An Open-Label, Multicenter, Non-Randomized, Dose-Confirmation and Cohort-Expansion Phase 1b Study to Evaluate the Safety, Tolerability, and Anti-Tumor Activity of Nous-PEV, with Pembrolizumab, in Patients with Unresectable Stage III / IV Cutaneous Melanoma and with Stage IV NSCLC (PDL1≥ 50%)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Nouscom SRL
- 入组人数
- 7
- 试验地点
- 7
- 主要终点
- Safety and tolerability: incidence of treatment- emerging adverse events. AEs characterized by type, severity (graded by CTCAE v.5.0), Timing, seriousness and relationship to study treatments.
研究概览
简要总结
From Protocol v3.0 dated 16Jun2022. This is an international, multicenter, open-label, multiple cohort, First in Human, phase 1b clinical study, designed to evaluate safety, tolerability, and immunogenicity, and to detect any preliminary evidence of anti-tumor activity of a personalized vaccine (PEV) based on GAd-PEV priming and MVA-PEV boosting, combined with SoC first-line immunotherapy using an anti-PD-1 checkpoint inhibitor in patients with unresectable stage III/IV cutaneous melanoma or with stage IV NSCLC (PDL1 ≥ 50%). The PEV vaccines will be prepared on an individual basis, following a tumor biopsy performed at the time of screening and subsequent NGS analysis, to identify patient-specific tumor mutations. Both neoantigen-encoding genetic vaccines are administered intramuscularly using 1 prime with GAd-PEV and 3 boosts with MVA-PEV in combination with the licensed programmed death receptor-1 (PD-1)-blocking antibody pembrolizumab in adult patients in patients with unresectable stage III/IV cutaneous melanoma (Cohort a) or with stage IV NSCLC (PDL1 ≥ 50%) (Cohort b).
详细描述
Overall Study Design:
• This is an open-label, non-randomized, dose-confirmation and cohort expansion phase 1b first-in-human study, in which 28 patients, expandable up to 34 evaluable patients in case of DLT.
Study IMPs:
Nous-PEV vaccine is composed of 2 sets of IMPs:
- GAd-PEV
- MVA-PEV
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Main Inclusion Criteria for Patients in Cohorts 1a and 2a:
- •Age ≥ 18 years.
- •Patients with histologically or cytologically confirmed unresectable stage III or stage IV Cutaneous Melanoma, as per AJCC staging system (8th edition). First-line treatment-naive patients.
- •Participation in this trial will be dependent upon supplying tumor tissue from newly obtained specimen. Newly obtained biopsies of a tumor lesion, not previously irradiated, must be provided in the form of excisional biopsies, resected tissue or core needle biopsies.
- •Presence of at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1 by the local site Investigator / radiologist assessment
- •Presence of at least one lesion amenable to repeated biopsy, ideally not the one being used for measuring.
- •Willingness to undergo a minimum of two fresh lesion biopsies (pre-treatment and on-treatment).
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to
- •Life expectancy of at least 12 months.
- •Adequate renal, hepatic, and hematologic functions
- •A female patient is eligible to participate if she is not pregnant and not breastfeeding
- •A male patient must agree to use an adequate contraception
- •Main Inclusion Criteria for Patients in Cohort 2b:
- •Age ≥ 18 years.
- •Histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without EGFR or ALK/ROS1 /RET genomic alteration.
- •Tumor expression with PD-L1 ≥50% tumor proportion score (TPS).
- •First-line treatment-naïve patients.
- •Participation in this trial will be dependent upon supplying tumor tissue from a newly obtained specimen. Newly obtained biopsies of a tumor lesion, not previously irradiated, must be provided in the form of excisional biopsies, resected tissue or core needle biopsies.
- •Presence of at least 1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST v1.1 as determined by the local site Investigator / radiologist assessment.
- •Presence of at least one tumor lesion amenable to repeated biopsy, if possible, ideally not the one being used for measuring.
- •Willingness to undergo a minimum of two fresh tumor biopsies (pre-treatment and on-treatment).
- •ECOG performance status 0 to
- •Life expectancy of at least 6 months.
- •Adequate renal, hepatic, and hematologic functions
- •A female patient is eligible to participate if she is not pregnant and not breastfeeding
- •A male patient must agree to use a contraceptive during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.
- •Main Exclusion Criteria for patients in all Cohorts:
- •Currently receiving treatment with another investigational medicinal product.
- •Prior therapy with immune checkpoint inhibitors. Patients must not have received any investigational immunotherapy either.
- •Prior radiotherapy within 2 weeks of enrolment, or within 4 weeks of enrolment in the case of radiation to central nervous system (CNS), which requires ≥ 4-week washout.
- •Prior allogenic tissue or solid organ transplant.
- •Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids and/or whose pulse oximetry is less than 92% "on room air".
- •Limiting cardiac criteria: prolonged QT interval or QT prolongation risk factors, clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g. complete LBBB, third degree heart block, risk of arrythmic events, ejection fraction under lower limit of normal.
- •Major (according to the Investigator's judgment) surgery within 12 weeks before enrolment.
- •Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry.
- •Immunosuppression including the continued use of systemic (at prednisone dose equivalent of > 10 mg) or topical steroids at or near the planned i.m. injection site or the use of immunosuppressive agents for any concurrent condition in the 4 weeks prior to first study treatment administration. Inhaled and eye drop-containing corticosteroids are permitted.
- •Previous vaccination (either therapeutic and/or prophylactic) against cancer.
- •History of autoimmune disease in the last 5 years, including any active autoimmune disease except vitiligo or childhood asthma.
- •Chronic or concurrent active infectious disease requiring systemic antibodies, antifungal, or antiviral treatment.
- •Known Medical History of human immunodeficiency virus (HIV) infection or known Medical History of acquired immunodeficiency syndrome (AIDS). HIV testing is not required unless mandated by the local health authority.
- •Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment, or at risk for HBV reactivation
- •Known CNS metastasis and/or carcinomatous meningitis.
- •Known cerebral edema.
- •Live vaccine received within 30 days before treatment initiation.
排除标准
- 未提供
研究组 & 干预措施
Cohort 1a
Cohort 1a: 3 patients (expandable to 9) with unresectable stage III / IV Cutaneous Melanoma.
干预措施: GAd-PEV (Biological)
Cohort 1a
Cohort 1a: 3 patients (expandable to 9) with unresectable stage III / IV Cutaneous Melanoma.
干预措施: MVA-PEV (Biological)
Cohort 2a
Cohort 2a:13 patients with unresectable stage III / IV Cutaneous Melanoma.
干预措施: GAd-PEV (Biological)
Cohort 2a
Cohort 2a:13 patients with unresectable stage III / IV Cutaneous Melanoma.
干预措施: MVA-PEV (Biological)
Cohort 2b
Cohort 2b: 12 patients with stage IV NSCLC (PDL1≥ 50%).
干预措施: GAd-PEV (Biological)
Cohort 2b
Cohort 2b: 12 patients with stage IV NSCLC (PDL1≥ 50%).
干预措施: MVA-PEV (Biological)
结局指标
主要结局
Safety and tolerability: incidence of treatment- emerging adverse events. AEs characterized by type, severity (graded by CTCAE v.5.0), Timing, seriousness and relationship to study treatments.
时间窗: Up to 110 weeks
* Frequency, duration, and severity of adverse events (AEs) and serious adverse events (SAEs) using CTCAE v5.0 criteria. * Changes in vital signs and clinical evaluations. * Changes in clinical laboratory blood samples. * Dose-limiting toxicity (DLT)
次要结局
- Clinical efficacy(Up to 110 weeks)
- RP2D confirmation 2. Clinical efficacy:(Up to 110 weeks)