A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an Adenovirus Vector Engineered to Express hIL-12, in Combination With an Oral Activator Ligand, in Subjects With Unresectable Stage III or IV Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 9
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events
研究概览
简要总结
This research study involves two investigational drugs, an Activator Ligand (INXN-1001) in combination with an Adenovirus Vector Engineered to Express hIL-12 (INXN-2001). IL-12 is a protein that may improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.
The main purpose of this study is to evaluate the safety and tolerability of tumor injections of INXN-2001 given in combination with different doses of INXN-1001.
详细描述
Single-arm, open label, Phase I/II dose escalation study of intratumoral injections INXN-2001 and oral INXN-1001 in subjects with unresectable Stage III or IV melanoma.
Four sequential dose escalation cohorts of INXN-1001 in combination with a fixed dose of INXN-2001 are planned. Subject enrollment and dose escalation will proceed according to a standard 3+3 design.
Approximately 15 additional subjects will be enrolled as an expansion cohort at a single dose level at or below the MTD.
- Safety and tolerability will be assessed by the incidence and severity of adverse events.
- The antitumor activity of study treatment will be assessed according to RECIST v1.1 guidelines. Additional assessment of anti-tumor activity will be explored based on total measurable tumor burden.
- Immunological and biological markers of response will include examinations of tumor biopsy samples, cytokine levels, peripheral blood mononuclear cells (PBMC) and antibody response to INXN-2001.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Males or females of all races ≥ 18 years of age, who have provided written informed consent prior to completing any study specific procedure.
- •Unresectable Stage III or Stage IV melanoma arising from any site other than ocular melanoma.
- •A minimum of 2 accessible nonvisceral lesions (shortest diameter ≥1 cm) or palpable tumor-involved lymph nodes (shortest diameter ≥1.5 cm).
- •ECOG performance status of 0 or 1 (Appendix 1).
- •Adequate bone marrow, liver, and renal function.
- •An expected survival of at least approximately 6 months.
- •Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the screening visit through 28 days after the last dose of study drug.
排除标准
- •Any prior anti-cancer therapy or investigational agent within 28 days prior to the first dose of study drug. (NOTE: For the expansion cohort ONLY, if subjects received ipilimumab, a 90-day washout period since last dose of ipilimumab is required. If subjects received other immunomodulating therapies (eg, anti-PD1 antibodies), the medical monitor should be contacted and an evaluation will be made.)
- •Clinically significant infection requiring systemic antibacterial, antifungal, or antiviral therapy within 2 weeks of the first dose of study drug.
- •History of HIV infection.
- •Active autoimmune disease requiring steroids (>10 mg prednisone or comparable) or other immunosuppressive therapy (e.g., methotrexate, etc.).
- •Documented symptomatic brain metastases. Screening for brain lesions by CT or MRI is not required for all potential subjects; however, if there are any neurological signs or symptoms consistent with brain metastases, then a brain CT or MRI should be performed as clinically indicated.
- •Any medications that induce, inhibit or are substrates of CYP450 3A4 within 7 days prior to the first dose of study drug.
- •Prior history of hematopoietic stem cell transplant or organ allograft.
- •Other concurrent clinically active malignant disease, with the exception of other cancers of the skin.
- •Females who are nursing or pregnant.
- •Subjects who have a history of hypersensitivity that may relate to any component of the study drugs, e.g. to benzoic acid since INXN-1001 contains two benzene rings.
- •Unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
研究组 & 干预措施
INXN-1001 in combination with INXN-2001
Intratumoral injections of INXN-2001 (Ad-RTS-hIL-12) at a constant dose in combination with inter-cohort escalating doses of INXN-1001 (activator ligand).
干预措施: INXN-2001 (Biological)
INXN-1001 in combination with INXN-2001
Intratumoral injections of INXN-2001 (Ad-RTS-hIL-12) at a constant dose in combination with inter-cohort escalating doses of INXN-1001 (activator ligand).
干预措施: INXN-1001 (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events
时间窗: From the signing of informed consent until 28 days after the last dose of study treatment, up to 28 weeks
Evaluation will be based on the incidence, intensity, and type of Adverse Events (AEs). Clinically significant changes in the subjects' physical examinations, vital signs, and ECG evaluations, and clinical manifestations relevant to abnormal laboratory values will be captured as AEs.
次要结局
- Area Under the Plasma Concentration-Time Curve (AUC) of INXN-1001 (Veledimex) in Cycle 1(Samples were collected in Cycle 1 on Day 1 (pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose), Day 2 (pre-dose), Day 7 (pre-dose and 1-2 and 4-6 hours post-dose), and Day 8 (24 hours after the Day 7 dose).)
- Progression-Free Survival (PFS)(From the first dose of study treatment for up to 1 year.)
- Change From Baseline in Tumor IL-12 Messenger RNA (mRNA) Expression Change in IL-12 mRNA Expression Level (Arbitrary Units)(Baseline (Screening) and at the Post-Treatment Safety Assessment (approximately 28 days after the end of Cycle 1).)
- Maximum Plasma Concentration (Cmax) of INXN-1001 (Veledimex) in Cycle 1(Samples were collected in Cycle 1 on Day 1 (pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose), Day 2 (pre-dose), Day 7 (pre-dose and 1-2 and 4-6 hours post-dose), and Day 8 (24 hours after the Day 7 dose))
- Best Overall Response (BOR) by RECIST 1.1 Criteria(From the first dose of study treatment for up to 1 year.)
- Time to Maximum Plasma Concentration (Tmax) of INXN-1001 (Veledimex) in Cycle 1(Samples were collected in Cycle 1 on Day 1 (pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose), Day 2 (pre-dose), Day 7 (pre-dose and 1-2 and 4-6 hours post-dose), and Day 8 (24 hours after the Day 7 dose).)
- Change From Baseline in Peripheral Blood Cytotoxic T-Lymphocytes (CTLs)(Baseline (Screening) and at Cycle 2, Day 7)
- Change From Baseline in Peripheral Blood Regulatory T-cells (Tregs)(Baseline (Screening) and at Cycle 2, Day 7.)
- Change From Baseline in Tumor Interferon-gamma (IFN-γ) Messenger RNA (mRNA) Expression(Baseline (Screening) and at the Post-Treatment Safety Assessment (28 days after the end of Cycle 1).)
- Ad-RTS-hIL-12 Vector Copy Numbers in Tumor Biopsy Samples(Day 2 of Cycle 1, Day 2 of Cycle 2, and Day 2 of Cycle 3.)