A phase I/II multicenter trial evaluating the association of hypofractionated stereotactic radiation therapy and the anti-PD-L1 Durvalumab (Medi4736) for patients with recurrent glioblastoma.

• Register: EUCTR
• Last refreshed on: 24 October 2016
• Main ID: EUCTR2016-001614-16-FR
• Date of registration: 19/10/2016
• Prospective Registration: No
• Primary sponsor: INSTITUT CLAUDIUS REGAUD
• Public title: A phase I/II multicenter trial evaluating the association of hypofractionated stereotactic radiation therapy and the anti-PD-L1 Durvalumab (Medi4736) for patients with recurrent glioblastoma.
• Scientific title: A phase I/II multicenter trial evaluating the association of hypofractionated stereotactic radiation therapy and the anti-PD-L1 Durvalumab (Medi4736) for patients with recurrent glioblastoma. - STERIMGLI
• Date of first enrolment: 22/09/2016
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001614-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Hypofractionated stereotactic radiation therapy alone Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: Coordinating Investigator
• Affiliation: INSTITUT CLAUDIUS REGAUD

• Name: Coordinating Investigator
• Affiliation: INSTITUT CLAUDIUS REGAUD

Key inclusion & exclusion criteria

Inclusion criteria:
INCLUSION CRITERIA:
1. Age = 18 years at time of study entry.
2. Previous Histopathologic confirmation of glioblastoma.
3. Any line of recurrence of glioblastoma proven by contrast enhanced MRI within 28 days prior to the first fraction of RT, per modified RANO criteria (Wen et al JCO 2010).
Note: Recurrence is defined as progression following therapy (i.e., chemotherapy, radiation, second surgery).
4. Recurrent nodule of an histologically confirmed diagnosis of World Health Organization (WHO) Grade IV malignant glioma (Glioblastoma) occurring in or out the previous irradiation fields.
5. Recurrent disease documented by MRI evidence with a size of the recurrence evaluated on T1 post-gadolinium sequence =35mm.
6. Patient for which a re-irradiation (by hFSRT) has been decided by the multidisciplinary medical board.
7. Patients with measurable disease.
8. Prior radiotherapy must be ended at least 12 weeks before the first fraction of RT (unless progressive disease outside of the radiation field or histopathologic confirmation of unequivocal tumor to eliminate pseudoprogression images according to RANO recommendations, Wen et al JCO 2010).
9. In case of previous anti-VEGF/VEGFR targeted therapy: at least 28 days between the last injection of anti-VEGF/VEGFR targeted therapy and the first fraction of RT.
10. Karnofsky performance status =70.
11. Adequate hematologic, renal and hepatic function, as defined below:
- Absolute Neutrophil Count = 1500/mm3
- Haemoglobin = 9.0 g/dL
- Platelet count = 100,000/mm3
- Total bilirubin = 1.5 x ULN (for patient with confirmed Gilbert’s syndrome, Total bilirubin = 3 x ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN
- Creatinine = 1.5 x ULN or creatinine clearance (CrCl) = 40 mL/min, using the Cockcroft-Gault formula:
o Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum creatinine in mg/dL
o Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL
12. Female Patients must either be of non-reproductive potential (i.e., post-menopausal by history: =60 years old and no menses for = 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
13. Written informed consent and any locally required authorization (e.g., Social security for France (Health Insurance)) obtained from the patient prior performing any protocol-related procedures, including screening evaluations.
14. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 62
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
EXCLUSION CRITERIA
1. Multifocal GBM recurrence.
2. Distance between tumor and optic ways including chiasma or brainstem <1 cm.
3. Prior re-irradiation.
4. Prior exposure to Durvalumab or other anti-PD-1, anti-PD-L1, anti-CTLA4 antibodies.
5. Patient who received a live vaccine within 30 days prior to the first fraction of RT.
6. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy,tumor embolization, monoclonal antibodies, other investigational agent) within 28 days prior to the first fraction of RT.
7. Current or prior use of immunosuppressive medication within 28 days before the first fraction of RT (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) - Topical, inhaled, nasal and ophthalmic steroids are not prohibited).
8. Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s Correction
9. Presence of diffuse leptomeningeal disease or extracranial disease.
10. Active suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and Hashimoto's thyroiditis).
Note: participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger, are permitted to enroll.
11. Known primary immunodeficiency or active HIV.
12. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or hepatitis C antibody.
13. History of organ transplant requiring use of immunosuppressive medication.
14. History of active tuberculosis.
15. Current pneumonitis or interstitial lung disease.
16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses.
17. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only.
18. History of severe allergic reactions to any unknown allergens or any components of the study drug.
19. Any prior Grade = 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.
20. Participation in any other clinical trial involving another investigational product within 4 weeks prior to the first fraction of RT.
21. Participation in any other clinical trial which delivered a dose >60 Gy for the primo-treatment for glioblastoma.
22. Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing highly effective method of birth control.
23. Any condition that, in the clinical judgment of the investigator, is likely to prevent the patient from complying with any aspect of the protocol or that may put the patient at unacceptable risk.
24. Mental impairment (psychiatric illness/social situations) that may compromise the ability of the patient to give informed consent and comply with the requirements of t

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Recurrent glioblastoma.
MedDRA version: 19.0 Level: PT Classification code 10018336 Term: Glioblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: MEDI4736
Product Code: MEDI4736
Pharmaceutical Form: Concentrate for solution for infusion

Product Name: MEDI4736
Product Code: MEDI4736
Pharmaceutical Form: Concentrate for solution for infusion

Primary Outcome(s)

Primary end point(s): PHASE I PART:
The schema will be defined as safe if one patient or less (i.e. 0 or 1) among 6 present DLT.

PHASE II PART:
The primary endpoint of the phase II part of the study is the local control rate (i.e. local progression of the irradiated tumor on the MRI according to the RANO criteria) at 6 months post-randomization.

Main Objective: Phase I part:
The primary objective is to evaluate the safety and tolerability of the combination of hypofractionated stereotactic radiation therapy and Durvalumab immunotherapy in recurrent glioblastoma.

Phase II part:
The main primary objective of the phase II part is to evaluate the local control at 6 months of the combination of hypofractionated stereotactic radiation therapy and Durvalumab immunotherapy versus hypofractionated stereotactic radiation therapy alone for recurrent glioblastoma.

Secondary Objective: Phase I part:
- To assess intracranial progression-free interval (both distant and local intracranial progression).
- To assess the overall survival.
- To assess the safety and tolerability of hFSRT combined with Anti-PD-L1.

Phase II part:
- To assess intracranial progression-free interval (both distant and local intracranial progression).
- To assess immune-related intracranial progression-free interval (both distant and local intracranial progression) in the experimental arm.
- To assess the overall survival.
- To evaluate acute and late toxicities of hFSRT combined with Anti-PD-L1.
- To study the quality of life.
- To study the neurologic and neurocognitive functions.

Timepoint(s) of evaluation of this end point: PHASE I PART: 1 month after the last radiotherapy fraction.

PHASE II PART: 6 months post randomization

Secondary Outcome(s)

Secondary end point(s): PHASE I PART:
- Intracranial progression-free interval is defined by the time from inclusion to local or distant (outside the re-irradiated volume) progression. Patients without progression at last follow-up news are censored at this date.
- Overall survival is defined as the time from inclusion to death from any cause. Patients alive at last follow-up news are censored at this date.
- Safety and tolerability will be evaluated using the NCI-CTCAE Version 4.03.
- Quality of life will be evaluated using EORTC QLQ-C30 and BN-20 questionnaires.
- Neurologic and neurocognitive functions will be evaluated using NANO scale and MoCA tests.

PHASE II PART:
- Intracranial progression-free interval is defined by the time from randomization to local or distant (outside the re-irradiated volume) progression according to RANO criteria. Patients without progression at last follow-up news are censored at this date.
- Immune-related intracranial progression-free interval is defined by the time from randomization to local or distant (outside the re-irradiated volume) progression (based on iRANO; Okada et al, 2015). Patients without progression at last follow-up news are censored at this date.
- Overall survival is defined as the time from randomization to death from any cause. Patients alive at last follow-up news are censored at this date.
- Acute and late toxicities will be evaluated using the NCI-CTCAE Version 4.03.
- Quality of life will be evaluated using EORTC QLQ-C30 and BN-20 questionnaires.
- Neurologic and neurocognitive functions will be evaluated using NANO scale and MoCA tests.
- Time to QoL deterioration is defined as the time interval between randomization and first decrease in QoL score greater or equal to 5 points. Patients without such a QoL decrease will be censored at last follow-up news or at initiation of a new therapeutic strategy.
- Time to neurocognitive deterioration is defined as the time interval between randomization and first of 3 points difference in MoCA as minimal clinically important difference. Patients without such a neurocognitive decrease will be censored at last follow-up news or at initiation of a new therapeutic strategy.

Timepoint(s) of evaluation of this end point: The secondary endpoints will be evaluated throughout the study until death or date of the last news (global survival).

Secondary ID(s)

16TETE04

Source(s) of Monetary Support

AstraZeneca