Glioblastoma is the primary brain tumour with the worst prognosis: median survival is only 12 months despite the use of the most advanced treatments. In the past 10 years, survival in the treatment of this disease has not advanced significantly, with the postoperative standard being the administration of chemoradiotherapy with temozolomide, followed by 6 cycles of sequential chemotherapy with temozolomide. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have shown a clear synergistic antitumour effect with temozolomide and radiotherapy in preclinical glioma models. THC and CBD have a wide variety of biological effects by binding with and activating the type 1 and type 2 cannabinoid receptors (CB1 expressed in certain neuronal areas of the brain and CB2 expressed in the immune system and in glial cells). The activation of these receptors initiates a signalling pathway, called the endoplasmic reticulum stress response, which generates tumour cell autophagy by activating TRB3. Given these data, the Spanish Group for Neuro-oncology (GEINO) proposes developing a phase Ib, open-label, multicenter, intrapatient dose-escalation clinical trial to assess the safety profile of the THC+CBD combination at a 1:1 ratio, adding temozolomide and radiotherapy in patients with newly-diagnosed glioblastoma. The number of patients to be recruited is 30 over 6 months at 8 sites specialising in neuro-oncology.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
TN-TC11G dose will be gradually increased as follows: Week 1: TN-TC11G: 0-0-5 mg (THC 5 mg + CBD 5 mg; in the mornings, 90 minutes after breakfast; in the afternoons, 90 minutes after lunch; in the evenings, 90 minutes after dinner). Week 2: TN-TC11G: 5-0-5 mg Week 3: TN-TC11G: 5-5-5 mg Week 4: TN-TC11G: 5-5-10 mg Week 5: TN-TC11G: 5-5-15 mg Week 6: TN-TC11G: 10-10-15 mg Week 7: TN-TC11G: 10-10-20 mg. Week 8: TN-TC11G: 15-15-30 mg Week 9: TN-TC11G: 20-20-40 mg TN-TC11G will be administered daily at the relevant dose level according to the individual titration performed in the first 9 weeks of treatment. If there is any dose reduction, the reduced dose must be administered.
During RT, patients will receive Temozolomide (TMZ). All patients will be given TMZ at 75 mg/m2/d concurrently with RT for a maximum of 42 days. At 4 weeks after RT completion, patients will start taking TMZ at 150 mg/m2/d for the first 5 days of a 28-day cycle. If first cycle is well tolerated, patients will receive TMZ at 200 mg/m2/d for the first 5 days of every subsequent 28-day cycle for another 5 cycles.
All the patients will receive the Stupp regimen. The radiotherapy (RT) treatment will be administered in fractions of 1.8-2.0 Gy/day delivered 5 days/week to a total dose of 58-60 Gy. Radiotherapy will be delivered to the gross tumor volume with a 2-3 cm margin for the clinical target volume.
Hospital Universitario Virgen del Rocío
Seville, Andalusia, Spain
Institut Català d'Oncología L'Hospitalet
L'Hospitalet de Llobregat, Barcelona, Spain
Hospital Universitario Son Espases
Palma de Mallorca, Mallorca, Spain
Hospital del Mar
Barcelona, Spain
Complejo Hospitalario Regional Virgen de las Nieves
Granada, Spain
Hospital Universitario 12 de Octubre
Madrid, Spain
Hospital Regional Universitario de Malaga
Málaga, Spain
Hospital Clínico Universitario de Salamanca
Salamanca, Spain
THC-CBD Maximum tolerated dose
After intra-patient dose escalation period, recommended dose of Glasdegib administeres with temozolamide during and after RT.
Time frame: 9 weeks
Incidence of Treatment-Emergent Adverse Events
Type and number or adverse events reported during THC-CBD treatment, based on the CTCAE reference criteria.
Time frame: 12 months
Antitumor activity of THC-CBD combination with temozolamide and radiotherapy
Based on the tumor response in patients with measurable disease, after comparison of baseline characteristics and follow-up evaluations
Time frame: 12 months
Overall survival
Time between the start of treatment to death
Time frame: 12 months
Progression free survival
Time between the start of treatment and progression of disease
Time frame: 12 months
Expression of Midkine
Correlation of expression of midkine in peripheral blood and response to the experimental treatment.
Time frame: 12 months
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