Radiodynamic Therapy (RDT) With Gliolan in Patients With First Recurrence of Brain Tumor (ALA-RDTinGBM)

• ClinicalTrials.gov Identifier: NCT05590689
• Recruitment Status: Recruiting
• First Posted: October 21, 2022
• Last Update Posted: November 22, 2022
• Sponsor: Westfälische Wilhelms-Universität Münster
• Collaborator: photonamic GmbH & Co. KG
• Information provided by (Responsible Party): Westfälische Wilhelms-Universität Münster

Study Description

Brief Summary:

The investigational drug 5-ALA (known under the trade name Gliolan®) is an approved drug for the surgical removal of malignant glioma (WHO grade III and IV). In this trial, the drug is being tested outside of its actual approval as a radiosensitizer in combination with conventional radiotherapy for first-time recurrence (relapse) of malignant glioma. In this clinical trial, the investigational drug 5-ALA is being used for the first time in a multiple dose escalation regimen in combination with radiotherapy following surgical removal of a recurrent malignant glioma in humans. The investigational drug, 5-ALA, has been used as a single dose to date as a standard of care for visualization of malignant tissue in the surgical removal of gliomas.

The planned clinical trial will first and foremost investigate how well repeated administration of the investigational drug 5-ALA is tolerated in combination with radiotherapy. At the same time, the design of the trial serves to optimize this novel therapeutic procedure with regard to the frequency of administration of the investigational drug 5-ALA in combination with radiotherapy for future clinical trials.

As a secondary objective, the efficacy of additional 5-ALA administration will also be investigated.

Condition or disease	Intervention/treatment	Phase
Glioblastoma	Drug: Gliolan; Radiation: Radiodynamic therapy	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: A modified 3+3 design is used. The maximum tolerated dose of repeated RDT (consisting of 5-ALA dosing an radiotherapy) and safety will be determined in 9 cohorts.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Dose Escalation Trial of Radiodynamic Therapy (RDT) With 5-Aminolevulinic Acid in Patients With First Recurrence of Glioblastoma
• Actual Study Start Date: November 9, 2022
• Estimated Primary Completion Date: July 2024
• Estimated Study Completion Date: January 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Radiodynamic therapy (RDT); All patients will be treated with RDT. Patients are devided into cohorts which differs in the total amount and frequence of RDT.	Drug: Gliolan; A repetitive dose of Gliolan will be administrated in combination with radiotherapy (radiodynamic therapy); Other Name: 5-Aminolevulinic acid; Radiation: Radiodynamic therapy; Radiotherapy will be performed in combination with Gliolan administration

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose (MTD) [ Time Frame: 6 weeks after last R(D)T in adjuvant phase ]

   In the resent study we will investigate the maximum-tolerated dose (MTD) of the combination of 5-ALA and radiation. MTD is defined as the highest number of RDT that does not cause unacceptable side effects, i.e. at which no more than 1 of 6 patients suffers a dose-limiting toxicity (DLT). DLT describes side effects of a drug that are serious enough to prevent an increase of dose (NCI dictionary of cancer terms). In the present study it is defined as any ≥ Gr.3 hematological toxicity, any ≥ Gr.3 neurological toxicity and any ≥ Gr.3 non-hematological toxicity occurring during the 6 week observation period, that does not resolve to pre-treatment baseline or ≤ Gr. 2 within 3 weeks, either spontaneously or with adequate treatment.

   To detect any relevant DLT the following aspects are monitored:

   • Toxicological safety of repeat doses of 5-ALA
   • Neurological safety of RDT
   • Dermatological safety of RDT
   • Assess all new AEs CTCAE grade 2 or higher

Secondary Outcome Measures :

1. Overall survival rate (OSR) [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Percentage of patients who are alive 6 months after first R(D)T
2. progression-free survival rate (PFS) [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Percentage of patients without tumor progression 6 months after first R(D)T in adjuvant phase
3. event-free survival rate (EFS) [ Time Frame: 6 months after inclusion ]
   Percentage of patients without suffering any disease related event such as DLT or progression until 6 months after inclusion
4. concentration changes of immunhistochemistry marker (e.g. Caspase-3, IBA1, H&E, EvG, P53, Ki 67, gammaH2AX) [ Time Frame: during surgery ]
   analytic results of pharma-radio-dynamic tissue changes. Tissue samples collected during surgery of cohort 0 and 1

Other Outcome Measures:

1. concentration changes of CPI and CPIII [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes as one combined sum parameter
2. concentration changes of radiobiological marker CD3 [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes
3. concentration changes of radiobiological marker CD4 [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes
4. concentration changes of radiobiological marker CD8 [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes
5. concentration changes of radiobiological marker C19 [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes
6. concentration changes of radiobiological marker for total leucocyte count [ Time Frame: 6 months after first R(D)T in adjuvant phase ]
   Analytic results for concentration changes

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Written patient consent after comprehensive information
• Age between 18 and 75 years
• First local recurrence (no remote lesion) of supratentorial glioblastoma after standard therapy (surgery, radio-chemotherapy, concomitant + adjuvant TMZ), second surgery completed, except for neo-adjuvant cohort 0 and 1
• Clinically indicated second radiotherapy
• Histological verification of recurrent glioblastoma, non-methylated MGMT promotor
• Karnofsky Performance Score ≥ 70

• For female and male patients and their female partners of childbearing/reproductive potential(*): Willingness to apply highly effective contraception (Pearl index <1) during the entire study (and for at least 6 months after the first application of 5-ALA). Such methods include:

  1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: I. oral II. intravaginal III. transdermal
  2. progestogen only hormonal contraception associated with inhibition of ovulation: I. oral II. injectable III. implantable
  3. intrauterine device (IUD)
  4. intrauterine hormone-releasing system (IUS)
  5. bilateral tubal occlusion
  6. vasectomised partner
  7. male patients have to use a condom
  8. sexual abstinence
• Pre-menopausal(*) female patients with childbearing potential: a negative pregnancy test must be obtained max. 72h prior to treatment start
• Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN), alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) < 3 times ULN. In the case of documented or suspected Gilbert's disease bilirubin < 3 times ULN.
• Adequate renal function: creatinine < 3 times above ULN; eGFR >/= 60 ml/min, Blood clotting: INR/Quick/PT and PTT within acceptable limits according to the investigator.

(*) Definition: A man is considered of reproductive potential after puberty unless permanently sterile by bilateral orchidectomy. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Exclusion Criteria:

• Patient unable to undergo imaging by MRI, PET or contrast-enhanced CT for whatever reason (e.g. pace-maker)
• Other invasive malignancy within 2 years (except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured)
• Pregnant and breastfeeding women
• Past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
• Any active infection (at the discretion of the investigator)
• Hypersensitivity against porphyrins
• Known diagnosis of porphyria
• Participation in another clinical trial with therapeutic intervention or use of any other therapeutic interventional agent other than the standard therapy since diagnosis of glioblastoma
• Known intolerance to study medication
• Pre-treatment with other potentially phototoxic or photosensitizing substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts, products containing St. John's wort ) during the 2 weeks preceding RDT

Contacts and Locations

Contacts

Contact: Walter Stummer, Prof. Dr.; +49 251 8347472; walter.stummer@ukmuenster.de

Contact: Hans Theodor Eich, Prof. Dr.; +49 251 8347384; hans.eich@ukmuenster.de

Locations

Germany

University Hospital Münster, Klinik für Neurochirurgie; Recruiting

Münster, Germany, 48149

Contact: Walter Stummer, Prof. Dr.

Principal Investigator: Walter Stummer, Prof. Dr.

Sub-Investigator: Hans Theodor Eich, Prof. Dr.

Sponsors and Collaborators

Westfälische Wilhelms-Universität Münster

photonamic GmbH & Co. KG

Investigators

• Principal Investigator: Walter Stummer, Prof. Dr.; University Hospital Muenster

More Information

• Responsible Party: Westfälische Wilhelms-Universität Münster
• ClinicalTrials.gov Identifier: NCT05590689
• Other Study ID Numbers: WWU20_0041; 2021-004631-92 ( EudraCT Number )
• First Posted: October 21, 2022
• Last Update Posted: November 22, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Glioblastoma; Recurrence; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Aminolevulinic Acid; Photosensitizing Agents; Dermatologic Agents