Phase Ib/II Multicentric Study Combining Glasdegib (PF-04449913) With Temozolomide in Patients With Newly Diagnosed Glioblastoma, Safety and Preliminary Efficacy for the Combination

Grupo Español de Investigación en Neurooncología8 sites in 1 country75 target enrollmentMarch 15, 2018

ConditionsGlioblastoma

InterventionsPF-04449913 Temozolomide Oral Capsule

DrugsPF-04449913 Temozolomide Oral Capsule

Overview

Phase: Phase 1
Intervention: PF-04449913
Conditions: Glioblastoma
Sponsor: Grupo Español de Investigación en Neurooncología
Enrollment: 75
Locations: 8
Primary Endpoint: Glasdegib Dose
Status: Completed
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Registry

clinicaltrials.gov

Start Date

March 15, 2018

End Date

November 29, 2023

Last Updated

2 years ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Grupo Español de Investigación en Neurooncología

Responsible Party

Sponsor

Eligibility Criteria

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).
•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.

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.

Arms & Interventions

Glasdegib and Temozolomide Oral Capsule

During Phase Ib, Four to six weeks after surgical diagnosis, concurrent with radiotherapy (STUPP) + temozolomide (75mg/m2/day for 42 days) + PF-04449913 (Glasdegib) (3 dose levels will be evaluated: 100mg QD, 150mg QD and 200mg QD, or 75-50mg) will be administered. During Phase II, Radiation therapy, temozolomide and glasdegib will be administered. This last, as the dose that have been selected previously, based on the Phase Ib results. Glasdegib ( PF-04449913) recommended dose until progresion of disease, unacceptable toxicity, non-compliance, consent withdrawal up to 2 years.

Intervention: PF-04449913