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

Inclusion Criteria:

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

• Histolopathological and/or molecular confirmation of either glioblastoma, IDHwildtype (GBM), (as defined by either the 2016 or 2021 World HealthOrganization [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 WHOclassifications) or anaplastic astrocytoma, IDH wildtype (AA) (as definedby the 2016 WHO classification)

• EGFR status: GBM/AA must have EGFRvIII mutation

• Brain Tumor Penetration (BTP) Cohort:

• Diagnosis: Histopathological or molecular confirmation of eitherglioblastoma, IDH wildtype (GBM) (as defined by either the 2016 or 2021WHO classifications) or anaplastic astrocytoma, IDH wildtype (AA) (asdefined by the 2016 WHO classification)

• EGFR status: GBM/AA must have been previously demonstrated to have eitherEGFR amplification and/or any activating EGFR mutation based on any priorresection

• 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. Followingprotocol 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 andtemozolomide

• Patients with NSCLC must have been previously treated with at least oneline 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 RANOcriteria

• Patients with NSCLC must have new or radiographic progression in thecentral nervous system (brain metastases and/or leptomeningealmetastases). Positive confirmation of CSF cytology is both necessary andsufficient to define the presence of leptomeningeal metastases forpatients in this study. Patients with positive CSF cytology and brainmetastases will be categorized as "leptomeningeal metastases."

• Measurable disease

• Eastern Cooperative Oncology Group (ECOG) 0 or 1. For patients with NSCLC withleptomeningeal 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 withradiation and temozolomide. First recurrence only (no additional systemictherapies have been administered for recurrent disease)

• Radiographic progression: Patients with GBM/AA must have radiographicprogression based on RANO criteria

• Patients remain eligible for enrollment if the recurrent disease has beensurgically removed

• Performance status: ECOG 0 or 1

• Brain Tumor Penetration (BTP) Cohort:

• Previous treatments: Patients must have been previously treated withradiation and temozolomide

• Radiographic progression: Patients with GBM/AA must have radiographicprogression based on RANO criteria

• Therapeutic surgical resection of GBM/AA required as part of routineclinical care

• Performance status: ECOG 0 or 1

• Non-Small Cell Lung Cancer (NSCLC) cohort:

• Previous treatments: No limitations

• Radiographic progression: Patients must have radiographic progressionbased on RECIST 1.1 criteria.

• Measurable Disease

• Performance Status: ECOG 0 or 1

• Registration - Inclusion Criteria Common to Dose Escalation and Dose ExpansionCohorts:

• Age >= 18 years old

• Ability to understand and the willingness to sign a written informed consentdocument

• 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 toregistration)

• 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 toparticipate if they have no signs of bleeding or clotting and theINR/prothrombin time (PT) and partial thromboplastin time (PTT)/activated (a)PTT results are compatible with an acceptable risk-benefit ratio as perthe 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 toparticipate if they have no signs of bleeding or clotting and the INR/PTand PTT/aPTT results are compatible with an acceptable risk-benefit ratioas 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 pyruvatetransaminase [SGPT]) =< 3 x ULN or =< 5 x ULN if due to liver involvement bytumor (obtained =< 14 days prior to registration)

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

• Negative pregnancy test done =< 7 days prior to registration, for persons ofchildbearing potential only

• Provision of signed and dated written informed consent prior to any studyspecific procedures, sampling, and analyses

• Willingness to provide mandatory blood specimens for correlative research

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

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

• Must be willing to take light-protective measures during the study and for 2weeks 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 adjustments should be minimized during cycle 1 oftherapy. Patients enrolling to the BTP expansion cohort do not have anyrestrictions on current steroid/dexamethasone dosing.

• Must not take enzyme-inducing anticonvulsants treatment for at least 2 weeksprior to enrollment. Patients on enzyme-inducing anticonvulsants will bechanged to non-enzyme inducing anticonvulsants

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

• Willingness to provide mandatory tissue specimens for correlative research (BTPcohort only)

Exclusion Criteria:

• Registration - Exclusion Criteria for Dose Escalation and Dose Expansion

• Any of the following because this study involves an investigational agent whosegenotoxic, mutagenic and teratogenic effects on the developing fetus andnewborn are unknown:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential who are unwilling to employ adequatecontraception

• Any of the following prior therapies:

• Any cytotoxic chemotherapy or other anticancer drugs for the treatment ofadvanced NSCLC from a previous treatment regimen =< 14 days prior toregistration

• In patients with NSCLC, treatment with an EGFR TKI (e.g., erlotinib,gefitinib, afatinib or osimertinib) must be discontinued prior toregistration. Additionally, prior EGFR TKI therapy must be discontinuedwithin 8 days or 5 half-lives, whichever is longer, prior to study therapyinitiation. If sufficient wash-out time has not occurred due to scheduleor PK properties, an alternative appropriate wash-out time based on knownduration and time to reversibility of drug related adverse events could beagreed 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 42days 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 EGFRvIIItherapies (erlotinib, gefitinib, afatinib, osimertinib, ABT-414, ABBV-221,AMG-595, AMG-596 etc.)

• Patients with GBM/AA who have been treated with bevacizumab within thelast 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 thejudgment of the investigator, would make the patient inappropriate for entryinto this study or interfere significantly with the proper assessment of safetyand toxicity of the prescribed regimens including uncontrolled hypertension andactive bleeding diatheses, which in the investigator's opinion makes itundesirable for the patient to participate in the trial or which wouldjeopardize compliance with the protocol. Screening for chronic conditions isnot 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 newanti-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 withcompliance and ability to tolerate treatment as outlined in the protocol

• Illness/social situations that would limit compliance with studyrequirements

• Receiving any other investigational agent which would be considered as a treatmentfor the primary neoplasm

• Patients with a "currently active" second malignancy other than non-melanoma skincancers 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 diseasefor 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) (CommonTerminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QTcorrection formula

• A history of additional risk factors for torsade de pointes (TdP) (e.g., heartfailure, 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 cistriple mutation (Del19/T790m/C797S or L858R/T790M/C797S)

• Past medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis which required steroid treatment, or any evidence ofclinically active interstitial lung disease. History of hypersensitivity to activeor inactive excipients of WSD0922-FU or drugs with a similar chemical structure orclass to WSD0922-FU

• Refractory nausea and vomiting if not controlled by supportive therapy, chronicgastrointestinal diseases, inability to swallow the formulated product or previoussignificant 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 ensurethat patients on this cohort can participate in the food effect study