A Phase 0 Study of AZD1775 in Recurrent GBM Patients

Glioblastoma Clinical Trial

Official title:

A Phase 0 Study of AZD1775 in Preoperative Glioblastoma Multiforme (GBM) Patients Scheduled for Resection to Evaluate for Central Nervous System (CNS) Penetration

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02207010
• Other study ID #: BBTRC 001
• Status: Completed
• Phase: Early Phase 1
• Start date: July 2014
• Est. completion date: March 25, 2019

Study information

• Verified date: December 2020
• Source: St. Joseph's Hospital and Medical Center, Phoenix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study would test how much of the new drug, AZD1775, is present in tumor, blood, and skin after one dose of the drug.

The purpose of the study is not to treat the tumor, but to see if the drug actually gets into the tumor cells. This study does not replace routine cancer treatment.

Description:

Patients will be administered one dose of AZD1775 prior to surgical resection of their tumor. There will be 2 portions of this trial, referred to as Part 1 and Part 2. Part 1 will involve a dose escalation strategy where 3 separate doses (100, 200, and 400mg) will be evaluated. Each dose cohort will involve 4 patients. Surgery, with tissue harvest for determination of both tissue drug level and biomarker evaluation, will occur at 8 hrs post drug administration.

Part 2 will determine the potential tumor drug level and PD effects at various time intervals after drug administration of a single select drug dose. Currently, we are planning to use a dose (200 mg) that has been deemed safe when used in combination with cytotoxic therapy. However, if results from Part 1 suggest an alternate dose may be preferable, we will consider using that alternate dose in Part 2. Dosing will be followed by surgical resection at 2-4 hrs and at 22-26 hrs post dose.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 25, 2019
• Est. primary completion date: December 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients with 1 prior resection of histologically-diagnosed de novo GBM

2. Patient must have MRI evidence of disease recurrence

3. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =2

4. Patients = 18 years of age

5. Adequate hematologic, renal, and hepatic function

6. Patients must not have co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical treatment

7. Patients must not have active infection or fever > 38.5°C

8. Patients must not be pregnant or nursing

9. Patients must have archival tumor tissue block available for research use

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

11. Patient has voluntarily agreed to participate by giving written informed consent.

Exclusion Criteria:

1. Less than 18 years of age

2. Diagnosis of anything other than first-recurrence GBM

3. GBM tissue from first-resection not available

4. Previous treatment with AZD1775

5. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

6. Patient has known hypersensitivity to the components of potential study therapy or its analogs.

7. Patient has had prescription or non-prescription drugs or other products known to be metabolized by cytochrome P450 3A4 (CYP3A4), or to inhibit or induce CYP3A4, which cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication (inhibitors generally for 5 half-lives). Medications of particular concern are the following inhibitors of CYP3A4: azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, HIV protease inhibitors, nefazodone and the following inducers of CYP3A4: phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include statins (lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride. CYP3A4.

8. Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.

9. Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

10. Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.

11. Patients expecting to reproduce within the projected duration of the study (estimated to be 1 year), and women who are pregnant or breastfeeding.

12. Patient is known to be suffering from Acquired Immune Deficiency Syndrome (AIDS).

13. Patient has known history of Hepatitis B or C.

14. Patient has symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.

15. Patient has a clinical history suggestive of Li-Fraumeni Syndrome.

Related Conditions & MeSH terms

• GBM
• Glioblastoma

Intervention

Biological:
• AZD1775
All patients receive a single dose of the oral study drug prior to surgery for resection of GBM.

Locations

Country	Name	City	State
United States	Barrow Neurological Institute at St. Joseph's Hospital Medical Center	Phoenix	Arizona

Sponsors (5)

Lead Sponsor	Collaborator
St. Joseph's Hospital and Medical Center, Phoenix	American Society of Clinical Oncology, Barbara Ann Karmanos Cancer Institute, The Ben & Catherine Ivy Foundation, Translational Genomics Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	P53 mutation status	Will be summarized using descriptive statistics	up to time of surgery
Other	Presence of checkpoint regulator genes in GBM specimens	checkpoint regulator genes in GBM specimens	up to time of surgery
Primary	Plasma concentration of AZD1775 following single dose of AZD1775	Will be summarized using descriptive statistics	at baseline, 2-4, 8-12, and 22-26 hours following single dose of AZD1775
Primary	Intratumoral concentration of AZD1775	Will be summarized using descriptive statistics	up to day of surgery
Secondary	Degree of CDC2 (Tyr15) phosphorylation in tissue	Will be summarized using descriptive statistics	at baseline and up to 26 hours post dosing
Secondary	Number of GBM cells in M-phase of cell cycle (PH3)	Will be summarized using descriptive statistics	at baseline and up to 26 hours post dose AZD1775
Secondary	Presence of double-strand DNA damage (?H2AX).	Will be summarized using descriptive statistics	at baseline and up to 26 hours post dose AZD1775