WSD0922-FU for the Treatment of Glioblastoma, Anaplastic Astrocytoma, or Non-small Cell Lung Cancer With Central Nervous System Metastases
WSD0922-FU for the Treatment of Glioblastoma, Anaplastic Astrocytoma, or Non-small Cell Lung Cancer With Central Nervous System Metastases
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.
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.

 III. To assess anti-tumor activity: intracranial and extracranial disease control rate (DCR)
 and change in tumor size compared with baseline according to RANO criteria for GBM/AA and
 RECIST 1.1 for NSCLC.

 IV. To assess anti-tumor activity: intracranial and extracranial duration of response (DOR)
 and change in tumor size compared with baseline according to RANO criteria for GBM/AA and
 RECIST 1.1 for NSCLC.

 V. To assess anti-tumor activity: intracranial and extracranial progression-free survival
 (PFS) and change in tumor size compared with baseline according to RANO criteria for GBM/AA
 and RECIST 1.1 for NSCLC.

 EXPLORATORY/CORRELATIVE RESEARCH OBJECTIVES:

 I. To investigate the presence and/or identity of the drug metabolites of WSD0922-FU, and the
 concentrations of these in the plasma, cerebrospinal fluid (CSF), and tumor.

 II. To assess plasma concentration of WSD0922-FU and metabolite SN16110801P1 and
 pharmacokinetics (PK) parameters after single and multiple doses of WSD0922-FU.

 III. To assess the brain tumor pharmacokinetics of WSD0922-FU and SN16110801P1 after a single
 dose of WSD0922-FU (Dose Expansion - Brain tumor penetration [BTP] cohort only).

 IV. To assess cerebrospinal fluid (CSF) concentration of WSD0922-FU and SN16110801P1 after
 multiple doses of WSD0922-FU (Dose Expansion - NSCLC leptomeningeal metastases [NSCLC LM]
 cohort only).

 V. To explore the impact of tumor markers (e.g. MGMT promoter methylation, EGFR mutation
 [including EGFR vIII], PTEN deletion, TP53 mutation, etc.) on clinical parameters associated
 with WSD0922-FU treatment.

 VI. To evaluate and measure pharmacodynamic biomarkers of inhibition of EGFR and downstream
 signals in tumor samples after a single dose of WSD0922-FU (Dose Expansion Cohort - BTP
 cohort only).

 VII. To evaluate the effect of food on the pharmacokinetics of single dose of WSD0922-FU in
 plasma (Dose Expansion - NSCLC LM cohort only).

 OUTLINE: This is a dose-escalation study.

 DOSE ESCALATION: Patients receive WSD0922-FU orally (PO) once daily (QD) or twice daily (BID)
 on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
 unacceptable toxicity.

 DOSE EXPANSION: Patients are assigned to 1 of 3 cohorts.

 COHORT I: Patients with GBM/AA receive WSD0922-FU PO BID on days 1-28. Cycles repeat every 28
 days in the absence of disease progression or unacceptable toxicity.

 COHORT II: 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.

 COHORT III: Patients with NSCLC LM 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.

 After completion of study treatment, patients are followed up at 4-6 weeks, then every 2
 months until progressive disease, at progressive disease, and then every 3 months after
 progressive disease for up to 5 years.
Inclusion Criteria:

 -  Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort

 -  Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic
 astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC)

 -  EGFR Status:

 -  GBM/AA must have EGFR amplification and/or EGFRvIII mutation

 -  NSCLC must have confirmed activating EGFR mutation (including Del19, L858R,
 EGFRvIII, G719A, L861Q)

 -  Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts

 -  Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort:

 -  Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM)
 or anaplastic astrocytoma, IDH wildtype (AA)

 -  EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation

 -  Brain Tumor Penetration (BTP) Cohort:

 -  Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM)
 or anaplastic astrocytoma, IDH wildtype (AA)

 -  EGFR status: GBM/AA must have been previously demonstrated to have EGFR
 amplification and/or EGFRvIII mutation based on any prior resection

 -  Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort:

 -  Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC)

 -  EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19,
 L858R, EGFRvIII, G719A, L861Q)

 -  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) and at least one line of chemotherapy (doublet chemotherapy such as
 carboplatin/paclitaxel, carboplatin/gemcitabine, cisplatin/paclitaxel,
 cisplatin/gemcitabine; single agent such as pemetrexed, gemcitabine, taxanes, or
 other regimens listed in the National Comprehensive Cancer Network [NCCN]
 guidelines)

 -  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 1. 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

 -  Radiographic progression: Patients with GBM/AA must have radiographic progression
 based on RANO criteria

 -  Measurable disease

 -  Performance status: ECOG 0 or 1 for patients with GBM/AA

 -  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 Leptomeningeal Metastases (NSCLC LM) cohort:

 -  Previous treatments: Patients must have had either:

 -  No prior treatment with an EGFR TKI, or

 -  Previous EGFR TKI treatment (e.g. gefitinib, erlotinib, afatinib, or
 osimertinib) followed by central nervous system (CNS) disease progression
 without extra-CNS progression

 -  Radiographic progression: Patients must have new or radiographic progression of
 leptomeningeal metastases. Positive confirmation of CSF cytology is both
 necessary and sufficient to define the presence of leptomeningeal metastases for
 patients in this study

 -  For the NSCLC LM expansion cohort, patients must have both positive confirmation
 of CSF cytology and at least one site of leptomeningeal disease that can be
 assessed by magnetic resonance imaging (MRI) and which is suitable for repeat
 assessments as per the investigator's discretion

 -  Performance Status: ECOG 0, 1, or 2

 -  Registration - Inclusion Criteria Common to Dose Escalation and Dose Expansion
 Cohorts:

 -  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

 -  aPTT =< 1.5 x 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/PT and
 PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the
 investigator's discretion

 -  Total bilirubin =< 1.5 x ULN and < 3 mg/dL for patients with Gilbert's disease
 (obtained =< 14 days prior to registration)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
 ULN or =< 5 x ULN if due to liver involvement by tumor (obtained =< 14 days prior to
 registration)

 -  Creatinine =< 1.5 x ULN or estimated glomerular filtration rate (estimated glomerular
 filtration rate [eGFR]) >= 60 mL/minute (obtained =< 14 days prior to registration)

 -  Negative pregnancy test done =< 7 days prior to registration, for persons of
 childbearing potential only

 -  Provision of signed and dated written informed consent prior to any study specific
 procedures, sampling, and analyses

 -  Willingness to provide mandatory blood specimens and mandatory tissue specimens for
 correlative research

 -  Willingness to return to enrolling institution for follow-up (during the active
 monitoring phase of the study i.e., active treatment and clinical follow-up)

 -  Male and female patients of child bearing potential must be willing to use
 contraception, (i.e., condoms, birth control) while on study and until 3 months after
 the last dose of study drug is taken

 -  Must be willing to take light-protective measures during the study and for 2 weeks
 after their last dose of WSD0922-FU

 -  Must have a minimum life expectancy of >= 3 months

 -  Must be stable on no more than 2 mg of dexamethasone (or equivalent steroids) per day.
 Steroid dose should not be adjusted during cycle 1 of therapy

 -  Must not take enzyme-inducing anticonvulsants treatment for at least 2 weeks prior to
 enrollment. Patients on enzyme-inducing anticonvulsants will be changed to non-enzyme
 inducing anticonvulsants. Drug-drug interactions (DDI) with proton pump inhibitor
 (PPI), H2 blockers or antacids have not been assessed; therefore it is suggested to
 avoid taking those drugs together with WSD0922-FU

 -  Strong inducers and strong inhibitors of CYP3A should be discontinued at least 14 days
 prior to registration

 Exclusion Criteria:

 -  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) within 8 days or approximately 5 x half-life, whichever
 is the longer, prior to registration (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 prior anti-EGFR or EGFRvIII therapies
 (erlotinib, gefitinib, afatinib, osimertinib, ABT-414, ABBV-221, AMG-595, AMG-596
 etc.) or prior treatment with bevacizumab

 -  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