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

University of Ulm

Status and phase

Completed

Phase 2

Phase 1

Conditions

Glioblastoma

Treatments

Drug: Celecoxib

Drug: Auranofin

Drug: Sertraline

Drug: Temozolomide

Drug: Ritonavir

Drug: Aprepitant

Drug: Captopril

Drug: Minocycline

Drug: Itraconazole

Drug: Disulfiram

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02770378

CUSP9v3

Details and patient eligibility

About

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

Full description

A proof-of-concept clinical trial assessing the safety of the coordinated undermining of survival paths by 9 repurposed drugs (aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, ritonavir and sertraline) combined with metronomic temozolomide (CUSP9v3 treatment protocol) for recurrent glioblastoma. This is a phase I study for subjects of 18 years and older with glioblastoma that has relapsed after radiation and chemotherapy, as confirmed by histology and MRI.

A total of 10 patients will be treated with the CUSP9v3 treatment protocol. This is a monocentric trial: all patients will be treated at Ulm University Hospital.

Enrollment

10 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

10 participants in 1 patient group

Temozolomide combined with 9 repurposed drugs

Experimental group

Description:

After enrollment, the subject goes into the induction cycle, which lasts 35 days. The induction cycle consists of a drug-by-drug addition and up-dosing process. Hereafter, the subject will enter the treatment cycles (up to 12). During the induction cycle and the first 2 treatment cycles, regimen adjustments (dropping of certain drugs, dose modification of certain drugs) may be executed to accommodate to the patients' individual toxicity reactions that may occur during this period.

Treatment: