Trial Summary
What is the purpose of this trial?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.
Is the drug Carboplatin, Paclitaxel a promising treatment for glioblastoma when used with ultrasound?Yes, using ultrasound to help deliver the drugs Carboplatin and Paclitaxel to the brain shows promise for treating glioblastoma. Ultrasound can temporarily open the blood-brain barrier, allowing these drugs to reach the brain more effectively, which could improve their ability to fight the tumor.1011121314
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you require treatment with enzyme-inducing antiepileptics or need to continue antiplatelet therapy. Also, you must not have received any investigational agents within 4 weeks of registration.
What safety data exists for ultrasound-assisted chemotherapy using paclitaxel and carboplatin?The safety data for the combination of paclitaxel and carboplatin, used in various cancers, indicates that the regimen is generally well tolerated. Common toxicities include myelosuppression, with occurrences of neutropenia, anemia, and thrombocytopenia. Other side effects include alopecia, mild myalgia, paresthesias, and fatigue. Severe allergic reactions and febrile neutropenia have been reported but are rare. The combination has been effective in treating non-small cell lung cancer and ovarian cancer, with manageable side effects when administered with appropriate dosing and intervals.23457
What data supports the idea that Ultrasound-assisted Chemotherapy for Glioblastoma is an effective treatment?The available research shows that using ultrasound to help deliver the drug carboplatin into the brain can increase its concentration in the tissue, which might make it more effective against glioblastoma. In one study, patients treated with carboplatin before radiation had a median survival of 19.2 months, which is promising. Additionally, more than half of the patients treated with carboplatin in another study were alive after 18 months, suggesting a beneficial effect. These results indicate that ultrasound-assisted chemotherapy could be a promising treatment for glioblastoma compared to traditional methods.168910
Eligibility Criteria
Adults over 18 with a specific type of brain cancer called IDH1 wild-type glioblastoma, who are fit for surgery and have had up to two prior treatments. They must not be pregnant, agree to use contraception, and have stable vital organ functions. Excluded are those with uncontrolled epilepsy, certain allergies or medical conditions that conflict with the trial's procedures.Inclusion Criteria
I am mostly able to care for myself and carry out daily activities.
My cancer can be measured or seen on tests.
I am eligible for surgery to remove part of my tumor.
My glioblastoma does not have the IDH1 mutation and is grade 4.
My tumor is 70 mm or smaller on an MRI before surgery.
My cancer has grown despite 1-2 previous treatments.
I am 18 years old or older.
Exclusion Criteria
I cannot take Abraxane or carboplatin due to health reasons.
I am allergic to or have had reactions to drugs similar to paclitaxel or carboplatin.
I have epilepsy that isn't well-controlled or need specific epilepsy drugs.
I do not have severe heart or lung conditions.
I am allergic to ingredients in the Definity ultrasound contrast agent.
My tumor is located in the back part of my brain.
Treatment Details
The trial tests if using ultrasound to open the blood-brain barrier before giving chemotherapy (albumin-bound paclitaxel followed by carboplatin) can safely improve treatment outcomes in recurrent glioblastoma patients. The study will determine safe dosages and measure how well this method delivers chemo into the tumor.
1Treatment groups
Experimental Treatment
Group I: SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)Experimental Treatment3 Interventions
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.
Carboplatin is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Paraplatin for:
- Ovarian cancer
- Testicular cancer
- Lung cancer
- Head and neck cancer
- Brain cancer
🇪🇺 Approved in European Union as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
🇨🇦 Approved in Canada as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
- Testicular cancer
Find a clinic near you
Research locations nearbySelect from list below to view details:
Northwestern Memorial HospitalChicago, IL
Loading ...
Who is running the clinical trial?
Northwestern UniversityLead Sponsor
CarTheraIndustry Sponsor
Bristol-Myers SquibbIndustry Sponsor
Lantheus Medical ImagingIndustry Sponsor
References
Carboplatin combined with carmustine and etoposide in the treatment of glioblastoma. [2019]The aim of this study was to verify the tolerability and efficacy of therapeutic chemotherapy protocols, employing different combinations of cisplatin, carboplatin, etoposide and carmustine in primary glioblastoma patients. The purpose was focused on 2 end points: the response index to treatment, the TTP (tumor progression) and the ST (survival time). Eighty-four out of a group of 99 consecutive glioblastoma patients, entered this study. Patients were divided into 4 disparate treatment groups: (A) BCNU alone; (B) CDDP + VP-16; (C) CBDCA + BCNU; (D) CBDCA + BCNU + VP-16. The effectiveness and the TTP of the protocols differed, but differences were not statistically significant. Data concerning platinum treatment compare favorably with the best literature results. At 18 months more than half the carboplatin-treated patients are alive. Moreover these patients had a significantly longer ST than those treated with BCNU. We conclude that platinum-based chemotherapy has a beneficial effect on glial tumors.
Carboplatin and paclitaxel in ovarian cancer. [2015]A phase I trial of carboplatin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) therapy for untreated patients with advanced ovarian cancer has been completed, demonstrating that these drugs can be combined in full doses with acceptable toxicity. This combination has now gone forward to be evaluated in prospective randomized trials. The Gynecologic Oncology Group will be doing a randomized trial comparing therapy with cisplatin plus paclitaxel versus carboplatin plus paclitaxel in patients with optimal stage III ovarian cancer. Patients with limited-stage disease but with poor prognostic features will be randomly assigned to receive either three or six cycles of carboplatin plus paclitaxel. Carboplatin will be dosed using the Calvert formula at an area under the plasma concentration versus time curve of 7.5 and paclitaxel will be administered at a dose of 175 mg/m2 by 3-hour continuous infusion. Cycles are planned to be administered every 21 days without granulocyte-colony stimulating factor.
Preliminary results of two dose-finding studies of paclitaxel (Taxol) and carboplatin in non-small cell lung and ovarian cancers: a European Cancer Centre effort. [2015]Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 24-hour infusion, and carboplatin have activity in advanced non-small cell lung cancer (NSCLC) and ovarian cancer. Two dose-finding studies were initiated to identify the optimal doses for the paclitaxel/carboplatin combination when paclitaxel is given in a 3-hour infusion. The fact that the pharmacologic interaction between paclitaxel and cisplatin increases the toxicity of paclitaxel when cisplatin is given before it also prompted an investigation of the influence of drug sequence on toxicity and pharmacokinetics in the NSCLC trial. Thirty-three patients with advanced NSCLC and 11 with advanced ovarian cancer previously untreated by chemotherapy have been enrolled to date. In the NSCLC trial escalating doses of paclitaxel were given in combination with a fixed carboplatin dose of 300 mg/m2, while both drugs were escalated in the ovarian cancer study. In both studies paclitaxel was infused over 3 hours and carboplatin over 30 minutes, and cycles were repeated every 4 weeks. The most frequent side effect has been neutropenia, although this did not result in any infectious episodes. Alopecia and mild emesis also have been frequently encountered. Mild skin reactions have been reported in a few patients. Bone pain and myalgia occur more frequently at the highest paclitaxel doses. No difference in toxicity has been observed thus far between the two drug sequences in the NSCLC study. Both studies are still accruing patients as the maximum tolerated doses of paclitaxel in combination with carboplatin have not yet been reached (carboplatin 300 mg/m2 with paclitaxel 175 mg/m2 in the NSCLC study; carboplatin 400 mg/m2 with paclitaxel 150 mg/m2 in the ovarian cancer study). An investigation of maximum tolerated doses with granulocyte colony-stimulating factor support is planned thereafter.
Paclitaxel and carboplatin in nonoperable non-small cell lung cancer. [2015]Based on the high activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in non-small cell lung cancer (NSCLC) and the superior 1-year survival rates of patients with NSCLC treated with carboplatin, the Hellenic Cooperative Oncology Group initiated a phase II trial to investigate the efficacy and toxicity of the combination of both agents in patients with nonoperable stage III and IV NSCLC. Since July 1995, 31 eligible patients have entered into this study. All patients received paclitaxel 175 mg/m2 as a 3-hour infusion plus carboplatin dosed to an area under the concentration-time curve of 7, every 3 weeks. No granulocyte colony-stimulating factor was given. Among the 29 male and two female patients, the median age was 55 years (range, 29 to 73 years) and the median performance status was I (range, 0 to 2). Most of the patients had stage IV adenocarcinoma (19 patients), with poor differentiation (15 patients). The median number of prior chemotherapy cycles was two, with a range of one to six. Among 21 evaluable patients, seven achieved a partial response, 10 had stable disease, and four had progressive disease. It is too early for evaluation in nine patients. Grade 2/3 nonhematologic toxicities included alopecia (46.4%), neurotoxicity (3.3%), and myalgia/arthralgia (7.1%). Grade 2/3 neutropenia was experienced by 10.7% of patients, whereas grade 2 thrombocytopenia was seen in only 3.3%. One patient died following complications of severe allergic reaction. In conclusion, although this study is ongoing, it is clear that the combination of paclitaxel and carboplatin is effective and well tolerated in patients with nonoperable NSCLC.
Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. [2015]The French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) conducted a multicenter phase II study of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to evaluate the efficacy and side effects of this combination in pretreated advanced ovarian cancer. Patients with progressive ovarian carcinoma during or after platinum-based chemotherapy received paclitaxel 175 mg/m2 intravenously over 3 hours followed by intravenous carboplatin over 30 minutes every 4 weeks. The dose of carboplatin was calculated using a projected area under the concentration-time curve of 5 mg/mL x min. Of the 50 patients entered, 50 were evaluable for toxicity and 42 for response. There were eight complete and 10 partial responses, for an overall response rate of 43% (95% confidence interval, 28% to 56%). Overall response rates in platinum refractory patients and in those with early (> or = 3 and or = 12 months) relapse was 28%, 33%, and 71%, respectively. Median response duration, progression-free survival, and overall survivals were 8, 6, and 14 months, respectively. The most frequent and severe toxicity was myelosuppression. Grades 3 and 4 neutropenia occurred in 30% and 23% of cycles, and granulocyte colony-stimulating factor was administered in 6%. Only one case of neutropenic fever was observed. Grades 3 and 4 thrombocytopenia occurred in 3% and 1% of cycles, respectively. Alopecia and moderate nausea or vomiting were frequent. Transitory peripheral neuropathy was present in 45% of patients but was severe in only one patient. One early death was observed due to progressive disease and possibly to therapy. The combination of paclitaxel 175 mg/m2 as a 3-hour infusion and carboplatin dosed to an area under the concentration-time curve of 5 is an effective therapy in patients previously treated with platinum-based chemotherapy and may be administered safely to outpatients who relapse after one or two lines of chemotherapy.
Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme. [2019]The authors evaluated the efficacy of neoadjuvant carboplatin chemotherapy before external-beam irradiation in patients who had histologically proven glioblastoma multiforme. Twenty-five patients were treated with carboplatin, 600 mg/m2, intravenously once every 4 weeks for a total of 4 planned cycles. External-beam irradiation (60 Gy involved field) was planned after carboplatin. Of 15 patients who had residual tumor assessable for response, seven had stable disease, six had partial responses, one had a complete response, and one had progressive disease. Two of the patients who had partial responses progressed before radiotherapy. Of 10 who had gross total resections, two progressed after 3 to 4 cycles. The median time to tumor progression was 8.4 months. Median survival was 19.2 months. Myelotoxicity and other side effects of treatment were modest. Carboplatin chemotherapy after biopsy or resection of glioblastoma multiforme before irradiation is feasible. These results warrant further clinical investigation of the role that carboplatin chemotherapy may have in the treatment of patients who have newly diagnosed glioblastoma multiforme.
Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study. [2015]This study was aimed to determine the activity and toxicity of combination paclitaxel and carboplatin in stage III B and IV NSCLC. Eligibililty required performance status. Paclitaxel was administered at a dose of 200 mg/m2, 3-hour infusion, followed by carboplatin at a tartgeted area under the concentration-time curve (AUC) of 6. Treatment was repeated at 3-week intervals for 6 courses. G-CSF 5 micrograms/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leukopenia or granulocytopenia in the previous course. From August 1996 through June 1997, 15 patients were enrolled. The median age was 47 years (range 20-68 years), 60 per cent were female. 73.3 per cent had adenocarcinoma, and 66.7 per cent had stage III B disease. Eighty three courses were administered; 13 patients (86.7%) completed all six cycles. The objective response rate was 53.3 per cent, with 1 (6.7%) complete response and 7 (46.7%) partial responses. Pleural effusion, lung lesion and lymph node were the three most common sites that responded to chemotherapy. The major toxicity was myelosuppression. Grade 3 or 4 granulocytopenia, anemia and thrombocytopenia were observed in 18 per cent, 7.2 per cent and 1.2 per cent, respectively, of 83 courses administered. Four episodes of febrile neutropenia (4.8%) occurred in 3 patients. There was one episode of anaphylaxis during Paclitaxel infusion. Other common toxicities were mild myalgia, paresthesias, alopecia and fatigue. Most of the toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.
Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. [2019]The combination of paclitaxel with carboplatin is effective in advanced-stage non-small cell lung cancer (NSCLC). This phase III study was designed to compare the efficacy and tolerability of a weekly versus an every-3-week schedule in the first-line treatment of advanced-stage NSCLC.
The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas. [2017]Carboplatin (CBDCA) and bevacizumab (BEV) are active in glioblastoma (GBM) with different profiles of toxicity. To date, no study has compared the value of the addition of BEV to historical or traditional cytotoxic chemotherapy. We sought to determine the relative value of BEV in combination with CBDCA versus CBDCA alone in patients with recurrent GBM.
Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device. [2016]Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model.
Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. [2019]The blood-brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations.
Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. [2021]Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood-brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models.
Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma. [2023]Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood-brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.
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. [2023]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.