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TN-TC11G (THC+CBD) Combination With Temozolomide and Radiotherapy in Patients With Newly-diagnosed Glioblastoma (GEINOCANN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03529448
Recruitment Status : Not yet recruiting
First Posted : May 18, 2018
Last Update Posted : July 23, 2020
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Information provided by (Responsible Party):
Grupo Español de Investigación en Neurooncología

Tracking Information
First Submitted Date  ICMJE April 23, 2018
First Posted Date  ICMJE May 18, 2018
Last Update Posted Date July 23, 2020
Estimated Study Start Date  ICMJE November 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2018)
  • THC-CBD Maximum tolerated dose [ Time Frame: 9 weeks ]
    After intra-patient dose escalation period, recommended dose of Glasdegib administeres with temozolamide during and after RT.
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: 12 months ]
    Type and number or adverse events reported during THC-CBD treatment, based on the CTCAE reference criteria.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2018)
  • Antitumor activity of THC-CBD combination with temozolamide and radiotherapy [ Time Frame: 12 months ]
    Based on the tumor response in patients with measurable disease, after comparison of baseline characteristics and follow-up evaluations
  • Overall survival [ Time Frame: 12 months ]
    Time between the start of treatment to death
  • Progression free survival [ Time Frame: 12 months ]
    Time between the start of treatment and progression of disease
  • Expression of Midkine [ Time Frame: 12 months ]
    Correlation of expression of midkine in peripheral blood and response to the experimental treatment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE TN-TC11G (THC+CBD) Combination With Temozolomide and Radiotherapy in Patients With Newly-diagnosed Glioblastoma
Official Title  ICMJE Phase Ib, Open-label, Multicenter, Intrapatient Dose-escalation Clinical Trial to Assess the Safety Profile of the TN-TC11G (THC+CBD) Combination With Temozolomide and Radiotherapy in Patients With Newly-diagnosed Glioblastoma
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
Phase Ib, intra-patient dose escalation trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Drug: TN-TC11G

    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.

  • Drug: Temozolomide Oral Product

    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.

    Other Name: Temozolomide
  • Radiation: Radiotherapy
    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.
    Other Name: STUPP
Study Arms  ICMJE Experimental: TN-TC11G, radiotherapy and Temozolomide Oral Product

During Phase Ib, Four to seven weeks after surgical diagnosis, concurrent with radiotherapy (STUPP)

+ temozolomide (75mg/m2/day for 42 days) +TN-TC11G will be evaluated. During radiation therapy, temozolomide and TN-TC11G will be administered. This last, as the dose that have been selected previously, based on dose-titration period. Patient specific dose will remain until progresion of disease, unacceptable toxicity, non-compliance, consent withdrawal up to 2 years.

  • Drug: TN-TC11G
  • Drug: Temozolomide Oral Product
  • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 7, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Ability to understand and sign the informed consent document
  • Men or women ≥18 years and ≤70 years
  • Newly-diagnosed GB confirmed by biopsy or by resection in the 4-7 weeks before being registered in the trial.
  • Patients must have at least 15 slides without staining or a tissue block (frozen or paraffin-embedded) available from a previous biopsy or surgery (tumour sample previously archived).
  • Patients must have recovered from previous surgeries (time between surgery and inclusion in the study: 6 weeks).
  • Karnofsky Index ≥60%.
  • Adequate bone marrow reserve: haemoglobin ≥10 g/dL, WBC >3,000/mcL, absolute neutrophil count (ANC) ≥1,500 cells/μL, platelets ≥100,000 cells/μL.
  • Adequate liver function: Bilirubin <1.5 times the upper limit of normal (ULN); AST ≤2.5 x ULN
  • Creatinine clearance >60 ml/min/1.73 m2.
  • The study treatment's effects on the development of the human foetus are not known. For this reason, women of childbearing age and men must agree to use a suitable birth control method (hormonal, barrier, abstinence or surgical sterilisation) before inclusion in the study, for the duration of the study and for at least 3 months after completing the trial treatment. The definition of an effective method of birth control is based on the judgement of the principal investigator or their designee. If a woman is pregnant or there is suspicion that she might be pregnant while participating in the study, she must inform the trial doctor immediately. All women of childbearing age should have a negative pregnancy test (serum/urine) in the 2 weeks prior to the beginning of treatment.

Exclusion Criteria:

  • Presence of extracranial metastatic disease.
  • Any previous treatment for glioblastoma.
  • Patients who have had a Gliadel implant in the surgery.
  • Use of an enzyme-inducing antiepileptic drug. Patients receiving this type of drug must have a washout period of at least 7 days prior to study inclusion.
  • Previous abuse of cannabinoids.
  • Presence of any clinically significant gastrointestinal abnormality that may affect the intake, transit or absorption of the study drug, such as the inability to take medication in the form of oral tablets or solution.
  • Presence of any psychiatric or cognitive impairment that limits understanding or the signing of the informed consent and/or compromises compliance with the requirements of this protocol.
  • Significant or uncontrolled cardiovascular disease, including: 1. Myocardial infarction in the previous 12 months. 2. Uncontrolled angina in the previous 6 months. 3. Congestive heart failure in the previous 6 months. 4. Diagnosed or suspected congenital long QT syndrome. 5. History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes). 6. QTc prolongation on an electrocardiogram prior to entry (>470 ms). 7. History of second- or third-degree heart block (these patients may be eligible if they carry pacemakers). 8. Heart rate <50/min on the baseline electrocardiogram. 9. Uncontrolled hypertension
  • Any patient with a history of significant cardiovascular disease, even if it is currently controlled, or who presents signs or symptoms that suggest impaired left ventricular function according to the investigator should have an assessment of left ventricular ejection fraction (LVEF) by ECCO or MUGA. If the LVEF in these circumstances is below the site's lower limit of normality or less than 50%, the patient will not be eligible.
  • History of any cancer, except in the following circumstances: Patients with a history of other malignancies are eligible if they have been disease-free for at least the last 3 years and if, in the investigator's opinion, there is a low risk of disease recurrence. People with the following cancers are eligible, even if they have been diagnosed and treated in the past 3 years: cervical carcinoma in situ and basal cell carcinoma.

Patients will not be eligible if there is evidence of another cancer that required therapy other than surgery in the past 3 years.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Federico Nepote +34 93 434 44 12
Contact: Verónica Roca +34 93 434 44 12
Listed Location Countries  ICMJE Spain
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03529448
Other Study ID Numbers  ICMJE GEINO-1601
2016-003216-12 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Grupo Español de Investigación en Neurooncología
Study Sponsor  ICMJE Grupo Español de Investigación en Neurooncología
Collaborators  ICMJE
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  • Voices Against Brain Cancer
  • Tilray
Investigators  ICMJE
Principal Investigator: Manuel Benavides, M.D., Ph.D. Hospital Universitario y Regional de Málaga y Virgen de la Victoria
PRS Account Grupo Español de Investigación en Neurooncología
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP