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

NCT02770378 | Completed Phase 1

• 1 other identifier: CUSP9v3
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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

Conditions

Glioblastoma

Keywords

Temozolomide; Recurrent Glioblastoma

Outcome Measures

Primary Outcomes (2)

• Endpoint for phase Ib is the number of patients experiencing dose-limiting toxicity defined as:

  * either any unmanageable grade 3-4 toxicity at the end of the second treatment cycle * or inability to receive at least 7 of the 10 drugs, all of them being given at ≥50% of the target doses at the end of the second treatment cycle * Modifications in terms of doses and/or number of drugs are accepted at any time during treatment.

  Week 12

• Endpoint for phase IIa of the trial is objective stable disease or a better tumor response (i.e., partial response, complete response)

  as assessed by non-contrast and contrast-enhanced standard cranial MRI interpreted using RANO criteria after 6 treatment cycles in comparison to the baseline MRI.

  Week 12

Secondary Outcomes (3)

• Overall survival according to Kaplan-Meier estimates

  through study completion, an average of 1 year

• Progression-free survival according to Kaplan-Meier estimates

  through study completion, an average of 1 year

• Best tumor response according to the Revised Assessment in Neuro-Oncology (RANO) criteria

  through study completion, an average of 1 year

Study Arms (1)

Temozolomide combined with 9 repurposed drugs

EXPERIMENTAL

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.

Drug: Temozolomide; Drug: Aprepitant; Drug: Minocycline; Drug: Disulfiram; Drug: Celecoxib; Drug: Sertraline; Drug: Captopril; Drug: Itraconazole; Drug: Ritonavir; Drug: Auranofin

Interventions

Temozolomide DRUG

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

Temozolomide combined with 9 repurposed drugs

Aprepitant DRUG

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

Temozolomide combined with 9 repurposed drugs

Minocycline 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

Temozolomide combined with 9 repurposed drugs

Disulfiram 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

Temozolomide combined with 9 repurposed drugs

Celecoxib 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

Temozolomide combined with 9 repurposed drugs

Sertraline 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

Temozolomide combined with 9 repurposed drugs

Captopril 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

Temozolomide combined with 9 repurposed drugs

Itraconazole 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

Temozolomide combined with 9 repurposed drugs

Ritonavir 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

Temozolomide combined with 9 repurposed drugs

Auranofin 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

Temozolomide combined with 9 repurposed drugs

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Ulm: lead
• Reliable Cancer Therapies: collaborator
• Anticancer Fund, Belgium: collaborator

Study Sites (1)

University of Ulm School of Medicine

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Related Publications (2)

• 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.

  PMID: 34959641 DERIVED

• 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.

  PMID: 34620071 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide; Aprepitant; Minocycline; Disulfiram; Celecoxib; Sertraline; Captopril; Itraconazole; Ritonavir; Auranofin

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Morpholines; Oxazines; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Disulfides; Sulfides; Sulfur Compounds; Benzenesulfonamides; Sulfonamides; Amides; Benzene Derivatives; Sulfones; Pyrazoles; 1-Naphthylamine; Amines; Naphthalenes; Proline; Imino Acids; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Triazoles; Piperazines; Thiazoles; Aurothioglucose; Organogold Compounds; Organometallic Compounds

Study Officials

• Marc-Eric Halatsch, MD

  Universitiy of Ulm School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: March 14, 2016
• First Posted: May 12, 2016
• Study Start: November 1, 2016
• Primary Completion: October 1, 2018
• Study Completion: December 1, 2020
• Last Updated: October 5, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)