Evaluation of SonoCloud-9 with Carboplatin Versus Lomustine or Temozolomide in First Recurrence Glioblastoma Post-Resection: A Randomized, Open-Label Trial
- Trial ID
- 2023-505829-14-00
- Protocol
- SC9-GBM-03
- Sponsor
- Carthera
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate and compare the **survival outcome** of patients with first recurrence of **glioblastoma** undergoing surgical debulking/resection. This is followed by either the implantation of the SC9 device and repeat blood-brain barrier (BBB) opening in association with **carboplatin** chemotherapy or standard of care second-line chemotherapy with either **lomustine** or **temozolomide**, as per the best physician’s choice and best practice. The clinical relevance of this objective lies in its potential to improve survival rates in patients with recurrent glioblastoma, a condition known for its poor prognosis and limited treatment options.
Secondary objectives include:
- To evaluate and compare the clinical efficacy of the treatment options.
- To evaluate and compare the safety of the treatment options.
- To evaluate and compare patient-reported outcomes with regards to quality of life.
Participants
The clinical trial involves a total of **299 participants** diagnosed with **first recurrence glioblastoma**. The study population includes both male and female subjects, aged 18 years and older, with a **WHO performance status** of 2 or less, indicating a relatively stable general health status. Participants were selected based on their ability to understand clinical trial information and willingness to provide informed consent. They must have a histologically proven glioblastoma without an IDH mutation and have received prior first-line therapy, including surgery or biopsy, radiotherapy, and maintenance chemotherapy. The trial population is characterized by individuals who are candidates for craniotomy and at least 50% resection of the enhancing region, with a maximal enhancing tumor diameter of 5 cm or less. Participants must have adequate hematologic, hepatic, and renal laboratory values and must be beneficiaries of a health plan covering routine patient care costs. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria ensure that participants have measurable tumor progression and are at least 12 weeks post-radiotherapy, unless specific conditions are met. The trial does not specify any particular lifestyle habits or restrictions beyond the medical criteria outlined.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicentric, two-arm pivotal study aimed at evaluating the survival outcomes of patients with first recurrence **glioblastoma**. Participants will be randomly assigned to one of two treatment arms: the experimental arm involving the implantation of the SC9 device combined with **carboplatin** chemotherapy, or the control arm receiving standard of care second-line chemotherapy with either **lomustine** or **temozolomide**, based on the physician's discretion. The primary objective is to compare overall survival, while secondary endpoints include tumor growth rate, progression-free survival, and patient-reported outcomes.
The trial is expected to span from September 2023 to November 2027, with participant involvement lasting up to 20 months, depending on the treatment arm. The study will commence with a screening visit to confirm eligibility based on criteria such as histologically proven glioblastoma, absence of IDH mutation, and adequate organ function. Following randomization, participants will undergo a series of study visits, including baseline assessments, treatment administration, and regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdraw consent. The trial will adhere to rigorous ethical standards, ensuring informed consent and compliance with regulatory requirements. The study's design and methodology aim to provide robust data on the efficacy and safety of the experimental treatment compared to standard care, contributing valuable insights into the management of recurrent glioblastoma.
Treatment
The clinical trial involves the administration of **Luminity**, a gas and solvent for dispersion for injection/infusion, containing the active substance **perflutren**. This pharmaceutical form is classified as a dispersion for injection/infusion and is administered intravenously. The maximum daily dose is 0.01 millilitres per kilogram, with a total maximum dose of 0.07 millilitres per kilogram over a treatment period of up to 18 weeks. The product is used in conjunction with ultrasound contrast media, specifically microspheres of phospholipids, to enhance imaging during the trial.
**Carboplatin**, a concentrate for solution for infusion, is another experimental medication used in this trial. It is administered intravenously and is classified under antineoplastic agents, specifically platinum compounds. The maximum daily dose is 680 milligrams, with a total maximum dose of 4760 milligrams over a treatment period of up to 18 weeks. This medication is used in combination with the SC9 device for blood-brain barrier opening in patients with glioblastoma.
The trial also includes the use of **temozolomide**, an oral antineoplastic agent. The pharmaceutical form is denoted as PHF00005MIG, and it is administered orally. The maximum daily dose is 200 milligrams per square meter, with a total maximum dose of 6000 milligrams per square meter over a treatment period of up to 20 weeks. Temozolomide serves as a comparator treatment, representing the standard of care in the trial.
**Lomustine** is another comparator treatment used in the trial, classified as a cytostatic and alkylating agent. It is administered orally, with the pharmaceutical form indicated as PHF00006MIG. The maximum daily dose is 130 milligrams per square meter, with a total maximum dose of 520 milligrams per square meter over a treatment period of up to 18 weeks. Lomustine is used as a standard-of-care therapy in the trial, providing a basis for comparison against the experimental treatments.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **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. This will be calculated using the Kaplan-Meier method. Secondary endpoints include Tumor Growth Rate, which will be determined by measuring hyperintense tumor volume using T1-weighted contrast-enhancing tumor-related regions from post-surgery MRI baseline to unequivocal progression MRI or week 20-22 MRI, whichever comes first. Progression-Free Survival (PFS) is defined as the time from randomization to unequivocal tumor progression per RANO criteria or death due to any cause. The frequency and severity of adverse events will be scored according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, from surgery to the End-of-Trial Intervention visit. Overall survival rates at 9, 12, 18, and 24 months (OS9, OS12, OS18, OS24) will also be evaluated, as well as the response rate in patients with evaluable disease per RANO criteria. The rate of patients who are progression-free at 3, 6, and 9 months (PFS3, PFS6, PFS9) will be assessed. Patient-reported outcomes will be evaluated using the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-BN20 quality of life questionnaires at baseline, 6 and 12 weeks after the start of treatment, and at the End-of-Trial Intervention visit. These outcomes will be collected from all patients, regardless of treatment arm or subsequent line therapy initiated in the meantime.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically proven glioblastoma (WHO criteria 2021), absence of IDH mutation demonstrated by negative IDH1 R132H staining on IHC.
- 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)
- 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
- Patient is candidate for craniotomy and at least 50% resection of enhancing region
- 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)
- WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status, KPS ≥ 70)
- Age ≥ 18 years
- 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
- 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 )
- Patient able to understand clinical trial information and willing to provide signed and informed consent
- 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
- 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.
- 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
- Multifocal enhancing tumor on T1w (unless all localized in a 5 cm diameter area)
- Posterior fossa tumor
- Known actionable BRAF/ and/or mutated patients
- 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)
- 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.
- Contra-indication to carboplatin, CCNU or TMZ
- Known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in ultrasound resonator
- Patient has received bevacizumab for other reasons (such as tumor progression) than treating edema
- Peripheral neuropathy or neuropathy ≥ grade 2
- Uncontrolled epilepsy or evidence of intracranial pressure
- Patient with known intracranial aneurism or having presented intra-tumor significant spontaneous hemorrhage
- 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.
- 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.
- Patient receiving enzyme-inducing antiepileptic drugs (namely phenytoin, carbamazepine and derivatives, phenobarbital), unless switched on another antiepileptic regimen
- 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
- Patient with known or suspected active or chronic infections
- 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
- Known, non-manageable, sensitivity/allergy to gadolinium, or other intravascular contrast agents
- Patient with impaired thermo-regulation or temperature sensation
- Pregnant, or breastfeeding patient
- 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
- Patients under guardianship, curatorship, under legal protection or deprived of liberty by an administrative or judicial decision
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 15 Sept 2023 | 14 |
 Belgium | Recruiting | 15 Sept 2023 | 33 |
 Denmark | Not Recruiting | 15 Sept 2023 | 20 |
 France | Recruiting | 15 Sept 2023 | 23 |
 Germany | Not Recruiting | 15 Sept 2023 | 102 |
 Italy | Recruiting | 15 Sept 2023 | 72 |
 The Netherlands | Recruiting | 15 Sept 2023 | — |
 Spain | Not Recruiting | 15 Sept 2023 | 12 |
 Sweden | Recruiting | 15 Sept 2023 | 20 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Luminity 150 microlitres/ml gas and solvent for dispersion for injection/infusion | Test | GAS AND SOLVENT FOR DISPERSION FOR INJECTION/INFUSION | INTRAVENOUS | 0.01 | 18 | PRD7434760 |
TEMOZOLOMIDE | Comparator | PHF00005MIG | ORAL | 200 | 20 | SCP835810 |
Carboplatin 10 mg/ml Concentrate for Solution for Infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 680 | 18 | PRD2005413 |
LOMUSTINE | Comparator | PHF00006MIG | ORAL | 130 | 18 | SCP725449 |