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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02770378
Recruitment Status : Active, not recruiting
First Posted : May 12, 2016
Last Update Posted : October 17, 2019
Sponsor:
Collaborators:
Reliable Cancer Therapies
Anticancer Fund, Belgium
Information provided by (Responsible Party):
Marc-Eric Halatsch, University of Ulm

Tracking Information
First Submitted Date  ICMJE March 14, 2016
First Posted Date  ICMJE May 12, 2016
Last Update Posted Date October 17, 2019
Study Start Date  ICMJE November 2016
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 14, 2019)
  • Endpoint for phase Ib is the number of patients experiencing dose-limiting toxicity defined as: [ Time Frame: Week 12 ]
    • 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.
  • Endpoint for phase IIa of the trial is objective stable disease or a better tumor response (i.e., partial response, complete response) [ Time Frame: Week 12 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2016)
  • The primary endpoint of this trial 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 [ Time Frame: Week 12 ]
  • The primary endpoint of this trial is the number of patients experiencing dose-limiting toxicity defined as: inability to receive at least 7 of the 10 drugs, all of them being given at ≥50% of the target doses Modifications in terms of doses [ Time Frame: up to 48 weeks ]
Change History Complete list of historical versions of study NCT02770378 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2016)
  • Overall survival according to Kaplan-Meier estimates [ Time Frame: through study completion, an average of 1 year ]
  • Progression-free survival according to Kaplan-Meier estimates [ Time Frame: through study completion, an average of 1 year ]
  • Best tumor response according to the Revised Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: through study completion, an average of 1 year ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.

Interventions:
  • Drug: Temozolomide
  • Drug: Aprepitant
  • Drug: Minocycline
  • Drug: Disulfiram
  • Drug: Celecoxib
  • Drug: Sertraline
  • Drug: Captopril
  • Drug: Itraconazole
  • Drug: Ritonavir
  • Drug: Auranofin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 11, 2016)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2020
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02770378
Other Study ID Numbers  ICMJE CUSP9v3
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Marc-Eric Halatsch, University of Ulm
Study Sponsor  ICMJE University of Ulm
Collaborators  ICMJE
  • Reliable Cancer Therapies
  • Anticancer Fund, Belgium
Investigators  ICMJE
Principal Investigator: Marc-Eric Halatsch, MD Universitiy of Ulm School of Medicine
PRS Account University of Ulm
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP