Glioblastoma Multiforme
Conditions
Brief summary
The study is designed as an open label, multi-center, Phase 1 study of single agent tinostamustine, used as adjuvant treatment in patients with newly diagnosed GBM who are MGMT unmethylated and have completed concomitant treatment with temozolomide and radiation. Treatment with adjuvant tinostamustine will start within 5 weeks of completion of concomitant temozolomide and radiation. The study is designed to define the MTD by evaluating toxicities during dose escalation. Tinostamustine will be administered on Day 1 of a 21-day treatment cycle. The total number of treatment cycles is 12 for patients who continue to benefit from treatment without disease progression or intolerable toxicity. Patients will enter a 3+3 design with dose escalation/de-escalation depending on safety from the last treated cohort.
Interventions
DRUGTinostamustine
infusion given over 60 minutes
Sponsors
Mundipharma Research Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have Grade 4 isocitrate dehydrogenase (IDH) wild type GBM with local pathology confirmed MGMT-promoter unmethylated status. 2. Patients must have undergone surgical resection of the GBM tumour and have completed standard radiation therapy with concurrent temozolomide and must not have clear signs of progression such as new disease outside the radiation area, neurological progression, or clinical progression that leads to other
Exclusion criteria
. 3. A baseline brain magnetic resonance imaging (MRI) obtained no more than 14 days prior to first dose of tinostamustine on a stable or decreasing dose of steroids for at least 5 days, is required prior to entrance of a patient onto the study. 4. Patients must be registered on the study within 5 weeks of completion of concurrent chemoradiation. 5. Patient must be willing and able to provide written informed consent for the study. 6. Age ≥18 years on day of signing informed consent. 7. Prescribed treatment with concomitant temozolomide must be consistent with the EORTC-22981-26981 study (NCT00006353). The dose must be 75 mg/m2 daily for the 6 to 6.5 weeks of radiation therapy. The patient must have completed at least 75% of temozolomide dosing during radiotherapy. 8. Confirmed IDH wild type. The presence of an IDH mutation will be exclusionary for study enrolment. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e., IDH wild type). If a mutation is identified, then the patient will be ineligible. 9. Patients must have a performance status of ≥60 on the Karnofsky Performance Scale (KPS). 10. If patient is on steroids, patient must be on a stable or decreasing dose of steroids for at least 5 days at the time of baseline brain MRI. 11. Demonstrate adequate organ function as defined in Table 3. All screening laboratories should be performed within 14 days (+/- 2 days) of treatment initiation. 12. Serum potassium and magnesium at least at the lowest limit of normal (LLN) range, before every tinostamustine administration. If it is below LLN, supplementation is permissible. 13. Female patients of childbearing potential should have a negative serum pregnancy test within 48 hours of starting first dose of tinostamustine. 14. Female study participants of childbearing potential and their partners, and male study participants who intend to be sexually active with a woman of childbearing potential, must be willing to use at least TWO highly effective forms of contraception. This should start from the time of study enrolment and continue throughout tinostamustine administration. Female study participants of childbearing potential must continue using contraception for at least 6 months after the last administration of the tinostamustine. Female study participants should be willing to have a pregnancy test performed at screening, on Day -1 of each tinostamustine administration and at tinostamustine discontinuation. Male study participants who are sexually active with a woman of childbearing potential should also use a condom during treatment and for at least 90 days after the last administration of tinostamustine. Vasectomised males are considered fertile; therefore, vasectomised partners and patients must be willing to use a secondary method of effective birth control. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the tinostamustine. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting toxicity | cycle 1 of treatment. Cycle 1 is 21 days duration with infusion given on day 1 | Toxicity will be evaluated according to the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) toxicity criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-tumour activity | Approx 1 year from start of treatment | Response assessment in neuro-oncology (RANO) criteria (to assess mPFS, PFS, ORR, OS, duration of response \[DoR\]) |
| Pharmacokinetic assessment | cycle 1 of treatment. Cycle is 21 days duration with infusion given on day 1 | plasma concentrations of tinostamustine |
Countries
Spain, Switzerland
Outcome results
None listed