Pilot Study of DS-8201a Pharmacodynamics in Patients With HER2-Expressing Advanced Solid Tumors
概览
- 阶段
- 1 期
- 干预措施
- Trastuzumab Deruxtecan
- 疾病 / 适应症
- Advanced Malignant Solid Neoplasm
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 62
- 试验地点
- 6
- 主要终点
- Tumor immune microenvironment response
- 状态
- 进行中（未招募）
- 最后更新
- 2个月前
概览
简要总结
This phase I trial studies the biological effects of DS-8201a on patients with HER2 positive cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). DS-8201a works by binding to a protein called HER2 that is present on the surface of tumor cells. This allows DS-8201a to kill the tumor cells by damaging their deoxyribonucleic acid (DNA), resulting in tumor cell death. This study looks at how DS-8201a may affect the levels of certain proteins and immune cells in tumors and how well the drug works against tumor cells by examining cells from a small piece tumor taken before and after DS-8201a is given.
详细描述
PRIMARY OBJECTIVE: I. To assess the effects of trastuzumab deruxtecan (DS-8201a) on total Top1 levels in biopsy specimens from patients with HER2-expressing advanced solid tumors, at early and late post-treatment time points, thereby establishing the degree and duration of DS-8201 target engagement. SECONDARY OBJECTIVES: I. To assess any associations between serum concentrations of DS-8201a and the effects of DS-8201a on total Top1 levels in tumor biopsy specimens. II. To determine the safety and tolerability of DS-8201a administered intravenously every 3 weeks, in 21-day cycles, at a dose of 5.4 mg/kg. III. To determine the overall response rate (complete response \[CR\] + partial response \[PR\]) for patients administered intravenously with DS-8201a every 3 weeks, in 21-day cycles, at a dose of 5.4 mg/kg. EXPLORATORY OBJECTIVES: I. To evaluate the effects of DS-8201a on CD8+ T cell infiltration and activation in tumor, tumor PD-L1 and HER2 expression, and DDR signaling (for example: gamma H2AX, RAD51, and phosphorylated \[p\]NBS1) in biopsy specimens. II. To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with DS-8201a response or resistance. III. To examine any associations between baseline tumor HER2 amplification or HER2 expression level and response to DS-8201a. IV. To evaluate the effects of DS-8201a on tumor levels of HER2 and DDR-associated proteins. V. To examine any tumor genomic alterations that may be associated with resistance to DS-8201a. VI. To evaluate anti-drug antibodies following administration of DS-8201a. OUTLINE: Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), computed tomography (CT) or magnetic resonance imaging (MRI), biopsies, and collection of blood samples throughout the study. After completion of study treatment, patients are followed up for 40 days.
研究者
入排标准
入选标准
- •Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
- •Patients must have measurable or evaluable disease
- •Age \>= 18 years of age
- •Patients must have HER2-positive or HER2-expressing tumors as defined by Clinical Laboratory Improvement Act (CLIA)-certified labs. Patients must have either:
- •A tumor HER2 immunohistochemistry (IHC) score of 1+ or greater (as determined by a CLIA-certified IHC test, per criteria specified) or
- •A tumor with HER2 amplification (as determined by CLIA-certified in situ hybridization \[ISH\] or a CLIA-certified next-generation sequencing assay)
- •Patients with HER2 mutations are eligible, as are patients with HER2-positive breast cancer
- •Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
- •Absolute neutrophil count \>= 1,500/mcL (within 8 days of enrollment)
- •Platelets \>= 100,000/mcL (within 8 days of enrollment)
排除标准
- •Patients who have had:
- •Chemotherapy (including antibody drug therapy, retinoid therapy, hormonal therapy for cancer-with the exception of standard of care androgen deprivation treatment) within:
- •4 weeks or five half-lives, whichever is shorter, for small-molecule targeted agents such as 5-fluorouracil-based agents, folinate agents, weekly paclitaxel or
- •6 weeks for nitrosoureas or mitomycin C or
- •Immunotherapy, including monoclonal antibody therapy, within 4 weeks
- •Patients with any of the following pulmonary-related illnesses:
- •A history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or for whom suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- •Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\] grade 3-4 per Global Initiative for Obstructive Lung Disease \[GOLD\] criteria, restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
- •Patients who have had radiation therapy within 4 weeks (or palliative stereotactic radiation therapy within 2 weeks)
- •Patients who have had a major surgery within 4 weeks
研究组 & 干预措施
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Trastuzumab Deruxtecan
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Biopsy Procedure
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Biospecimen Collection
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Computed Tomography
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Echocardiography Test
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Magnetic Resonance Imaging
Treatment (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, biopsies, and collection of blood samples throughout the study.
干预措施: Multigated Acquisition Scan
结局指标
主要结局
Tumor immune microenvironment response
时间窗: Up to day 1 of cycle 3 (each cycle is 21 days) or optionally, up to time of disease progression or restaging follow-up
Tumor-adjacent CD8+, CD3ζ pY142+ cells/mm\^2 .
Total topoisomerase 1 (Top1)
时间窗: Up to day 1 of cycle 3 (each cycle is 21 days) or optionally, up to time of disease progression or restaging follow-up
次要结局
- Overall response rate(From the start of the treatment until disease progression/recurrence)
- Incidence of adverse events(Up to 30 days post-treatment)
- Association between serum concentrations of DS-8201a and total Top1 levels in tumor biopsies(Up to day 1 of cycle 3 (each cycle is 21 days) or optionally, up to time of disease progression or restaging follow-up)