An Open-Label Study of Rovalpituzumab Tesirine in Subjects With Delta-Like Protein 3-Expressing Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 200
- 试验地点
- 30
- 主要终点
- Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups
研究概览
简要总结
The primary objective of this study is to assess the safety and tolerability of rovalpituzumab tesirine in subjects with specific delta-like protein 3-expressing advanced solid tumors.
详细描述
This is a multicenter, open-label study involving multiple specific advanced solid tumor types, consisting of a dose escalation part A followed by an expansion part B. Cancer subtypes will be studied in separate disease-specific cohorts in both Parts. Eight separate cohorts will enroll malignant melanoma, medullary thyroid cancer (MTC), glioblastoma, large cell neuroendocrine carcinoma (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC), other NEC, and solid tumors other than the above.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed, unresectable advanced solid malignancy with documented disease progression after at least 1 prior systemic therapy
- •Disease is relapsed/refractory to prior standard systemic therapy or for which standard or curative therapy does not exist or is not considered appropriate by the Investigator.
- •Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Delta-like protein 3 (DLL3)-expressing malignancy based on central immunohistochemical (IHC) testing of representative baseline tumor tissue (archived tissue or on-study biopsy). Positive is defined as staining in ≥ 1% of tumor cells.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Minimum life expectancy of at least 12 weeks
- •Subjects with a history of central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment and within 2 weeks prior to first dose of Study Drug, off or on a stable dose of corticosteroids. Definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy. (Applicable to tumor types of non-CNS primary origin only)
- •Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to initiation of study drug administration
- •Adequate hematologic and organ function as confirmed by laboratory values
- •Last dose of any prior therapy administered by the following time intervals before the first dose of study drug:
- •Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks.
- •Immune-checkpoint inhibitors (e.g., anti-programmed death protein 1 [PD-1], anti-programmed death-ligand 1 [PD-L1], or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies: 4 weeks (2 weeks with documented disease progression).
- •Females of childbearing potential must have a negative beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of study drug. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.
排除标准
- •Any significant medical condition, including any suggested by screening laboratory findings that, in the opinion of the investigator or sponsor, may place the subject at undue risk from the study, including but not necessarily limited to uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
- •Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to their first dose of study drug.
- •Recent or ongoing serious infection, including:
- •Any active grade 3 or higher (per National Cancer Institute Common Terminology Criteria for Adverse Events version [NCI CTCAE] 4.03) viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drug. Routine antimicrobial prophylaxis is permitted.
- •Known seropositivity for or active infection by human immunodeficiency virus (HIV).
- •Active Hepatitis B (by surface antigen expression or polymerase chain reaction) or C (by polymerase chain reaction) infection or on hepatitis-related antiviral therapy within 6 months of first dose of study drug.
- •Women who are pregnant or breastfeeding
- •Systemic therapy with corticosteroids at >20 mg/day prednisone or equivalent within 1 week prior to the first dose of study drug
- •History of another invasive malignancy that has not been in remission for at least 3 years. Exceptions to the 3year limit include non-melanoma skin cancer, curatively treated localized prostate cancer, ductal carcinoma in situ, and cervical cancer in situ on biopsy or squamous intraepithelial lesion on pap smear.
- •Prior exposure to a pyrrolobenzodiazepine (PBD)-based drug, prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity to rovalpituzumab tesirine or excipient contained in the drug formulation, unless undergoing retreatment with rovalpituzumab tesirine in the context of this protocol
研究组 & 干预措施
Rovalpituzumab Tesirine
Rovalpituzumab tesirine 0.2-0.4 mg/kg administered intravenously on Day 1 of each 6-week cycle. Dexamethasone 8 mg administered orally twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle.
干预措施: Rovalpituzumab tesirine (Drug)
Rovalpituzumab Tesirine
Rovalpituzumab tesirine 0.2-0.4 mg/kg administered intravenously on Day 1 of each 6-week cycle. Dexamethasone 8 mg administered orally twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups
时间窗: From first dose of study drug through 30 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0).
The number of participants with TEAEs, serious TEAEs, study drug-related TEAEs, and study drug discontinuations or dose reductions due to TEAEs, summarized by dose received and neuroendocrine (NEC) or non-NEC disease groups. An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: is fatal or life-threatening; results in death or hospitalization; is disabling/incapacitating or a congenital anomaly/birth defect; is medically significant. AE severity was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 terminology: grade 1=mild; grade 2=moderate; grade 3=severe; grade 4 life-threatening; grade 5=death. TEAEs were defined as AEs that were newly occurring or worsened following study treatment.
次要结局
- Objective Response Rate (ORR)(Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.)
- Clinical Benefit Rate (CBR)(Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.)
- Duration of Response (DOR)(Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.)
- Progression Free Survival (PFS)(Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.)
- Overall Survival (OS)(Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.)
- Serum Concentrations of Rovalpituzumab Tesirine Over Time(Cycle 1: 0, 0.5, 6, 48, 168, 336, 672 hours postdose)
- Number of Participants With Anti-therapeutic Antibodies (ATA)(Day 1 and 42 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0).)