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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oncopole Claudius Regaud

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2017 → 2 Nov 2024

Decision date (initial)

2024-08-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca

External identifiers

EU CT number

2024-515000-39-00

EudraCT number

2016-001614-16

ClinicalTrials.gov

NCT02866747

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety, Therapy

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 primary objective of the phase II part is to evaluate whether the
combination of hypofractionated stereotactic radiation therapy and
Durvalumab immunotherapy improves overall survival in patients with
recurrent glioblastoma compared to hypofractionated stereotactic
radiation therapy alone.

Secondary objectives 8

1. Phase I part: - To assess intracranial progression-free interval (both distant and local intracranial progression).
2. Phase I part:- To assess the overall survival.
3. Phase I part:- To assess the safety and tolerability of hFSRT combined with Anti-PDL1.
4. Phase II part: - To assess intracranial progression-free interval (both distant and local intracranial progression).
5. Phase II part:- To assess immune-related intracranial progression-free interval (both distant and local intracranial progression) in the experimental arm.
6. Phase II part:- To study the quality of life.
7. Phase II part:- To study the quality of life.
8. Phase II part:- To study the neurologic and neurocognitive functions.

Conditions and MedDRA coding

Recurrent glioblastoma.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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.

Exclusion criteria 25

1. Multifocal GBM recurrence (exception: multisite nodular recurrence (maximum: 2 sites) that can be irradiated by hFSRT according to investigator's judgement).
2. Distance between tumor and optic ways including chiasma or brainstem <1 cm.
3. Prior re-irradiation (except if fulfilling the following requirements: ended at least 6 months before the first fraction of RT in the study, localized outside the target of interest for the trial, and previously reirradiated lesion controlled at the time of study entry). 4. Prior exposure to Durvalumab or other anti-PD-1, anti-PD-L1, anti- CTLA4 antibodies.
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 10 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, 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 the study.
25. Patient who has forfeited his/her freedom by administrative or legal award or who is under guardianship.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PHASE I PART: The schema will be defined as safe if one patient or less (i.e. 0 or 1) among 6 present DLT.
2. PHASE II PART: The primary endpoint of the phase II part of the study is the overall survival which is defined as the time from randomization to death from any cause. Patients alive at last follow-up news are censored at this date.

Secondary endpoints 12

1. 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.
2. PHASE I PART:- 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.
3. PHASE I PART:- Safety and tolerability will be evaluated using the NCI-CTCAE Version 4.03.
4. PHASE I PART:- Quality of life will be evaluated using EORTC QLQ-C30 and BN-20 questionnaires.
5. PHASE I PART:- Neurologic and neurocognitive functions will be evaluated using NANO scale and MoCA tests.
6. 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.
7. PHASE II PART:- 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.
8. PHASE II PART:- Acute and late toxicities will be evaluated using the NCI-CTCAE Version 4.03.
9. PHASE II PART:- Quality of life will be evaluated using EORTC QLQ-C30 and BN-20 questionnaires.
10. PHASE II PART:- Neurologic and neurocognitive functions will be evaluated using NANO scale and MoCA tests.
11. PHASE II PART:- 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.
12. PHASE II PART:- 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oncopole Claudius Regaud

Sponsor organisation

Oncopole Claudius Regaud

Address

1 Avenue Irene Joliot Curie

City

Toulouse

Postcode

31100

Country

France

Scientific contact point

Organisation

Oncopole Claudius Regaud

Contact name

Pr Elizabeth COHEN-JONATHAN MOYAL,

Public contact point

Organisation

Oncopole Claudius Regaud

Contact name

Muriel MOUNIER

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications