A Phase 1a/b, Open-label, Dose-escalation Study of the Safety, Pharmacokinetics, and Initial Efficacy of 225Ac-ABD147 in Patients With Small Cell Lung Cancer and Large Cell Neuroendocrine Carcinoma of the Lung Following Platinum-based Chemotherapy
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 17
- 试验地点
- 16
- 主要终点
- Ph 1a: Safety of 225Ac-ABD147 - Number and Grade of Adverse Events
研究概览
简要总结
The study has 2 parts, Phase 1a and Phase 1b. The goal of Phase 1a is to gather safety, PK and initial efficacy data for 225Ac-ABD147 to better understand best doses for patients with small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung following platinum-based chemotherapy.
An initial group of patients will also be given an experimental imaging agent called 111In-ABD147 to help understand where ABD147 goes in the body.
The goal of Phase 1b is to gather additional safety and efficacy data on 225Ac-ABD147 to determine the best dose and to understand how those doses affect the same types of patients' cancers explored enrolled in Phase 1a.
详细描述
This is an open-label, Phase 1a/b, first-in-human study to assess the safety profile, tolerability, biodistribution, pharmacokinetics (PK), and preliminary antitumor activity of 225Ac-ABD147 in patients with confirmed locally advanced or metastatic small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung. All patients must have previously received platinum-based chemotherapy.
Phase 1a will determine the safety, tolerability, dosimetry, PK, and the dose of 225Ac-ABD147 for expansion in the Phase 1b portion.
In addition to receiving treatment, a subset of patients in Phase 1a will undergo either 111In-ABD147-based or 225Ac-ABD147 dosimetry assessments to confirm tumor specificity, identify biodistribution, and to provide insight into dose absorption into tumor and normal tissues.
Phase 1b will evaluate the safety and preliminary efficacy of 225Ac-ABD147 as based on the Phase 1a dose level for expansion by the Safety Review Committee to determine the recommended Phase 2 dose (RP2D).
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
- •Has confirmed, locally advanced or metastatic SCLC or LCNEC of the lung.
- •Has received platinum-based chemotherapy.
- •Mentally competent and able to understand and sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved Informed Consent Form (ICF) prior to any study specific evaluation.
- •Age ≥18 years old at the time the ICF is signed.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to
- •Expected life expectancy of >12 weeks per the Investigator.
- •Has disease that is measurable by RECIST v1.
- •Patients with known brain metastases are eligible provided they are considered by the Investigator to be neurologically stable and meet the following criteria: a. Radiotherapy or surgery for brain metastases was completed at least 2 weeks prior to Cycle 1 Day 1 (C1D1); b. Symptoms are stable and steroid/antiepileptic doses remain unchanged for a minimum of 2 weeks prior to C1D
- •At least 4 weeks from prior major surgery (other than for brain metastases), or at least 7 days from prior non-study-related minor surgery prior to C1D
- •In all cases, the patient must be sufficiently recovered and stable before the study treatment administration.
- •Willing to provide archival tumor tissue for central analysis; if unavailable, a pre-study treatment biopsy may be collected and provided.
- •Female and male patients of childbearing potential agree to use at least 2 highly effective forms of contraception (1 at least must be barrier method) or agree to completely remain abstinent for duration of study and for 6 months after the last administration of study drug for both female patients and male patients.
- •Patients agree to not make semen/egg donations during treatment, within 2 weeks following the last dose of 111In-ABD147, and for 6 months following the last dose of 225Ac-ABD
排除标准
- •Was previously treated with 225Ac-ABD
- •Has a history of steroid dependent hepatitis caused by treatment with a checkpoint inhibitor.
- •Is actively enrolled in another clinical study unless it is an observational (noninterventional) clinical study or the follow-up component of an interventional study.
- •Use of an anticancer therapy, radiotherapy (external beam radiotherapy [EBRT], brachytherapy, inoperative radiation therapy, radiopharmaceuticals), or immunotherapy within 3 weeks prior to C1D
- •Prior treatment with DLL3-targeting agent is acceptable with appropriate washout.
- •Has a medical history of myocardial infarction or unstable angina within 6 months before C1D
- •Has clinically significant cardiac disease not controlled by medical therapy (eg, congestive cardiac failure, arrhythmia, coronary heart disease).
- •Has evidence of active infection requiring intravenous (IV) antibiotics during Screening requiring therapy within 7 days prior to C1D
- •Has active uncontrolled bleeding or a bleeding diathesis within 28 days prior to C1D
- •Has serious or non-healing wound, fistula, skin ulcer, or non-healing bone fracture within 7 days prior to C1D
- •Has received any thoracic radiotherapy within 8 weeks prior to C1D
- •Has a history of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis (requiring steroids or immunosuppressive agents), or idiopathic pneumonitis, or evidence of active pneumonitis on the Screening chest computed tomography (CT) scan. Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Has known hypersensitivity to Ac-225; for patients participating in the 111In-ABD147 dosimetry substudy, also has known hypersensitivity to In-
- •Has known hypersensitivity to Chinese hamster ovary cell products.
- •Has a history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
- •Has human immunodeficiency virus infection; patients who are taking an effective antiviral therapy with undetectable viral load prior to C1D1 are eligible.
- •Has chronic hepatitis B virus (HBV) infection. Patients who are taking an effective suppressive therapy and have an undetectable HBV viral load are eligible.
- •Has a history of hepatitis C virus (HCV) infection, unless treated and cured; patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible.
- •Has carcinomatous meningitis.
- •Has active symptomatic cord compression.
- •Has active symptomatic superior vena cava syndrome.
- •Has another primary malignancy that has not been treated with curative intent (discuss with Medical Monitor), except for non-metastatic cutaneous basal cell or squamous cell carcinoma, or non-muscle invasive bladder cancer.
- •Is unwilling or unable to follow protocol requirements.
- •Has any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational product or interpretation of the patient's safety or study results.
研究组 & 干预措施
Phase 1a Dose Escalation Group
225Ac-ABD147 administered in escalating dose cohorts
干预措施: 225Ac-ABD147 (Drug)
Phase 1b Dose Expansion Group
Expansion Dose Level selected from Phase 1a Dose Escalation
干预措施: 225Ac-ABD147 (Drug)
结局指标
主要结局
Ph 1a: Safety of 225Ac-ABD147 - Number and Grade of Adverse Events
时间窗: 12 months
Incidence of adverse events and serious adverse events graded according to NCI-CTCAE v5.0; Clinically significant changes from baseline for laboratory values, ECGs, and vital signs will be evaluated as adverse events.
Ph 1a: Tolerability of 225Ac-ABD147 - Number of Dose Limiting Toxicities
时间窗: 12 months
Incidence and nature of dose limiting toxicities.
Ph 1b: Safety of 225Ac-ABD147 to Determine the RP2D for Further Development - Number and Grade of Adverse Events
时间窗: 12 months
Incidence of adverse events and serious adverse events graded according to NCI-CTCAE v5.0; Clinically significant changes from baseline for laboratory values, ECGs, and vital signs will be evaluated as adverse events.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - Overall Response Rate (ORR)
时间窗: 12 months
ORR of confirmed complete response (CR) and partial response (PR) per investigator assessment using RECIST v1.1.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - Disease Control Rate (DCR)
时间窗: 12 months
DCR per investigator assessment using RECIST v1.1.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - Duration of Response (DOR)
时间窗: 12 months
DOR of confirmed CR and PR per investigator assessment using RECIST v1.1.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - Duration of Progression Free Survival (PFS)
时间窗: 12 months
PFS per investigator assessment using RECIST v1.1.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - Overall Survival (OS)
时间窗: 12 months
OS.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - PFS Rate
时间窗: 12 months
6 monthly PFS rate per investigator assessment using RECIST v1.1.
Ph 1b: Preliminary Efficacy of 225Ac-ABD147 - OS Rate
时间窗: 12 months
6 monthly OS rate.
Ph 1b: Biodistribution and Absorbed Dose - Measurement of Activity
时间窗: 6 months
Whole blood radioactivity with whole blood gamma counting.
Ph 1b: Immunogenicity of 225Ac-ABD147 - Measurement of Anti-drug Antibodies
时间窗: 6 months
Anti-drug antibody to ABD147.
次要结局
- Ph 1a: Determination of 225Ac-ABD147 Dose for Expansion (Phase 1b)(12 months)
- Ph 1a: Safety and Tolerability of Multiples Doses of 225Ac-ABD147 - Number and Grade of Adverse Events(12 months)
- Ph 1a: PK Profile of 225Ac-ABD147 - Peak Plasma Concentration (Cmax)(6 months)
- Ph 1a: PK Profile of 225Ac-ABD147 - Area under the plasma concentration versus time curve (AUC)(6 months)
- Ph 1a: PK Profile of 225Ac-ABD147 - Volume of Distribution (Vd)(6 months)
- Ph 1a: Safety of 111In-ABD147 - Number and Grade of Adverse Events(2 weeks)
- Ph 1a: Immunogenicity of 225Ac-ABD147 - Measurement of Anti-drug antibodies(6 months)
- Ph 1a: PK Profile of 225Ac-ABD147 - Elimination(6 months)