Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial

Adam M Sonabend ¹, Andrew Gould ², Christina Amidei ², Rachel Ward ², Karyn A Schmidt ², Daniel Y Zhang ³, Cristal Gomez ², John F Bebawy ⁴, Benjamin P Liu ⁵, Guillaume Bouchoux ⁶, Carole Desseaux ⁶, Irene B Helenowski ⁷, Rimas V Lukas ⁸, Karan Dixit ⁸, Priya Kumthekar ⁸, Víctor A Arrieta ⁹, Maciej S Lesniak ², Alexandre Carpentier ¹⁰, Hui Zhang ¹¹, Miguel Muzzio ¹², Michael Canney ⁶, Roger Stupp ¹³

Affiliations Expand

·         PMID: 37142373

·         PMCID: PMC10256454

DOI: 10.1016/S1470-2045(23)00112-2 Summary

Background

Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood–brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.

Methods

We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m², 80 mg/m², 135 mg/m², 175 mg/m², 215 mg/m², and 260 mg/m²) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood–brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual.

Findings

17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12–12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40–215 mg/m²), and 12 patients were treated at dose level 6 (260 mg/m²). A total of 68 cycles of LIPU-MB-based blood–brain barrier opening were done (median 3 cycles per patient [range 2–6]). At a dose of 260 mg/m², encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m² in the case of the grade 3 encephalopathy, and to 215 mg/m² in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m² albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood–brain barrier opening was most commonly associated with immediate yet transient grade 1–2 headache (12 [71%] of 17 patients). The most common grade 3–4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood–brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 μM [95% CI 0·022–0·063] in non-sonicated brain to 0·139 μM [0·083–0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 μM [0·562–1·747] in non-sonicated brain to 5·878 μM [3·462–9·980] μM in sonicated brain [5·9-times increase], p=0·0001).

Interpretation

LIPU-MB using a skull-implantable ultrasound device transiently opens the blood–brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing.

Funding

National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Summary(요 약)

Background (배경)

정맥 내 마이크로버블을 함께 투여하면서 저강도 맥동 초음파(LIPU-MB) 를 사용하면 혈액-뇌 장벽(blood–brain barrier, BBB) 을 열 수 있다. 본 연구에서는 재발성 교모세포종 환자에서 LIPU-MB를 사용하여 알부민 결합 파클리탁셀(albumin-bound paclitaxel) 을 종양 주변 뇌로 전달하는 데 있어 안전성과 약동학적 특성을 평가하고자 하였다.

Methods (방법)

·         대상: ≥18세, 재발성 교모세포종, 종양 ≤70 mm, KPS ≥70

·         디자인: 용량상승 1상 임상시험

·         시술:

o    종양 절제 후 두개골 창(window)에 9개 방출기 장착 초음파 기기 이식

o    3주 간격, 최대 6주기 동안 정맥 알부민 결합 파클리탁셀 + LIPU-MB

·         파클리탁셀 용량: 40, 80, 135, 175, 215, 260 mg/m²

·         평가 변수:

o    1차: 1주기 내 용량제한 독성(DLT) 발생

o    BBB 개방 여부: 초음파 전후 MRI

o    약동학 분석: 본 시험 + 유사 시험(NCT03744026, 카보플라틴 투여군)

·         등록번호: NCT04528680 (현재 2상 진행 중)

Findings (결과)

·         등록 환자: 17명 (남 9, 여 8)

·         기간: 2020.10.29 ~ 2022.2.21

·         추적: 중앙값 11.9개월 (IQR 11.1–12.8)

·         투여: 총 68주기 시행 (환자당 중앙값 3주기, 범위 2–6)

부작용

·         260 mg/m² 용량:

o    3등급 뇌병증 1명 (1주기), 2등급 뇌병증 1명 (2주기) → 회복 후 저용량으로 치료 지속

o    2등급 말초신경병증 1명 (3주기)

·         LIPU-MB 관련: 진행성 신경학적 결손 없음

·         가장 흔한 부작용: 시술 직후 일시적 두통 (71%, 1–2등급)

·         주요 3–4등급 이상반응:

o    호중구감소증 47%

o    백혈구감소증 29%

o    고혈압 29%

·         치료 관련 사망: 없음

영상·약동학 결과

·         BBB 개방: 목표 부위에서 확인, 1시간 내 점차 감소

·         약물 농도 변화:

o    파클리탁셀: 0.037 → 0.139 μM (3.7배 증가, p<0.0001)

o    카보플라틴: 0.991 → 5.878 μM (5.9배 증가, p=0.0001)

Interpretation (해석)

  두개골 이식형 초음파 기기를 이용한 LIPU-MB는 BBB를 일시적·반복적으로 개방하여→ 항암제의 뇌 침투를 안전하게 증강시킴  본 연구 결과는 후속 2상 임상시험(NCT04528680, LIPU-MB + 파클리탁셀 + 카보플라틴 병용) 으로 이어짐