Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922-FU
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Mayo Clinic
- 入组人数
- 56
- 试验地点
- 6
- 主要终点
- Recommended phase 2 dose
研究概览
简要总结
This phase I trial studies the side effects and best dose of WSD0922-FU for the treatment of glioblastoma, anaplastic astrocytoma, or non-small cell lung cancer that has spread to the central nervous system (central nervous system metastases). WSD0922-FU is a targeted treatment which blocks the EGFR protein - a strategy that has led to a lot of benefit in patients with many different cancers. WSD0922-FU may also be able to get into cancers in the brain and spinal cord and help patients with brain and spinal cord cancers.
Funding Source - FDA OOPD
详细描述
PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of EGFR/EGFRvIII inhibitor WSD0922-FU (WSD0922-FU) in subjects with recurrent glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) and central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC).
SECONDARY OBJECTIVES:
I. To evaluate the incidence of treatment-emergent adverse events (TEAEs) related to WSD0922-FU.
II. To assess anti-tumor activity: intracranial and extracranial overall response rate (ORR), and change in tumor size compared with baseline according to Response Assessment in Neuro-Oncology (RANO) criteria for GBM/AA and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for NSCLC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort
- •Histolopathological and/or molecular confirmation of either glioblastoma, IDH wildtype (GBM), (as defined by either the 2016 or 2021 World Health Organization [WHO] classifications) anaplastic astrocytoma, IDH wildtype (AA) (as defined by the 2016 WHO classification) or non-small cell lung cancer (NSCLC)
- •EGFR Status:
- •GBM/AA must either EGFR amplification and/or any activating EGFR mutation (e.g. A289T, EGFRvIII , etc.)
- •NSCLC must have a confirmed activating EGFR mutation (e.g. Del19, L858R, EGFRvIII, G719A, L861Q, T790M, C797S, etc.)
- •Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts
- •Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort:
- •Diagnosis: Histological or molecular confirmation of either glioblastoma, IDH wildtype (GBM) (as defined by either the 2016 or 2021 WHO classifications) or anaplastic astrocytoma, IDH wildtype (AA) (as defined by the 2016 WHO classification)
- •EGFR status: GBM/AA must have EGFRvIII mutation
- •Brain Tumor Penetration (BTP) Cohort:
- •Diagnosis: Histopathological or molecular confirmation of either glioblastoma, IDH wildtype (GBM) (as defined by either the 2016 or 2021 WHO classifications) or anaplastic astrocytoma, IDH wildtype (AA) (as defined by the 2016 WHO classification)
- •EGFR status: GBM/AA must have been previously demonstrated to have either EGFR amplification and/or any activating EGFR mutation based on any prior resection
- •Non-Small Cell Lung Cancer (NSCLC) cohort:
- •Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC)
- •EGFR status: NSCLC must have confirmed activating EGFR mutation. Following protocol amendment 7, NSCLC must have EGFR C797S mutation.
- •Registration -Inclusion Criteria Specific to Dose Escalation Cohort
- •Previous treatments:
- •Patients with GBM/AA must have been previously treated with radiation and temozolomide
- •Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. gefitinib, erlotinib, afatinib, or osimertinib)
- •Radiographic progression:
- •Patients with GBM/AA must have radiographic progression based on RANO criteria
- •Patients with NSCLC must have new or radiographic progression in the central nervous system (brain metastases and/or leptomeningeal metastases). Positive confirmation of CSF cytology is both necessary and sufficient to define the presence of leptomeningeal metastases for patients in this study. Patients with positive CSF cytology and brain metastases will be categorized as "leptomeningeal metastases."
- •Measurable disease
- •Eastern Cooperative Oncology Group (ECOG) 0 or
- •For patients with NSCLC with leptomeningeal metastases, ECOG 2 is also acceptable
- •Registration - Inclusion Criteria Specific to Dose Expansion Cohorts
- •Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort:
- •Previous treatments: Patients must have been previously treated with radiation and temozolomide. First recurrence only (no additional systemic therapies have been administered for recurrent disease)
- •Radiographic progression: Patients with GBM/AA must have radiographic progression based on RANO criteria
- •Patients remain eligible for enrollment if the recurrent disease has been surgically removed
- •Performance status: ECOG 0 or 1
- •Brain Tumor Penetration (BTP) Cohort:
- •Previous treatments: Patients must have been previously treated with radiation and temozolomide
- •Radiographic progression: Patients with GBM/AA must have radiographic progression based on RANO criteria
- •Therapeutic surgical resection of GBM/AA required as part of routine clinical care
- •Performance status: ECOG 0 or 1
- •Non-Small Cell Lung Cancer (NSCLC) cohort:
- •Previous treatments: No limitations
- •Radiographic progression: Patients must have radiographic progression based on RECIST 1.1 criteria.
- •Measurable Disease
- •Performance Status: ECOG 0 or 1
- •Registration - Inclusion Criteria Common to Dose Escalation and Dose Expansion Cohorts:
- •Age >= 18 years old
- •Ability to understand and the willingness to sign a written informed consent document
- •Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
- •Leukocytes >= 3.0 x 10^9/L (obtained =< 14 days prior to registration)
- •Absolute neutrophil count >= 1.5 x 10^9/L (obtained =< 14 days prior to registration)
- •Platelets >= 100 x 10^9/L (obtained =< 14 days prior to registration)
- •International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration)
- •Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/prothrombin time (PT) and partial thromboplastin time (PTT)/activated (a)PTT results are compatible with an acceptable risk-benefit ratio as per the investigator's discretion
- 另有 16 项未显示
排除标准
- •Registration - Exclusion Criteria for Dose Escalation and Dose Expansion
- •Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- •Pregnant persons
- •Nursing persons
- •Persons of childbearing potential who are unwilling to employ adequate contraception
- •Any of the following prior therapies:
- •Any cytotoxic chemotherapy or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen =< 14 days prior to registration
- •In patients with NSCLC, treatment with an EGFR TKI (e.g., erlotinib, gefitinib, afatinib or osimertinib) must be discontinued prior to registration. Additionally, prior EGFR TKI therapy must be discontinued within 8 days or 5 half-lives, whichever is longer, prior to study therapy initiation. If sufficient wash-out time has not occurred due to schedule or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug related adverse events could be agreed upon by the Investigator and Wayshine)
- •Radiation therapy to the brain =< 12 weeks prior to registration
- •Patients with GBM/AA must not have received (i) nitrosoureas within 42 days of registration, (ii) any chemotherapy or experimental therapy within 28 days or 5 half-lives, whichever is longer, prior to registration
- •Patients with GBM/AA must not have received prior anti-EGFR or EGFRvIII therapies (erlotinib, gefitinib, afatinib, osimertinib, ABT-414, ABBV-221, AMG-595, AMG-596 etc.)
- •Patients with GBM/AA who have been treated with bevacizumab within the last four months are not eligible
- •Received prior systemic biologic therapy (CAR-T, anti-PD-1 / anti-PD-L1, anti-CTLA-4, etc.) within 28 days prior to registration.
- •Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required
- •Subjects who are human immunodeficiency virus (HIV), hepatitis virus B (HBV), and/or hepatitis virus C (HCV) positive
- •Uncontrolled inter-current illness including, but not limited to:
- •Symptomatic CNS complications that require urgent neurosurgical or medical (e.g. mannitol) intervention
- •Seizures requiring a change in anti-epileptic medications (addition of new anti-epileptic or increase in dose) =< 2 weeks of registration
- •Known intracranial hemorrhage which is unrelated to tumor
- •Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol
- •Illness/social situations that would limit compliance with study requirements
- •Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
- •Patients with a "currently active" second malignancy other than non-melanoma skin cancers and carcinoma-in-situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration
- •Any of the following cardiac criteria:
- •A marked baseline prolongation of QT/corrected QT (QTc) interval
- •(e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QT correction formula
- •A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome)
- •The use of concomitant medications that prolong the QT/QTc interval
- •Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S)
- •Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU
- •Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU
- •Inadequate bone marrow reserve or organ function
- •Patients with NSCLC LM who are unable to undergo collection of CSF
- •Patients who are unable to tolerate dairy (GBM/AA cohort only). This is to ensure that patients on this cohort can participate in the food effect study
研究组 & 干预措施
Dose expansion Cohort II (WSD0922-FU, surgery)
Patients with BTP receive a single dose of WSD0922-FU prior to surgery. Patients then undergo surgical resection of brain tumor. After surgery, patients receive WSD0922-FU PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study.
干预措施: Biospecimen Collection - blood samples (Procedure)
Dose escalation (WSD0922-FU)
Patients receive WSD0922-FU PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and blood sample collection on study. Patients with NSCLC with LM also undergo collection of CSF samples on study.
干预措施: EGFR/EGFRvIII Inhibitor WSD0922-FU (Drug)
Dose escalation (WSD0922-FU)
Patients receive WSD0922-FU PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and blood sample collection on study. Patients with NSCLC with LM also undergo collection of CSF samples on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Dose expansion Cohort I (WSD0922-FU)
Patients with GBM/AA receive WSD0922-FU PO on days 1 and 4 of cycle 0. Patients then receive WSD0922-FU PO BID on days 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study. Patients may undergo additional optional blood sample collection on study.
干预措施: Biospecimen Collection - blood samples (Procedure)
Dose expansion Cohort II (WSD0922-FU, surgery)
Patients with BTP receive a single dose of WSD0922-FU prior to surgery. Patients then undergo surgical resection of brain tumor. After surgery, patients receive WSD0922-FU PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study.
干预措施: EGFR/EGFRvIII Inhibitor WSD0922-FU (Drug)
Dose expansion Cohort II (WSD0922-FU, surgery)
Patients with BTP receive a single dose of WSD0922-FU prior to surgery. Patients then undergo surgical resection of brain tumor. After surgery, patients receive WSD0922-FU PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Dose expansion Cohort III (WSD0922-FU)
Patients with NSCLC receive WSD0922-FU PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and CT during screening and on study, as well as blood sample collection on study. Patients with LM also undergo collection of CSF samples on study. Patients may also undergo optional blood sample collection on study.
干预措施: Biospecimen Collection - CSF samples (Procedure)
Dose expansion Cohort III (WSD0922-FU)
Patients with NSCLC receive WSD0922-FU PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and CT during screening and on study, as well as blood sample collection on study. Patients with LM also undergo collection of CSF samples on study. Patients may also undergo optional blood sample collection on study.
干预措施: Computed Tomography (Procedure)
Dose expansion Cohort III (WSD0922-FU)
Patients with NSCLC receive WSD0922-FU PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and CT during screening and on study, as well as blood sample collection on study. Patients with LM also undergo collection of CSF samples on study. Patients may also undergo optional blood sample collection on study.
干预措施: EGFR/EGFRvIII Inhibitor WSD0922-FU (Drug)
Dose escalation (WSD0922-FU)
Patients receive WSD0922-FU PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and blood sample collection on study. Patients with NSCLC with LM also undergo collection of CSF samples on study.
干预措施: Biospecimen Collection - blood samples (Procedure)
Dose escalation (WSD0922-FU)
Patients receive WSD0922-FU PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and blood sample collection on study. Patients with NSCLC with LM also undergo collection of CSF samples on study.
干预措施: Biospecimen Collection - CSF samples (Procedure)
Dose escalation (WSD0922-FU)
Patients receive WSD0922-FU PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and blood sample collection on study. Patients with NSCLC with LM also undergo collection of CSF samples on study.
干预措施: Computed Tomography (Procedure)
Dose expansion Cohort I (WSD0922-FU)
Patients with GBM/AA receive WSD0922-FU PO on days 1 and 4 of cycle 0. Patients then receive WSD0922-FU PO BID on days 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study. Patients may undergo additional optional blood sample collection on study.
干预措施: EGFR/EGFRvIII Inhibitor WSD0922-FU (Drug)
Dose expansion Cohort I (WSD0922-FU)
Patients with GBM/AA receive WSD0922-FU PO on days 1 and 4 of cycle 0. Patients then receive WSD0922-FU PO BID on days 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study. Patients may undergo additional optional blood sample collection on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Dose expansion Cohort II (WSD0922-FU, surgery)
Patients with BTP receive a single dose of WSD0922-FU prior to surgery. Patients then undergo surgical resection of brain tumor. After surgery, patients receive WSD0922-FU PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study, as well as blood sample collection on study.
干预措施: Therapeutic Conventional Surgery (Procedure)
Dose expansion Cohort III (WSD0922-FU)
Patients with NSCLC receive WSD0922-FU PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and CT during screening and on study, as well as blood sample collection on study. Patients with LM also undergo collection of CSF samples on study. Patients may also undergo optional blood sample collection on study.
干预措施: Biospecimen Collection - blood samples (Procedure)
Dose expansion Cohort III (WSD0922-FU)
Patients with NSCLC receive WSD0922-FU PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and CT during screening and on study, as well as blood sample collection on study. Patients with LM also undergo collection of CSF samples on study. Patients may also undergo optional blood sample collection on study.
干预措施: Magnetic Resonance Imaging (Procedure)
结局指标
主要结局
Recommended phase 2 dose
时间窗: Up to 28 days
The RP2D is either the maximum tolerated dose (MTD) or the highest dose tested (in the case that none of the doses are deemed higher than the MTD), whichever is higher.
次要结局
- Incidence of adverse events(Up to 4-6 weeks after study completion)
- Overall response rate(Up to 5 years)
- Duration of response (DOR)(From the first occurrence of a PR (or better) and progression, assessed up to 5 years)
- Progression Free Survival (PFS)(From study entry to disease progression, assessed up to 5 years)
- Incidence of adverse events(Up to 4-6 weeks after study completion)
- Overall response rate(Up to 5 years)
- Duration of response (DOR)(From the first occurrence of a PR (or better) and progression, assessed up to 5 years)
- Progression Free Survival (PFS)(From study entry to disease progression, assessed up to 5 years)