A Phase II, Multi-center, Open-label Study of AUY922 Administered IV on a Once-weekly Schedule in Patients With Advanced Non-small-cell Lung Cancer Who Have Received at Least Two Lines of Prior Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 153
- 试验地点
- 5
- 主要终点
- Response Assessment by Study Stratum - Per Investigator Assessment
研究概览
简要总结
This study will assess the efficacy of AUY922, when administered weekly at 70 mg/m2, in adult patients with advanced Non-small-cell Lung Cancer (NSCLC), who have received at least two prior lines of chemotherapy. Patients will be retrospectively, and prospectively, stratified based on their molecular tumor etiology. The following strata was assigned: Patients with Epidermal growth factor receptor (EGFR) activating mutations, Patients with Kirstin Raus sarcoma virus (KRAS) activating mutations, Patients with EML4-ALK (anaplastic lymphoma kinase) translocations and patients that were both EGFR and Kras wild type.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Patients with histologically or cytologically confirmed advanced (stage IIIB or stage IV) NSCLC who have received at least two prior lines of treatment. Patients who, in the investigators opinion, are deemed unsuitable for the standard 2nd line chemotherapy will be eligible for protocol participation. One of the prior lines must have included a platinum agent. Prior treatment with a platinum agent is not a requirement for EGFR mutant patients and patients with EML4-ALK translocations
- •Patients enrolled to the fifth stratum, modified EGFR mutant, must have documented prior response to EGFR TKI as defined by CR, PR or SD for 6 months or greater unless patient has de novo resistance to EGFR TKI (e.g. exon 20 insertions.)
- •All patients must have at least one measurable lesion as defined by RECIST criteria. Previously irradiated lesions are not measurable unless the lesion is new or has demonstrated clear progression after radiation
- •World Health Organization (WHO) performance status ≤
- •For patients enrolled to the fifth stratum, modified EGFR mutant, World Health Organization (WHO) performance status ≤ 1
- •Patients enrolled to the fifth stratum, modified EGFR mutant, must be willing and suitable to undergo fresh baseline biopsy prior to study treatment (unless patient had recent biopsy after EGFR TKI progression that concluded resistance to EGFR TKI.)
- •Hematologic:
- •Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L.
- •Hemoglobin (Hgb) ≥ 9 g/dl.
- •Platelets (plt) ≥ 100 x 109/L.
- •Biochemistry:
- •Total calcium (corrected for serum albumin) within normal limits or correctable with supplements.
- •Magnesium within lower normal limits or correctable with supplements.
- •Adequate liver function defined as:
- •AST/SGOT and ALT/SGPT ≤ 3.0 x Upper limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastasis are present.
- •Serum bilirubin ≤ 1.5 x ULN.
- •Serum albumin > 2.5 g/dL.
- •Serum creatinine ≤ 1.5 x ULN or 24 hour clearance ≥ 50 mL/min.
排除标准
- •Patients who have received more than four lines of prior treatment. Exception: Patients enrolled to the fifth stratum, modified EGFR mutant, must not have received more than two prior lines of therapy. Chemotherapy administered as adjuvant treatment more than six months prior to study enrollment is not considered a prior line of therapy for purposes of this study.
- •Patients with a history of CNS metastasis. Note: Patients without clinical signs and symptoms of CNS involvement are not required to have MRI of the brain. Exception: Patients with treated brain metastases who are asymptomatic, who has discontinued corticosteroids, and who have been clinically stable for one month will be eligible for protocol participation. This exception is not valid for patients enrolled to the fifth stratum, modified EGFR mutant. These patients must not have CNS involvement.
- •Prior anti-neoplastic treatment with any HSP90 or HDAC inhibitor compound.
- •Patients must not have received:
- •any systemic anti-cancer treatment or radiotherapy within 4 weeks prior to first dose of study treatment and should have recovered to baseline or less than Grade 1 from toxicities of such therapy prior to the first dose of study treatment
- •2 weeks for palliative radiotherapy to bones, 6 weeks for nitrosoureas and mitomycin
- •4 weeks for monoclonal antibodies
- •and ≤5 half-life of the agent or active metabolites [if any] for continuous systemic anti-cancer treatment or investigational
- •Patients who do not have either an archival tumor sample available or are unwilling to have a fresh tumor sample collected at baseline.
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
EGFR mutant patients
Patients with EGFR activating mutation tumors (Note: These patients must have progressed on one prior EGFR TKI containing regimen unless they have documented T790M activating mutation). Patients received AUY922 at 70 mg/m^2 weekly infusions.
干预措施: AUY922 (Drug)
Kras mutant patients
Patients with KRAS mutant tumors. Patients received AUY922 at 70 mg/m^2 weekly infusions.
干预措施: AUY922 (Drug)
EGFR and Kras wild type patients
Patients exhibiting both mutations were stratified to the KRAS mutation stratum. Patients received AUY922 at 70 mg/m^2 weekly infusions.
干预措施: AUY922 (Drug)
Patients with EML4-ALK translocation
Patients with NSCLC who have tumors with an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene leading to the production of an EML4-ALK fusion tyrosine kinase. ALK is a transmembrane protein, which has a kinase domain and is not usually expressed in the lung. EML4 mediate ligand-independent dimerization, and therefore constitutive activity of the ALK tyrosine kinase domain. Patients received AUY922 at 70 mg/m^2 weekly infusions.
干预措施: AUY922 (Drug)
Modified EGFR mutant patients
The modified EGFR stratum was defined as patients less heavily pretreated who had received one or two lines of prior therapy, with a documented response to a EGFR tyrosine kinase inhibitor (TKI) (complete response (CR), partial response (PR) or stable disease (SD) for ≥ 6 months), unless the patient had de novo resistance to EGFR TKI. Patients received AUY922 at 70 mg/m^2 weekly infusions.
干预措施: AUY922 (Drug)
结局指标
主要结局
Response Assessment by Study Stratum - Per Investigator Assessment
时间窗: 18 weeks
The primary endpoint of the study was the investigator assessment of efficacy at 18 weeks in terms of response complete response (CR)/partial response (PR), stable disease (SD), or non clinical benefit (NCB) as assessed by response evaluation criteriain solid tumors (RECIST) version 1.0. ORR = patients with confirmed complete or partial response. Stable disease at 18 weeks = patients without response and with no assessment of progressive disease up to 18 weeks, but with an assessment of stable disease or better either within 2 weeks prior to the 18 week time point, or at the next non-missing assessment after the 18 week time point. No clinical benefit = all other patients.
次要结局
- Overall Survival Rate Using Kaplan Meier Estimates - Per Investigator Radiological Review(Week 12, Week 18)
- Progression Free Survival (PFS) Rate as Per Investigator Using Kaplan Meier Estimates - Per Investigator Radiological Review(Week 12, Week 18)
- Pharmacokinetics (PK) of Plasma Concentration of AUY922 and Its Metabolite BJP762: AUCinf(1 hour after infusion)
- Pharmacokinetics (PK) of Plasma Concentration of AUY922 and Its Metabolite BJP762: AUClast(1 hour after infusion)
- Pharmacokinetics (PK) of Plasma Concentration of AUY922 and Its Metabolite BJP762: Cmax(1 hour after infusion)