Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma
Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma
Glioblastomas (GBMs) are the most common malignant primary brain tumors. Despite
 multimodality aggressive therapies (surgery followed by chemoradiotherapy based on TMZ and
 adjuvant TMZ), median overall survival is only 12 to 15 months. This dramatic behavior is
 mainly due to the high invasiveness and proliferation rate of GBM.

 In addition, GBM exhibits a high resistance to standard chemotherapy and radiotherapy.
 Current strategies for the treatment of GBM are only palliative, and include surgical
 resection (which is frequently incomplete due to the proximity of the tumour to vital brain
 structures) and focal radiotherapy. A large number of chemotherapeutic agents (e.g.
 alkylating agents such as TMZ and nitrosoureas such as carmustine) have also been tested, but
 they display limited efficacy.

 The current gold standard first line treatment for glioma for patients less than 70 years old
 includes radiation and concurrent TMZ followed by adjuvant TMZ (i.e., the "Stupp regimen").
 However, results are disappointing and there is an unmet medical need of new drugs in this
 setting.

 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.
Inclusion Criteria:

 -  Ability to understand and the willingness to sign a written informed consent document.

 -  Male or Female ≥18 years old.

 -  Newly diagnosed GBM confirmed by biopsy or resection no more than 4 to 6 weeks before
 registration.

 -  Patients candidates for Stupp treatment

 -  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).

 -  Patients must have sufficient time for recovery from prior surgery (at least 4 weeks).

 -  ECOG ≤ 1.

 -  Adequate hematologic function: Hematocrit ≥ 29%, Leukocytes > 3,000/mcL, ANC ≥ 1,500
 cells/ul, platelets ≥ 100,000 cells/ul.

 -  Adequate liver function: Bilirubin ≤ 2 x ULN; AST (SGOT) ≤ 2.5 X ULN

 -  Creatinine within normal institutional limits or creatinine clearance > 60 mL/min for
 subjects with creatinine levels above institutional normal.

 -  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.

 -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by
 history: ≥60 years old and no menses for ≥1 year without an alternative medical cause;
 OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
 bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

 Exclusion Criteria:

 -  Presence of extracranial metastatic disease.

 -  Participants may not be receiving any other investigational agents.

 -  Patients must not have received prior Gliadel wafers.

 -  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.

 -  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.

 -  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.

 -  Congenital or known history of 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).

 -  Current (or within 6 months) significant cardiovascular disease, including, but not
 limited to myocardial infarction, cerebrovascular accident, transient ischemic attack
 or symptomatic pulmonary embolism, bradycardia defined as <50 bpms.

 -  Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (eg, atrial fibrillation) or QTcF
 interval (QTc using Fridericia's formula) >470 msec.

 -  Active and clinically significant infections.

 -  Current use or anticipated requirement for drugs known to be moderate or strong
 cytochrome p450 inhibitors.

 -  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.

 -  Patients who have had prior stereotactic radiotherapy, convection enhanced delivery or
 brachytherapy (as gliosis/scarring from these modalities may limit delivery).

 -  Patients will not be eligible if they present with leptomeningeal dissemination.

 -  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.

 -  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.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to glasdegib.

 -  Other severe acute or chronic medical condition, uncontrolled intercurrent illness or
 laboratory abnormality that may increase the risk associated with trial participation
 or investigational product administration or may interfere with the interpretation of
 trial results and, in the judgment of the investigator, would make the patient
 inappropriate for entry into this trial.

 -  Female patients who are pregnant or breastfeeding or male or female patients of
 reproductive potential who are not willing to employ highly effective birth control
 from screening to 180 days after the last dose of the study treatment.