Evaluate the Safety and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma

• ClinicalTrials.gov Identifier: NCT04091503
• Recruitment Status: Unknown
• First Posted: September 16, 2019
• Last Update Posted: September 17, 2019
• Sponsor: Center Trials & Treatment Europe
• Information provided by (Responsible Party): Center Trials & Treatment Europe

Study Description

Brief Summary:

The purpose of this pilot study is to determine the safety, tolerability, and the maximum tolerated dose intranasal administration of temozolomide (TMZ) as a single agent in Treatment on the patients with GBM.

Intranasal administration is a new method of treating brain tumours for the direct administration of drugs, inhibitors or viruses, with minimal involvement of the BBB. The investigators know the orally prescribed standard chemotherapy temozolomide (TMZ) is widely used to treat glioma tumours.

Received evidence of safety and efficacy in a full cycle of preclinical trials (on GLP Standart) and tests of calculated doses of intranasal administration of TMZ in healthy volunteers.

Intranasal administration of temozolomide is considered as GBM therapy, which provides direct access to a therapeutic dose of the drug into the brain (to the neoplastic process) with low toxicity

Condition or disease	Intervention/treatment	Phase
Glioma, Malignant; Gliosarcoma; Astrocytoma of Brain	Drug: Intranasal Modified Temozolomide	Phase 1

Detailed Description:

The investigators are trying to evaluate a clinically potentially effective intranasal way of delivering TMZ to the brain, taking into account the anatomical structure of os ethmoidal.

The most important factor in the effectiveness of the drug is the achievement of an adequate amount of the active agent in its unbound state with albumin on the blood of a patient and the exposure time to the tumour process. Failure to comply with this requirement (difficulties in overcoming the BBB) was identified as the main obstacle to the successful treatment of all types of brain tumours. Translation to improved clinical outcomes in a patient with GBM has not yet been realized. The investigators will use modified temozolomide (without changing the chemical formula) to exclude as much as possible Anosmia, Hyposmia and other violation of the identification of odours with participants.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Pilot Study to Evaluate the Safety, Tolerability and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma (Phase I)
• Estimated Study Start Date: December 10, 2019
• Estimated Primary Completion Date: September 15, 2020
• Estimated Study Completion Date: November 15, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Intranasal Modified Temozolomide 75 mg/M2 per day; 75 mg/M2 per day Intranasal Modified Temozolomide administration of within 5 days per week (max: 30 days)	Drug: Intranasal Modified Temozolomide; Intranasally Modified Temozolomide is administered to patients at a dose of 75/150/200 mg / M2 for five days continuously. After the 5-day course, patients do not take treatment for two days, and they will be examined on an outpatient basis (blood tests, kidney and liver tests, visually mucous membranes of the mouth, nasal cavity, olfactory rapid tests, including the University of Pennsylvania test, etc.). After 30 days after the first intranasal administration of Modified Temozolomide (IM-TMZ), all patients undergo an MRI of the brain with perfusion and ultrasound of the abdominal cavity as an outpatient, after which the results are evaluated; Other Names: Temozolomide; TMZ; IM-TMZ
Active Comparator: Intranasal Modified Temozolomide 150 mg/M2 per day; 150 mg/M2 per day Intranasal Modified Temozolomide administration of within 5 days per week (max: 30 days)	Drug: Intranasal Modified Temozolomide; Intranasally Modified Temozolomide is administered to patients at a dose of 75/150/200 mg / M2 for five days continuously. After the 5-day course, patients do not take treatment for two days, and they will be examined on an outpatient basis (blood tests, kidney and liver tests, visually mucous membranes of the mouth, nasal cavity, olfactory rapid tests, including the University of Pennsylvania test, etc.). After 30 days after the first intranasal administration of Modified Temozolomide (IM-TMZ), all patients undergo an MRI of the brain with perfusion and ultrasound of the abdominal cavity as an outpatient, after which the results are evaluated; Other Names: Temozolomide; TMZ; IM-TMZ
Active Comparator: Intranasal Modified Temozolomide 200 mg/M2 per day; 200 mg/M2 per day Intranasal Modified Temozolomide administration of within 5 days per week (max: 30 days)	Drug: Intranasal Modified Temozolomide; Intranasally Modified Temozolomide is administered to patients at a dose of 75/150/200 mg / M2 for five days continuously. After the 5-day course, patients do not take treatment for two days, and they will be examined on an outpatient basis (blood tests, kidney and liver tests, visually mucous membranes of the mouth, nasal cavity, olfactory rapid tests, including the University of Pennsylvania test, etc.). After 30 days after the first intranasal administration of Modified Temozolomide (IM-TMZ), all patients undergo an MRI of the brain with perfusion and ultrasound of the abdominal cavity as an outpatient, after which the results are evaluated; Other Names: Temozolomide; TMZ; IM-TMZ

Outcome Measures

Primary Outcome Measures :

1. The randomized study to determine the safety of Intranasal Administration of modified Temozolomide. [ Time Frame: up to 60 days (or withdrawal of consent or another discontinuation criterion) from date of randomization ]
   Incidence of Treatment-Emergent Adverse Events will be estimated by the number of participants with Glioblastoma or Gliosarcoma according to the NCI CTC (5.0) with adverse events (AE) in all cohorts.

Secondary Outcome Measures :

1. The maximum tolerated therapeutic dose (MTD) of modified Temozolomide for intranasal administration [ Time Frame: up to 90 days (or withdrawal of consent or another discontinuation criterion) from date of randomization ]
   In the present study, the maximum dose of modified Temozolomide for intranasal administration is 200 mg / M2 a single daily intranasal administration in a course of 5 days. The frequency of adverse events, unacceptable toxicity, or haematological reactions is estimated on a scale the NCI CTCAE (v. 5.0)

Other Outcome Measures:

1. Percentage of Participants Alive 6 Months After Start of Treatment of Temozolomide for intranasal administration [ Time Frame: 180 days ]

   Overall survival (OS) will be determined as the time in days from the start of treatment ( randomizations day ) to death due to any cause was estimated by the Kaplan-Meier method.

   If it was not known for certain that the participant to die, time will be censored at the last date the participant with GBM or Gliosarcomawas known to be alive, date of magnetic resonance imaging (MRI), etc, - assessment, which will be defined as the latest among the date of the last visit.

2. The effectiveness of intranasal administration of modified Temozolomide [ Time Frame: up to 90 days (or withdrawal of consent or another discontinuation criterion) from date of randomization ]
   The effectiveness of the intranasal administration of modified Temozolomide will be evaluated by four MRIs with perfusion (first MRI performed one day before randomization day). The results of all MRI in dynamics will be appreciated by a consultation of radiologists.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Informed consent signed
• 21 years or older
• Histologically confirmed the diagnosis of Grade 4 astrocytic tumour, which includes glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components
• The availability of histological material for the possibility of revising histological verification
• IDH 1 Mutation and IDH2 Mutation are not taken into account when enrolling in that study
• MGMT promoter methylation MUST BE CONFIRMED
• Must have a Karnofsky performance status of ≥ 70% and the ability to use intranasal administration
• Sexually active fertile subjects (male and female) must agree to use accepted methods of contraception during the course of the study and for 3 months after the last intranasal administration of Temozolomide
• Female subjects of childbearing potential must have a negative pregnancy test at screening.
• Must be capable of understanding and complying with the protocol requirements

Exclusion Criteria:

• History of hypersensitivity to TMZ or any of its excipients
• The subject has had major surgery within 28 days prior to starting study treatment, or had non-water-tight dural closure during previous surgery, or has unhealed wounds from previous surgery
• The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• The subject is pregnant or breastfeeding
• The subject suffered a stroke according to the results of the first MRI upon admission
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the effects of prior chemotherapy (haematological and bone marrow suppression effects), generally at least 3 weeks from the most recent administration (6 weeks for nitrosoureas). Subjects may not have received more than 1 cycle of Irinotecan and Temozolomide as previous relapse therapy
• Subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

Contacts and Locations

Contacts

Contact: Silvia Hanton, Dr.; +41315207002; trials@e.mail.fr

Contact: Daniel Stoyanov; +33367390414; stoyanov@top-email.net

Locations

Bosnia and Herzegovina

Central Contact

Banja Luka, Bosnia and Herzegovina, 78000

Bulgaria

Central Contact

Plovdiv,, Bulgaria, 4004

Georgia

Central Contact

Tbilisi, Georgia, 0008

Sponsors and Collaborators

Center Trials & Treatment Europe

More Information

• Responsible Party: Center Trials & Treatment Europe
• ClinicalTrials.gov Identifier: NCT04091503
• Other Study ID Numbers: 7SQZ309D4W
• First Posted: September 16, 2019
• Last Update Posted: September 17, 2019
• Last Verified: September 2019

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

Keywords provided by Center Trials & Treatment Europe:

TMZ; Temozolomide; Intranasal Administration; Nasal Spray; Intranasal Modified Temozolomide

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Gliosarcoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents