Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel and Carboplatin for Recurrent Glioblastoma

Study Overview
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Brief Summary
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Paclitaxel is among the most active agents against glioblastoma in preclinical models. However, its clinical use has been hampered by the blood-brain barrier (BBB). In this trial we will implant a novel device with 9 ultrasound emitters allowing to temporarily and reversibly open the BBB immediately prior to chemotherapy infusion with albumin-bound paclitaxel. In the phase 1 component, increasing doses of chemotherapy will be delivered as long deemed safe based on the prior patient not experiencing severe toxicity. Once the the recommended dosing has been established, carboplatin will be added to the regimen and additional patients will be treated in order to better evaluate the antitumor efficacy of this novel treatment. The device will be implanted at the time of surgical resection of the recurrent tumor. During that procedure and when feasible, a first test dose of the chemotherapy will be administered in the operating room after sonication (procedure of activating ultrasound and opening the BBB) and tissue concentrations in different parts of the resected tumor will be measured. In select patients, the sonication procedure may occur immediately after the test dose of chemotherapy is administered. The objectives of this trial are to establish a safe and effective dose of albumin-bound paclitaxel, to demonstrate that the opening of the BBB increases chemotherapy concentration in the tumor, and to estimate how effective this treatment is in reducing the tumor burden and prolonging life.

Detailed Description
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Eligible patients will undergo craniotomy for tumor resection. During the tumor resection and when possible, an initial low dose of albumin-bound paclitaxel will be given following sonication. In select patients, the sonication procedure may occur immediately after the test dose of chemotherapy is administered. The sonication device will be implanted at the end of the procedure. In phase 1, about two weeks after surgery, patients will undergo sonication and albumin-bound paclitaxel administration with MRI to quantify extent of blood brain barrier opening. Sonication and administration of albumin-bound paclitaxel will continue every 3 weeks until disease progression. The planned albumin-bound paclitaxel starting dose is 40 mg/m2, to be escalated in the absence of significant toxicity up to 260 mg/m2. Blood samples for circulating tumor DNA will also be collected before and after each sonication. In phase 2, pre-sonication carboplatin at AUC 5 will be added to the regimen, with a safety run-in for the first 6 patients.

Official Title
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Phase 1 / 2 Trial of Blood-brain Barrier Opening With an Implantable Ultrasound Device SonoCloud-9 and Treatment With Albumin-bound Paclitaxel and Carboplatin in Patients With Recurrent Glioblastoma

Conditions
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GBM, Recurrent Glioblastoma, Glioblastoma, Gliosarcoma, Glioblastoma Multiforme, Glioblastoma, IDH-wildtype

Intervention / Treatment
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* Device: Sonication for opening of blood-brain barrier
* Drug: Chemotherapy, albumin-bound paclitaxel
* Drug: Chemotherapy, carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Isocitrate Dehydrogenase 1 (IDH1) wild-type glioblastoma on pathology from initial surgery (e.g. IDH R132H neg); morphologic or molecular determination of grade 4 Ability to undergo contrast-enhanced MRI Radiographic evidence of tumor recurrence/progression after failure of 1 - 2 lines of prior therapy Measurable or evaluable disease Measurable: contrast-enhancement (bidirectional diameters ≥ 1cm) on MRI Non-measurable/evaluable: contrast-enhancement diameters < 1 cm Maximal tumor diameter pre-surgery ≤ 70 mm on T1wMRI Candidate for at least partial surgical resection Greater 12 weeks from completion of radiation therapy Age ≥ 18 years If receiving dexamethasone for mass effect, a stable daily dose of dexamethasone at < 6 mg within 7 days of registration, or if dexamethasone dose is decreasing, average daily dose of < 6 mg in the 7 days prior to registration. Patients on dexamethasone for reasons other than mass effect may still be enrolled. WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status (KPS) of ≥70) Adequate hepatic, renal and bone marrow function, documented with normal laboratory values or no more than grade 1 outside the norm performed within 14 days prior to registration For patients with a childbearing potential Negative pregnancy test within 14 days prior to registration Agreement to use adequate contraception for the duration of study participation, and for 3 and 6 months after the last dose of albumin-bound paclitaxel for men and women of childbearing potential, respectively. Have the ability to understand and the willingness to sign a written informed consent prior to registration on study Be willing and able to comply with the protocol for the duration of the study Provide written, signed and dated informed consent prior to study registration. NOTE: no study-specific screening procedures may be performed until written consent has been obtained Exclusion Criteria: Have multifocal disease that cannot be encompassed in the ultrasound fields: e.g. > 70-mm apart tumor located in the posterior fossa Patients at risk of cranial wound dehiscence Have uncontrolled epilepsy or require treatment with enzyme-inducing antiepileptics Have clinical evidence of peripheral neuropathy on examination Have received any other investigational agents within 4 weeks of registration Have received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel or carboplatin Medical contraindications to Abraxane® or carboplatin Have an uncontrolled intercurrent illness Are pregnant or nursing Have a history of active malignancy within 3 years prior to registration. Have a known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in Definity® (the FDA-approved ultrasound contrast agent to be used in this study) Patients with coils, clips, shunts, intravascular stents, and/or non-removable wafer, non resorbable dura substitute, or reservoirs. Patients with medical need to continue antiplatelet therapy. Patients with known significant cardiac disease, known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure > 90 mmHg), uncontrolled systemic hypertension, or adult respiratory distress syndrome (patient at risk for microbubble reaction). Patients with impaired thermo-regulation or temperature sensation (due to device)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)<br>Infusion of albumin-bound paclitaxel immediately followed by sonication using the SC9 device and microbubbles in order to open the blood-brain barrier in phase 1. In phase 2, patients will receive carboplatin immediately prior to sonication using the SC9 device and microbubbles in order to open the blood-brain barrier, then will receive albumin-bound paclitaxel upon completion of sonication. | Device: Sonication for opening of blood-brain barrier<br>* Implantation of SC-9 device and repeat activation of 9 ultrasound emitters during i.v. injection of microbubbles<br>* Other names: SonoCloud-9 device, SC-9;Drug: Chemotherapy, albumin-bound paclitaxel<br>* Intravenous infusion of ABX over 30 minutes<br>* Other names: ABX;Drug: Chemotherapy, carboplatin<br>* Intravenous infusion of carboplatin over 30 minutes<br>* Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (Phase1) | Occurrence of ≥ grade 3 treatment related toxicity | 1st treatment cycle = 3 weeks | 
| 1-year survival rate (Phase 2) | Survival time from date of tumor resection and device implantation | 12-months | 
| Relationship between overall survival and SSR3 (Phase 2) | Survival time from date of tumor resection and device implantation | through study completion, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of side effects/toxicity associated with Sonication/ABX treatment | Safety and tolerance | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ultrasound, SonoCloud, blood-brain barrier, paclitaxel, albumin-bound paclitaxel, Abraxane®, carboplatin