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

October 4, 2021 updated by: Marc-Eric Halatsch, University of Ulm
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 Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

10

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Baden-Württemberg
      • Ulm, Baden-Württemberg, Germany, 89081
        • University of Ulm School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Week 12
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.
Week 12

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall survival according to Kaplan-Meier estimates
Time Frame: through study completion, an average of 1 year
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
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
through study completion, an average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Ulm

Collaborators

Anticancer Fund, Belgium
Reliable Cancer Therapies

Investigators

  • Principal Investigator: Marc-Eric Halatsch, MD, Universitiy of Ulm School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2016

Primary Completion (Actual)

October 1, 2018

Study Completion (Actual)

December 1, 2020

Study Registration Dates

First Submitted

March 14, 2016

First Submitted That Met QC Criteria

May 11, 2016

First Posted (Estimate)

May 12, 2016

Study Record Updates

Last Update Posted (Actual)

October 5, 2021

Last Update Submitted That Met QC Criteria

October 4, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CUSP9v3

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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