A randomized, open-label, multicentric, two-arm pivotal trial of SonoCloud-9 combined with carboplatin (CBDCA) vs standard of care lomustine (CCNU) or temozolomide (TMZ) in patients undergoing planned resection for first recurrence glioblastoma - SONOBIRD

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Carthera, Carthera

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Dec 2023 → ongoing

Decision date (initial)

2023-11-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

CARTHERA

External identifiers

EU CT number

2023-505829-14-00

ClinicalTrials.gov

NCT05902169

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate and compare the survival outcome of patients with first recurrence of glioblastoma undergoing surgical debulking/resection followed by either implantation of the SC9 device and repeat BBB opening in association with carboplatin chemotherapy or standard of care 2nd line chemotherapy with either lomustine or temozolomide (per best physician’s choice and best practice)

Secondary objectives 4

1. To evaluate and compare the clinical efficacy
2. To evaluate and compare the safety
3. To evaluate and compare the clinical efficacy
4. To evaluate and compare patient reported outcome with regards to quality of life.

Conditions and MedDRA coding

First recurrence glioblastoma

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Swissmedic Swiss Agency for Therapeutic Products, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Histologically proven glioblastoma (WHO criteria 2021), absence of IDH mutation demonstrated by negative IDH1 R132H staining on IHC.
2. Patient must have received prior first line therapy that must have contained both: a) Prior surgery or biopsy and standard fractionated radiotherapy (1.8-2 Gy/fraction, >56 Gy<66 Gy) or hypofractionated radiotherapy (15 x 2.66 Gy or similar regimen) b) One line of maintenance chemotherapy and/or immune- or biological therapy, (with or without TTFields)
3. First, unequivocal disease progression with a) measurable tumor (>100 mm2 or 1 cm3, based on RANO criteria) documented (e.g., increase of 25% in tumor diameter) on MRI and, b) interval of a minimum of 12 weeks since the completion of prior radiotherapy, unless there is a new lesion outside the radiation field or unequivocal evidence of viable tumor on histopathological sampling
4. Patient is candidate for craniotomy and at least 50% resection of enhancing region
5. Maximal enhancing tumor diameter prior to inclusion ≤ 5 (+/- 7%) cm on MRI performed within 14 days prior to inclusion . (In case of planned lobectomy, post operative peritumoral brain or residual size ≤5 cm)
6. WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status, KPS ≥ 70)
7. Age ≥ 18 years
8. Participant must be recovered from acute toxic effects (≤grade 2) of all prior anticancer therapies. Interval since last therapy to presumed date of surgery of at least: a) ≥ 4 weeks or 5 half-lives (whichever is shorter) for i) Cytotoxic ii) Other small chemical entity (e.g., targeted therapy) iii) For biologics (e.g., antibodies, except bevacizumab) b) ≥ 6 weeks of prior bevacizumab
9. Adequate hematologic, hepatic, and renal laboratory values within 14 days prior to inclusion i.e.: a) Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, neutrophils ≥ 1500/mm3. b) Liver function test with ≤ grade 1 alterations, except if due to antiepileptic drug therapy or isolated increased bilirubin due to Gilbert syndrome c) Estimated glomerular filtration rate of at least 60 mL/min/m2 using Appendix 12.5 formula d) AST(SGOT)/ALT(SPGT) ≤ 3 X institutional ULN (upper Limit of Normal )
10. Patient able to understand clinical trial information and willing to provide signed and informed consent
11. Patient of childbearing potential must have a negative pregnancy test within 14 days prior to inclusion and must agree to use a medically-acceptable method of birth control during the treatment period and, if randomized in the experimental arm, for at least 1 month after the last cycle of carboplatine a medically-acceptable method of birth control during the treatment period and, if randomized in the experimental arm, for at least 1 month after the last cycle of carboplatin
12. A male patient must agree to use condoms during the treatment period and, if randomized in the experimental arm, for at least 3 months after the last cycle of carboplatin; the patient must also refrain from donating sperm during this period.
13. Patient must be a beneficiary of a health plan that covers routine patient care costs. Patient must be a beneficiary of or affiliated with a social security scheme (according to country-specific requirements)

Exclusion criteria 23

1. Multifocal enhancing tumor on T1w (unless all localized in a 5 cm diameter area)
2. Posterior fossa tumor
3. Known actionable BRAF/ and/or mutated patients
4. Patient at risk of surgery site infection (e.g., 2 or more previous craniotomies/neurosurgery within the last 3 months, poor skin condition, known impaired wound healing and/or previously infected surgical field, uncontrolled diabetes or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)oor skin condition, and/or previously infected surgical field, or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)
5. Patient treated at high, stable -or average- dose of corticosteroids (≥ 6 mg/day dexamethasone or equivalent) in the 7 days prior to inclusion. Patients on dexamethasone for reasons other than mass effect may still be enrolled.
6. Contra-indication to carboplatin, CCNU or TMZ
7. Known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in ultrasound resonator
8. Patient has received bevacizumab for other reasons (such as tumor progression) than treating edema
9. Peripheral neuropathy or neuropathy ≥ grade 2
10. Uncontrolled epilepsy or evidence of intracranial pressure
11. Patient with known intracranial aneurism or having presented intra-tumor significant spontaneous hemorrhage
12. Patient with unremovable coils, clips, shunts, intravascular stents, and/or wafer, or reservoirs that may be in the zone targeted by the device (extending to the contralateral bone).nd prior authorization by the Sponsor, patient may be eligible: - if anticoagulation therapy can be interrupted prior to surgery and before each treatment intervention, - if anti-platelet aggregation therapy can be discontinued before randomization through end-of-trial intervention.
13. Patient with medical need to be on continued anti-platelet aggregation therapy and/or anticoagulation. Patients for whom anticoagulation/platelet aggregation can be temporarily interrupted may be eligible after discussion and prior authorization by the sponsor.
14. Patient receiving enzyme-inducing antiepileptic drugs (namely phenytoin, carbamazepine and derivatives, phenobarbital), unless switched on another antiepileptic regimen
15. History of other malignancy within 2 years prior to study start with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma, non-melanomatous skin cancer. prostate cancer or carcinoma in situ of the uterine cervix
16. Patient with known or suspected active or chronic infections
17. Patient with known significant cardiac disease, known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure > 90 mm Hg), uncontrolled systemic hypertension, or acute respiratory distress syndrome
18. Known, non-manageable, sensitivity/allergy to gadolinium, or other intravascular contrast agents
19. Patient with impaired thermo-regulation or temperature sensation
20. Pregnant, or breastfeeding patient
21. Any other serious patient medical or psychological condition that may interfere with adequate and safe delivery of treatment and care (e.g., positive human immunodeficiency virus [HIV] status, potential blood-borne infections, malnutrition …), circumstance (e.g., sinus opening during surgery), psychological, morphological characteristics (e.g., skin characteristics, bone thickness), or any pre-existing comorbidities that in the investigator’s opinion may prevent the implantation of the device, may impair the ability of the patient to receive treatment with SonoCloud-9 or may be confounding for evaluation of the clinical trial endpoints
22. Patients under guardianship, curatorship, under legal protection or deprived of liberty by an administrative or judicial decision
23. Occurrence of any major medical illnesses or impairments (e.g., increased infectious risk, diagnostic of a second malignancy that requires treatment which would interfere with this study) or of contra-indications, that in the Investigator’s opinion may hamper the ability of the patient to receive treatment with SonoCloud-9 or may be confounding for evaluation of the clinical endpoints. The examples are of illustrative intent only, and not exhaustive.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause or censored at the time of last follow-up, calculated according to the Kaplan Meier method.

Secondary endpoints 6

1. Progression Free Survival (PFS) Progression-free survival is defined as the time from randomization date to the earlier of the following events: unequivocal tumor progression as determined per RANO criteria or death due to any cause
2. Tumor Growth Rate Tumor Growth Rate will be determined by measuring hyperintense tumor volume using T1w contrast-enhancing tumor-related region from post-surgery MRI baseline to unequivocal progression MRI (i.e., suspected radiologic progression confirmed by repeat scan) or W20-22 MRI, whichever comes first
3. Overall survival at 9, 12, 18 and 24 months defined as rate of patients alive at 9, 12, 18 and 24 months (OS9, OS12, OS18, OS24)
4. Response rate (in patients with evaluable disease, per RANO criteria)
5. Rate of patients who are progression-free at 3,6 and 9 months (PFS3, PFS6, PFS9)
6. Patient Reported Outcome will be assessed using the EQ-5D-5L, the EORTC QLQ-C30, and the EORTC QLQ-BN20 quality of life questionnaires at inclusion (baseline), 6 and 12 weeks after start of treatment as well as End-of-Trial Intervention visit. Patient Reported Outcome will be collected in all patients, irrespective of treatment arm and irrespective of subsequent line therapy initiated in the meantime

Investigational products

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

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Carthera

Sponsor organisation

Carthera

Address

Bioparc Laennec, 60 Avenue Rockefeller 60 Avenue Rockefeller

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Carthera

Contact name

Charlotte Schmitt

Public contact point

Organisation

Carthera

Contact name

Charlotte Schmitt

Carthera

Sponsor organisation

Carthera

Address

Immeuble Weitz, 1 Place Vaclav Havel 1 Place Vaclav Havel

City

Lyon

Postcode

69007

Country

France

Scientific contact point

Organisation

Carthera

Contact name

Sonobird Desk

Public contact point

Organisation

Carthera

Contact name

Sonobird Desk

Third parties 5

Locations

9 EU/EEA countries · 32 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 9 · Art. 38 CTR

Results and documents

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

Documents 137 files

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

Application history

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