Repurposed Drugs in Research for Cancer Clinical Trials- Pitavastatin

Study Overview
=================
Brief Summary
-----------------
The goal of this Phase 0 trial is to study if pre-operative oral pitavastatin administration reaches the tumour in patients with primary or a recurrent glioblastoma. The main question[s] it aims to answer are: Does pitavastatin reach a cytotoxic concentration in gadolinium-enhanced tumour tissue after oral administration? Does pitavastatin achieve a concentration that can synergize with temozolomide in the gadolinium non-enhanced area of the tumour? Participants will receive pitavastatin in differing dosages a week before their elective surgery and blood and tumour samples will be collected.

Official Title
-----------------
Phase 0 lead-in Trial of Pitavastatin in Primary and Recurrent Glioblastoma Patients

Conditions
-----------------
Glioblastoma Multiforme, Adult, Recurrent Glioblastoma

Intervention / Treatment
-----------------
* Drug: Pitavastatin calcium


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eligible for resection of a suspected primary glioblastoma or a recurrent glioblastoma. MRI- measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 1 perpendicular measurement of at least 0.5 cm. Adequate Renal Function defined as: estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 by Chronic Disease Epidemiology Collaboration (CKD-EPI) equation. CK elevation 3 X ULN. Ability to understand and the willingness to sign a written informed consent document. Participant has voluntarily agreed to participate by giving written informed consent Written informed consent for participation in the protocol must be obtained prior to any screening procedures taking place. Willingness and ability to comply with all scheduled visits, treatment plans, laboratory tests and other procedures. Age ≥18 years at time of consent. Ability and willingness to swallow oral medication. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause. For females of reproductive potential: use of highly effective contraception method defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Females of child-bearing potential must agree not to breastfeed starting at screening, and throughout the study period. Exclusion Criteria: Pregnancy or lactation. Known allergic reactions to components of the pitavastatin calcium tablets. Patients with ALAT and ASAT levels 3 X ULN. Unwillingness to temporarily stop an already prescribed statin, during treatment with pitavastatin. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal or antiviral therapy. Concomitant use of cyclosporin, gemfibrozil, systemic fusidic acid, fibrates, niacin or colchicine. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, unexplained elevated liver transaminase levels, and active and chronic hepatitis as determined by the investigator. Suspicion of oral malabsorption, influencing the uptake of drugs from the ileum, such as Morbus Crohn. Treatment with another investigational drug or other intervention within 30 days prior to enrolment or within 5 half-lives of the investigational product, whichever is longer.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: open label, dose-finding, 3+3-like dose-escalation study design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose group 1: 16 mg<br>Pitavastatin 16 mg via oral route in the form of daily tablets for 6 days before SOC surgery | Drug: Pitavastatin calcium<br>* Daily Pitavastatin administration<br>* Other names: Alipza;|
| Experimental: Dose group 2: 32 mg<br>Pitavastatin 32 mg via oral route in the form of daily tablets for 6 days before SOC surgery | Drug: Pitavastatin calcium<br>* Daily Pitavastatin administration<br>* Other names: Alipza;|
| Experimental: Dose group 3: 48 mg<br>Pitavastatin 48 mg via oral route in the form of daily tablets for 6 days before SOC surgery | Drug: Pitavastatin calcium<br>* Daily Pitavastatin administration<br>* Other names: Alipza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intratumoral pitavastatin concentration as assessed by LC-MS analysis on tumour tissue. | Detection of pitavastatin in gadolinium enhanced and gadolinium non-enhanced tumour. tissue in relation to serum levels after preoperative administration. | From the last patient visit of each dose cohort at day 9 to 2 weeks after the last patient visit of each dose cohort. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of short-term pitavastatin treatment as assesseb by a customized questionnaire related to adverse events found during the use of pitavastatin. | Number of AEs, SAEs and SUSARs collected at the end of the trial. Events will be scored according to CTC criteria version 5.0 (Published November 27th, 2017). | From the last patient visit of the last dose cohort to 2 weeks after the last patient visit of the last dose cohort on day 9. | 
| Relation of plasma pitavastatin concentration and intratumoral pitavastatin concentration as assessed by LC-MS analysis on plasma and tumour tissue. | Correlation of pitavastatin concentration in plasma to pitavastatin concentration in different tumour sites(gadolinium enhanced, gadolinium non-enhanced and tumour periphery). | From the moment the LC-MS analysis of the last patient tumour tissue and plasma is performed to two weeks after the last patient visit on day 9 of the last dose cohort. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 0, GBM, Glioma, Pitavastatin