and the polysaccharide GM-CT-01. GM-CT-01 is a vegetal galactomannan oligomer, currently under clinical investigation in several types of solid malignancies for its capacity to inhibit galectins and to synergize with chemotherapy drugs.
Our observations suggest that treatment of cancer patients with GM-CT-01 could correct TIL anergy and induce a more efficient and long-lasting anti-tumoral immune response following peptide vaccination.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with histologically proven cutaneous melanoma at one of the following American Joint Committee on Cancer stages : Regional metastatic disease (any T; N2c or N3; M0), no amenable to curative treatment by surgery or isolated limb perfusion.Distant metastatic disease (any T; any N; M1a, M1b or M1c*).*except uncontrolled brain metastasis and except Lactate dehydrogenase >1.5 upper normal value
- •HLA-A1 or HLA-A2 (by serology or molecular biology)
- •At least one of the two following conditions:
- •MAGE-3 gene expression by the tumor if patient is HLA-A1 NA17 gene expression by the tumor if patient is HLA-A2 (determined by reverse transcription and polymerase chain reaction amplification).
- •Measurable Disease. Patients must have at least 1 measurable metastasis at study entry for all patients. In addition, patients candidates for enrollment in Group 2 who will receive peri-tumoral injections of GM-CT-01 must have at least 1 superficial metastasis (cutaneous, subcutaneous or superficial lymph node metastasis, with its largest diameter equal to or greater than 5, 5, or 10 mm, respectively) at study entry.
- •Age ≥ 18 years.
- •Karnofsky Performance status ≥70 or WHO performance status of 0 or 1
- •Expected survival of at least 6 months.
- •Laboratory values :
- •Platelet count ≥100x103/μL Leukocyte count ≥ 3x103/μL Hemoglobin ≥ 9 g/dL Aspartate transaminase and Alanine transaminase ≤ 2 times upper normal value Serum creatinine ≤1.5 times upper normal value Total bilirubin ≤ 1.5 times upper normal value Lactate dehydrogenase ≤ 1.5 times upper normal value
- •Viral serology : negative antibodies for Hepatitis C Virus & HIV; negative antigens for Hepatitis B Virus.
- •Patient should agree to perform biopsies and blood collections for translational research.
- •Signed informed consent from the patient must be obtained.
排除标准
- •Uncontrolled brain or central nervous system metastasis.
- •Previous treatment for the melanoma within 6 weeks from inclusion, with any reagent known to modulate the immune system such as a cancer vaccine, interferon-alpha, interleukins or anti-CTLA-4 antibodies.
- •Previous chemotherapy, radiotherapy, corticotherapy, or other immune suppressive therapy within 4 weeks from inclusion.
- •Clinically significant cardiovascular disease (including cardiac insufficiency New York Heart Association grade III and IV, unstable angina, arrythmia, myocardial infarction, symptomatic congestive heart failure) in the past 12 months before enrollment.
- •Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders or other conditions requiring concurrent medications not allowed during this study.
- •Other malignancy within 3 years prior to entry in the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma.
- •Active immunodeficiency disease or autoimmune disease (vitiligo is not an exclusion criterion).
- •Lack of availability for immunological and clinical follow-up assessments.
- •Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
- •Subject pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment.
- •Subject (male or female) not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months after the end of treatment.
研究组 & 干预措施
Group 1 : peptides + GM-CT-01 IV
Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 plus Galectin-3 inhibitor: GM-CT-01 systemic injections
干预措施: Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 (Biological)
Group 1 : peptides + GM-CT-01 IV
Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 plus Galectin-3 inhibitor: GM-CT-01 systemic injections
干预措施: Galectin-3 inhibitor: GM-CT-01 systemic injections (Biological)
Group 2 : peptides + GM-CT-01 IV+PT
Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 plus Galectin-3 inhibitor: GM-CT-01 systemic injections and Galectin-3 inhibitor: GM-CT-01 Peri-tumoral administration
干预措施: Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 (Biological)
Group 2 : peptides + GM-CT-01 IV+PT
Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 plus Galectin-3 inhibitor: GM-CT-01 systemic injections and Galectin-3 inhibitor: GM-CT-01 Peri-tumoral administration
干预措施: Galectin-3 inhibitor: GM-CT-01 systemic injections (Biological)
Group 2 : peptides + GM-CT-01 IV+PT
Tumor specific peptides: MAGE-3.A1 and / or NA17.A2 plus Galectin-3 inhibitor: GM-CT-01 systemic injections and Galectin-3 inhibitor: GM-CT-01 Peri-tumoral administration
干预措施: Galectin-3 inhibitor: GM-CT-01 Peri-tumoral administration (Biological)
结局指标
主要结局
Response rate in both arms
时间窗: Change from baseline at week 7 and week 20
Efficacy of the combination of a peptide vaccine and GM-CT-01 injections measures performed by CT-scan or MRI
Number of participants with adverse events
时间窗: 30 days after last administration of Study drugs
Change from baseline in adverse events will be recorded at each patient's visit and up to 30 days after last administration of study drugs. Measurements will use the Common Toxicity Criteria for Adverse Effects 4,0 scale
次要结局
- Time to Progression(From date of inclusion until the date of first documented progression or date of death from any cause, which ever came first, assessed up to 100 weeks)
- Immunogenicity of the treatment(Change from baseline at week 20)
- Response rate in group 2 versus group 1(Change from baseline at week 7 and week 20)
- Overall Survival(From day of inclusion to date of death)