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

NCT ID: NCT02770378

Last Updated: 2021-10-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-30
• Study Completion Date: 2020-12-31

Brief Summary

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

Detailed 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.

Conditions

Glioblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Temozolomide combined with 9 repurposed drugs

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.

Group Type: EXPERIMENTAL

Temozolomide

Intervention Type: DRUG

Patients will receive temozolomide at a dose of 20 mg/m² BSA twice daily with start day 1 during induction and treatment cycles

Aprepitant

Intervention Type: DRUG

Patients will receive aprepitant at a dose of 80 mg p.o. once daily with start day 1 during induction and treatment cycles

Minocycline

Intervention Type: DRUG

Induction cycle day 3-4: minocycline 50 mg p.o. twice daily from day 19-20; minocycline 100 mg p.o. twice daily during treatment cycle 1-12 (28 days); minocycline 100 mg p.o. twice daily

Disulfiram

Intervention Type: DRUG

Induction cycle day 5-6: disulfiram 250 mg p.o. once daily from day 21-22; disulfiram 250 mg p.o. twice daily during treatment cycle 1-12 (28 days); disulfiram 250 mg p.o. twice daily

Celecoxib

Intervention Type: DRUG

Induction cycle day 1-35: day 7-8: celecoxib 200 mg p.o. twice daily from day 23-24; celecoxib 400 mg p.o. twice daily during treatment cycle 1-12 (28 days); celecoxib 400 mg p.o.twice daily

Sertraline

Intervention Type: DRUG

Induction cycle day 1-35: day 9-10: sertraline 50 mg p.o. twice daily, day 31-32: sertraline 100 mg p.o. twice daily; treatment cycle 1-12: sertraline 100 mg p.o. twice daily

Captopril

Intervention Type: DRUG

Induction cycle day 1-35: day 11-12: captopril 25 mg p.o. twice daily, day 25-26: captopril 50 mg p.o. twice daily; treatment cycle 1-12 (28 days): captopril 50 mg p.o. twice daily

Itraconazole

Intervention Type: DRUG

Induction cycle day 1-35: day 13-14: itraconazole 200 mg p.o. once daily day 27-28; itraconazole 200 mg p.o. twice daily; treatment cycle 1-12 (28 days): itraconazole 200 mg p.o.twice daily

Ritonavir

Intervention Type: DRUG

Induction cycle day 1-35: day 15-16: ritonavir 200 mg p.o. once daily, day 29-30: ritonavir 200 mg p.o. twice daily, day 35: ritonavir 400 mg p.o. twice daily; treatment cycle 1-12 (28 days): ritonavir 400 mg p.o. twice daily

Auranofin

Intervention Type: DRUG

Induction cycle day 1-35: day 17-18: auranofin 3 mg p.o. once daily, day 33-34 auranofin 3 mg p.o. twice daily; treatment cycle 1-12 auranofin 3 mg p.o. twice daily

Interventions

Temozolomide

Patients will receive temozolomide at a dose of 20 mg/m² BSA twice daily with start day 1 during induction and treatment cycles

Intervention Type: DRUG

Aprepitant

Patients will receive aprepitant at a dose of 80 mg p.o. once daily with start day 1 during induction and treatment cycles

Intervention Type: DRUG

Minocycline

Induction cycle day 3-4: minocycline 50 mg p.o. twice daily from day 19-20; minocycline 100 mg p.o. twice daily during treatment cycle 1-12 (28 days); minocycline 100 mg p.o. twice daily

Intervention Type: DRUG

Disulfiram

Induction cycle day 5-6: disulfiram 250 mg p.o. once daily from day 21-22; disulfiram 250 mg p.o. twice daily during treatment cycle 1-12 (28 days); disulfiram 250 mg p.o. twice daily

Intervention Type: DRUG

Celecoxib

Induction cycle day 1-35: day 7-8: celecoxib 200 mg p.o. twice daily from day 23-24; celecoxib 400 mg p.o. twice daily during treatment cycle 1-12 (28 days); celecoxib 400 mg p.o.twice daily

Intervention Type: DRUG

Sertraline

Induction cycle day 1-35: day 9-10: sertraline 50 mg p.o. twice daily, day 31-32: sertraline 100 mg p.o. twice daily; treatment cycle 1-12: sertraline 100 mg p.o. twice daily

Intervention Type: DRUG

Captopril

Induction cycle day 1-35: day 11-12: captopril 25 mg p.o. twice daily, day 25-26: captopril 50 mg p.o. twice daily; treatment cycle 1-12 (28 days): captopril 50 mg p.o. twice daily

Intervention Type: DRUG

Itraconazole

Induction cycle day 1-35: day 13-14: itraconazole 200 mg p.o. once daily day 27-28; itraconazole 200 mg p.o. twice daily; treatment cycle 1-12 (28 days): itraconazole 200 mg p.o.twice daily

Intervention Type: DRUG

Ritonavir

Induction cycle day 1-35: day 15-16: ritonavir 200 mg p.o. once daily, day 29-30: ritonavir 200 mg p.o. twice daily, day 35: ritonavir 400 mg p.o. twice daily; treatment cycle 1-12 (28 days): ritonavir 400 mg p.o. twice daily

Intervention Type: DRUG

Auranofin

Induction cycle day 1-35: day 17-18: auranofin 3 mg p.o. once daily, day 33-34 auranofin 3 mg p.o. twice daily; treatment cycle 1-12 auranofin 3 mg p.o. twice daily

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Reliable Cancer Therapies

INDUSTRY

Sponsor Role: collaborator

Anticancer Fund, Belgium

OTHER

Sponsor Role: collaborator

University of Ulm

OTHER

Sponsor Role: lead

Responsible Party

Marc-Eric Halatsch

Prof. Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marc-Eric Halatsch, MD

Role: PRINCIPAL_INVESTIGATOR

Universitiy of Ulm School of Medicine

Locations

University of Ulm School of Medicine

Ulm, Baden-Wurttemberg, Germany

Countries

Germany

References

Halatsch ME, Dwucet A, Schmidt CJ, Muhlnickel J, Heiland T, Zeiler K, Siegelin MD, Kast RE, Karpel-Massler G. In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma. Pharmaceuticals (Basel). 2021 Nov 29;14(12):1241. doi: 10.3390/ph14121241.

Reference Type: DERIVED

PMID: 34959641 (View on PubMed)

Romo-Perez A, Dominguez-Gomez G, Chavez-Blanco A, Taja-Chayeb L, Gonzalez-Fierro A, Garcia-Martinez E, Correa-Basurto J, Duenas-Gonzalez A. BAPST. A Combo of Common Use Drugs as Metabolic Therapy for Cancer: A Theoretical Proposal. Curr Mol Pharmacol. 2022;15(6):815-831. doi: 10.2174/1874467214666211006123728.

Reference Type: DERIVED

PMID: 34620071 (View on PubMed)

Other Identifiers

CUSP9v3

Identifier Type: -

Identifier Source: org_study_id