| Eligibility |
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.
Exclusion Criteria:
1. Patient has received prior interstitial brachytherapy, implanted chemotherapy, or
therapeutics delivered by local injection or convection enhanced delivery. Prior
treatment with Gliadel® wafers will be excluded. Concomitant use of the tumour
treating fields will also be excluded.
2. Use of chemotherapy or immunotherapy within 21 days (apart from TMZ), use of targeted
therapy within 14 days or 5 times the half-life of the agent, whichever is longer,
prior to the first dose of tinostamustine. After the respective durations mentioned
above, patients may be enrolled if they have recovered from any related toxicities =
Grade 1 (except alopecia). This applies to any prior systemic anticancer therapy
including investigational agents.
3. Any serious medical condition that interferes with adherence to study procedures.
4. Patient has had prior chemotherapy (excluding radiotherapy + temozolomide), targeted
small molecule therapy, within 2 weeks prior to study Day 1 or who has not recovered
(i.e., =Grade 1 at baseline) from AEs due to a previously administered agent.
1. Note: Patients with =Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
2. Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
5. Patients with a history of a second malignancy diagnosed within 3 years of study
enrolment or have a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy.
6. Implanted pacemaker or implantable cardiac defibrillator or New York Heart Association
(NYHA) Stage III/IV congestive heart failure or with the following arrhythmias: atrial
fibrillation/flutter with poor rate control; documented sustained ventricular
tachycardia (defined as >30 seconds or requiring cardioversion before 30 seconds have
elapsed) or TdP; ventricular pre excitation (Wolff Parkinson White syndrome) Brugada
Syndrome; complete left bundle branch block (LBBB); QRS >120 ms; myocardial infarction
or acute coronary syndrome within previous 6 months.
7. Severe chronic obstructive pulmonary disease (COPD) or severe uncontrollable
hypertension.
8. Patients who did not complete at least 75% of temozolomide dosing during radiotherapy
per EORTC-22981-26981 study.
9. Patients who had a platelet count <75,000/mm3 during concomitant temozolomide therapy
during radiation.
10. Patients with QTc interval (Fridericia's formula) >450 ms.
11. Patients who are on treatment with drugs known to prolong the QT/QTc interval.
Selective serotonin reuptake inhibitors (SSRIs): Patients treated with a SSRI AND
displaying a QTc prolongation are NOT eligible in the study.
Nevertheless, there is no need to stop or change a SSRI if a patient is on a stable
dose AND with no impact on QT/QTc interval, since it is not expected that plasma
concentration of the SSRI will be affected by the administration of tinostamustine.
12. Patient has known gliomatosis cerebri, leptomeningeal disease, extracranial disease,
or multifocal disease. Patient has multifocal GBM, defined as discrete sites of
contrast enhancing disease without contiguous T2/FLAIR abnormality that require
distinct radiotherapy ports. Satellite lesions that are associated with a contiguous
area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the
same radiotherapy port as the main lesion(s) are permitted.
13. Patient has an active infection requiring systemic therapy.
14. Patient has an ongoing or previous history of spontaneous intratumoral haemorrhage.
15. Patient has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.
16. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study.
17. Patient is pregnant or breastfeeding or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit.
18. Patient has a known history of human immunodeficiency virus (HIV type 1 or 2
antibodies). Testing not required.
19. Patient has known active hepatitis B (e.g., HBs Ag reactive) or hepatitis C (e.g., HCV
RNA [qualitative]) is detected.
20. Patient has received a live vaccine within 30 days prior to the first dose of
tinostamustine.
21. Contraindication for undergoing MRIs.
22. Use of any drug with histone deacetylase (HDAC) inhibiting activity including use of
valproate in any of its indications (epilepsy, mood disorder). Valproate, due to its
HDAC inhibiting activity is contraindicated. For those patients on valproate,
valproate will need to be discontinued and switched to a different anti epileptic
agent or psychotropic agent. A washout period of 4 days from valproate acid will be
allowed prior to enrolling into the study.
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