Glasdegib (SHH pathway inhibitor) is a rational therapeutic agent for patients with newly diagnosed Glioblastoma since inhibits SHH pathway interfering with cancer stem cells and endothelial migration. MedDRA version: 20.0 Level: PT Classification code 10018336 Term: Glioblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Glasdegib
Product Code: PF-04449913-11
Pharmaceutical Form: Tablet
INN or Proposed INN: Glasdegib
CAS Number: 1095173-27
Other descriptive name: PF-04449913
Concentration unit: mg millig
Sponsors
Grupo Español de Investigación en Neurooncología (GEINO)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Ability to understand and the willingness to sign a written informed consent document. 2.Male or Female =18 years old. 3.Newly diagnosed GBM confirmed by biopsy or resection no more than 4-6 weeks before registration. 4.Patients candidates for Stupp treatment. 5.Patients must have at least 15 unstained slides or 1 tissue block (frozen or paraffin embedded) available from a prior biopsy or surgery (archival tumor material). 6.Patients must have sufficient time for recovery from prior surgery (at least 4 weeks). 7.ECOG = 1. 8.Adequate hematologic function: Hematocrit = 29%, Leukocytes > 3,000/mcL, ANC = 1,500 cells/ul, platelets = 100,000 cells/ul. 9.Adequate liver function: Bilirubin = 2 x ULN; AST (SGOT) = 2.5 X ULN 10.Creatinine within normal institutional limits or creatinine clearance > 60 mL/min for subjects with creatinine levels above institutional normal. 11.The effects of SHH pathway inhibitors on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; surgical sterilization) prior to study entry and for the duration of study participation and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 2 weeks prior to starting treatment. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 75 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.Presence of extracranial metastatic disease. 2.Participants may not be receiving any other investigational agents. 3.Patients must not have received prior Gliadel wafers. 4.Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures. 5.Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol. 6.Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form. 7.Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia, right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as 470 msec. 9.Active and clinically significant infections. 10.Current use or anticipated requirement for drugs known to be moderate or strong cytochrome p450 inhibitors. Strong cytochrome P450 3A4 inducers. 11.Current (or within 6 months) significant cardiovascular disease or QTcF (QTc using Fridericia's formula) more than 470 milliseconds. 12.Individuals with a history of a different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patients will not be eligible if they have evidence of other malignancy requiring therapy other than surgery within the last 3 years. 13.Patients who have had prior stereotactic radiotherapy, convection enhanced delivery or brachytherapy as gliosis/scarring from these modalities may limit delivery. 14.Patients will not be eligible if they present with leptomeningeal dissemination. 15.Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects is unknown (glasdegib has been shown to be teratogenic in nonclinical embryo-fetal development studies in rats and mice at subtherapeutic exposures). Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated. 16.HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. 17.History of allergic reactions attributed to compounds of similar chemical or biologic composition to glasdegib. 18.Other severe acute or chronic medical condition, uncontrolled intercurrent illness or labor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib: To determine the MTD and RDP2 are the primary endpoint of this part of the study. The MTD is defined as the dose at which one-third of patients experienced dose-limiting toxicity (DLT) from Glasdegib and/or TMZ using a standard “3+3” dose escalation determined from the toxicities during the first 12 weeks of therapy. The RDP2 is defined as the dose at which equal or fewer than one-sixth of patients experienced dose-limiting toxicity (DLT) form Glasdegib and/or TMZ using a standard “3+3” dose escalation determined from the toxicities during the first 12 weeks of therapy. Phase II: To evaluate overall survival.;Secondary Objective: To assess progression free survival (PFS). To evaluate safety and tolerability of Glasdegib administered at MTD in newly diagnosed GBM. To assess anti-tumor response according to RANO criteria. To assess PFS at 24 months (PFS24). To assess changes in glucocorticoid use. To assess changes in neurological status. Biomarkers: correlation SHh, SMO, GLI-1, and CD133 by immunohistochemistry and OS and treatment response.;Primary end point(s): Overall Survival: Median of overall survival. Time from the start of the trial treatment to the date of exitus for any cause. In those patients who are alive at the last follow-up, OS will be censored by the date of the last follow-up in which the patient was alive. The median SG will be estimated using Kaplan Meier curves. Maximum Tolerated Dose and Recommended Doses for Phase II (RDP2): The primary endpoint for these variables will be the number of patients treated with dose limiting toxicities during the DLT observation period of 12 weeks.;Timepoint(s) of evaluation of this end point: 4 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety/Toxicity Profile: Type, incidence, severity, frequency, severity and relation to the treatment of adverse events collected in the eCRF of the participating patients. It will be studied using descriptive statistics techniques, such as frequency tables and contingency tables. Antitumor Activity: Using RANO criteria, Progression-Free Survival, 24-month progression-free survival rate (PFS24), and response rates in patients with measurable disease. Changes in the use of corticosteroids: Percentage of patients who have increased / decreased the dose of glucocorticoids. Changes in neurological status: Percentage of patients who increase / decrease the MMS / Barthel score. Biomarker study: correlation of SHh, SMO GLI-1, and CD133 by immunohistochemistry and OS. This correlation will be studied using descriptive statistics techniques, such as frequency and contingency tables.;Timepoint(s) of evaluation of this end point: 4 years | — |
Countries
Spain
Contacts
Public ContactFederico Nepote
MFAR Clinical Research
Outcome results
None listed