A Proof-of-concept Clinical Trial Assessing the Safety of the Coordinated Undermining of Survival Paths by 9 Repurposed Drugs Combined With Metronomic Temozolomide (CUSP9v3 Treatment Protocol) for Recurrent Glioblastoma

Inclusion Criteria:

* Patients with a diagnosis of glioblastoma World Health Organization (WHO) grade IV (histologically confirmed by a pathologist). Patients with prior low-grade glioma are eligible if histological transformation to WHO grade IV glioblastoma was confirmed.
* Progression (according to RANO criteria) after prior radiation and temozolomide treatment
* No more than 3 prior episodes of tumor progression
* ≥ 4 weeks between surgical resection or chemotherapy
* ≥ 12 weeks since last radiotherapy
* Patients \> 18 years of age.
* Karnofsky performance status (KPS) of ≥ 70%
* Stable steroid dose for ≥ 1 week
* Hemoglobin ≥ 10 g/l
* Absolute neutrophil count (ANC) \> 10³ cells/µl
* Platelet count \> 100/µl
* Maximum 5 years since last Pneumovax (or equivalent) and varicella vaccination
* Serum creatinine, aspartat-aminotransferase (AST) and bilirubin ≤ 1.5 times the upper limit of normal (ULN)
* Female patients of childbearing potential with a negative pregnancy test within 7 days of initiation of study treatment. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
* Male and female patients of reproductive potential who agree to employ an effective method of birth control throughout the study and for up to 6 months following discontinuation of study drug. Patients must be counseled on the possibility of cryopreservation of oocytes or sperm.
* Signed informed consent prior to initiation of any study procedure (must understand, voluntarily sign the informed consent form and be able to adhere to the study visit schedule and other protocol requirements).

Exclusion Criteria:

* Female patients who are pregnant or breast-feeding
* Any uncontrolled/unstable medical condition except glioblastoma, including but not limited to uncontrolled/unstable hypertension, uncontrolled/unstable diabetes, uncontrolled endocrinopathies of any kind, uncontrolled/unstable psychiatric conditions
* Renal failure (eGFR \< 60 ml/min)
* Active infection, including pneumonia as shown on X-ray
* Therapeutic anticoagulation use
* Prior stereotactic radiosurgery
* Radiation implants
* Radiolabeled monoclonal antibody therapy unless there was unequivocal disease progression (e.g. a new lesion or biopsy-confirmed recurrence)
* QT interval (QTc) \< 470 msec (based on the mean value of triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome, or known history of QTc prolongation or Torsade de Pointes
* Uncontrolled electrolyte disorders that can aggravate the effects of a QTc-prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)
* History of severe hypersensitivity reaction (≥ grade 3) to any component of the investigational drugs or excipients
* Unable to undergo contrast-enhanced MRI
* Patients who have been treated with any investigational agent(s) within 28 days of the first day of administration of study drugs
* Current active second malignancy other than non-melanoma skin cancers and post-treatment of localized prostate cancer. Patients are not considered to have a currently active malignancy if they are in complete remission for \> 3 years prior to study
* Known HIV infection, active Hepatitis B or C infection
* Any ongoing toxicity from prior anti-cancer therapy that is \> grade 1 and/or that is progressing in severity (except alopecia) and delayed recovery following last temozolomide cycle
* Additional anti-cancer treatment for glioblastoma other than study drug and supportive measures (i.e. dexamethasone)
* Patients refusing consent for registration, storage, and processing of individual disease characteristics, information on the course of the disease, and information obtained from the family physician and/or other physicians involved in the treatment of the patient about study participation.