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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

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ClinicalTrials.gov Identifier: NCT02770378
Recruitment Status : Active, not recruiting
First Posted : May 12, 2016
Last Update Posted : April 12, 2018
Sponsor:
Collaborators:
Reliable Cancer Therapies
Anticancer Fund, Belgium
Information provided by (Responsible Party):
Marc-Eric Halatsch, University of Ulm

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

Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Temozolomide Drug: Aprepitant Drug: Minocycline Drug: Disulfiram Drug: Celecoxib Drug: Sertraline Drug: Captopril Drug: Itraconazole Drug: Ritonavir Drug: Auranofin Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.

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

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

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

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

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

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

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

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

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

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




Primary Outcome Measures :
  1. 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 [ Time Frame: Week 12 ]

Secondary Outcome Measures :
  1. Overall survival according to Kaplan-Meier estimates [ Time Frame: through study completion, an average of 1 year ]
  2. Progression-free survival according to Kaplan-Meier estimates [ Time Frame: through study completion, an average of 1 year ]
  3. Best tumor response according to the Revised Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: through study completion, an average of 1 year ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02770378


Locations
Germany
University of Ulm School of Medicine
Ulm, Baden-Württemberg, Germany, 89081
Sponsors and Collaborators
University of Ulm
Reliable Cancer Therapies
Anticancer Fund, Belgium
Investigators
Principal Investigator: Marc-Eric Halatsch, MD Universitiy of Ulm School of Medicine

Responsible Party: Marc-Eric Halatsch, Prof. Dr., University of Ulm
ClinicalTrials.gov Identifier: NCT02770378     History of Changes
Other Study ID Numbers: CUSP9v3
First Posted: May 12, 2016    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Marc-Eric Halatsch, University of Ulm:
Temozolomide
Recurrent Glioblastoma

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Ritonavir
Itraconazole
Hydroxyitraconazole
Minocycline
Celecoxib
Disulfiram
Captopril
Auranofin
Aprepitant
Fosaprepitant
Sertraline
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors