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

  • STATUS
    Recruiting
  • days left to enroll
    75
  • participants needed
    72
  • sponsor
    Mayo Clinic
Updated on 4 October 2022
paclitaxel
measurable disease
metastasis
pemetrexed
neutrophil count
carboplatin
erlotinib
gemcitabine
EGFR
brain metastases
afatinib
gefitinib

Summary

Funding Source - FDA OOPD

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.

Description

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.

Details
Condition Anaplastic Astrocytoma, IDH-Wildtype, Glioblastoma, IDH-Wildtype, Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Central Nervous System, Metastatic Malignant Neoplasm in the Leptomeninges
Treatment therapeutic conventional surgery, EGFR/EGFRvIII Inhibitor WSD0922-FU
Clinical Study IdentifierNCT04197934
SponsorMayo Clinic
Last Modified on4 October 2022

Eligibility

Yes No Not Sure

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
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
leptomeningeal metastases. Positive confirmation of CSF cytology is both
Performance Status: ECOG 0, 1, or 2
necessary and sufficient to define the presence of leptomeningeal metastases
Registration - Inclusion Criteria Common to Dose Escalation and Dose Expansion
for patients in this study
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
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
Total bilirubin =< 1.5 x ULN and < 3 mg/dL for patients with Gilbert's disease
Provision of signed and dated written informed consent prior to any study specific procedures, sampling, and analyses
(obtained =< 14 days prior to registration)
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
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
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
Known intracranial hemorrhage which is unrelated to tumor
of the investigator, would make the patient inappropriate for entry into this
Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol
study or interfere significantly with the proper assessment of safety and
Illness/social situations that would limit compliance with study requirements
toxicity of the prescribed regimens including uncontrolled hypertension and
active bleeding diatheses, which in the investigator's opinion makes it
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
undesirable for the patient to participate in the trial or which would
Any of the following cardiac criteria
jeopardize compliance with the protocol. Screening for chronic conditions is
A marked baseline prolongation of QT/corrected QT (QTc) interval
not required
(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
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
Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis
triple mutation (Del19/T790m/C797S or L858R/T790M/C797S)
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