Cathy Brewer

Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme

Approximately 40–50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. Patients with non-small cell lung cancer and ≥grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60xa0Gy in 30 fractions with concurrent temozolomide 75xa0mg/m2/dayxa0×xa042xa0days, followed in four weeks by temozolomide 150–200xa0mg/m2/dayxa0×xa05, every 28xa0days for 12 cycles. Patients received erlotinib, 50xa0mg/day and increased by 50xa0mg/day every 2xa0weeks until the occurrence of grade 2 rash or to a maximum dose of 150xa0mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 [67%]) or adverse events (4 [15%]). Eighteen patients (67%) have died. Median progression-free survival was 2.8xa0months, and the median overall survival was 8.6xa0months. Five patients remain on study with a median follow-up of 16xa0months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity.

Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: clinical article.

OBJECTnLaser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM).nnnMETHODSnAdults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation.nnnRESULTSnTen patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose.nnnCONCLUSIONSnNeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).

Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1–3 newly diagnosed brain metastases

Patients with 1–3 brain metastases (BM) often receive sterotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT). SRS without WBRT carries a high rate of relapse in the central nervous system (CNS). This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Eligible patients with 1–3 newly diagnosed BM, RTOG RPA class 1–2, received sunitinib after SRS. Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapyxa0+xa0sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50xa0mg/days 1–28 every 42xa0days until CNS progression. Neuropsychological testing and MRIs were obtained every two cycles. The primary endpoint was the rate of CNS progression at 6xa0months (PFS6) after SRS. Fourteen patients with a median age of 59xa0years were enrolled. Primary cancers included lung 43xa0%, breast 21xa0%, melanoma 14xa0%. Toxicity included grade 3 or higher fatigue in five patients and neutropenia in two patients. The CNS PFS6 and PFS12 were 43xa0±xa014 and 34xa0±xa014xa0%, respectively. Of the ten patients who completed >1 neurocognitive assessment, none showed cognitive decline. Sunitinib after SRS for 1–3 BM was well tolerated with a PFS6 of 43xa0%. The prevention of progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient’s primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of BM after definitive local therapy.

Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases.

Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.

Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150xa0mg/m2xa0days 1–7 and 15–21, every 28xa0days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8xa0% achieved complete remission, 56xa0% had stable disease and 36xa0% had progression. The median PFS and OS were 27.2xa0months (95xa0% CI 11.9–36.3) and 105.8xa0months (95xa0% CI 51.5–N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (pxa0<xa00.001) and OS (pxa0<xa00.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (pxa0=xa00.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (pxa0<xa00.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.

Phase I Trial of Radiosurgery Dose Escalation Plus Bevacizumab in Patients With Recurrent/Progressive Glioblastoma.

BACKGROUNDnThe effectiveness of stereotactic radiosurgery (SRS) for recurrent glioblastoma (rGBM) remains uncertain. SRS has been associated with a high risk of radionecrosis in gliomas.nnnOBJECTIVEnTo determine the safety of dose escalation of single-fraction radiosurgery for rGBM in the setting of bevacizumab therapy.nnnMETHODSnWe conducted a prospective trial to determine the safety and synergistic benefit of higher doses of SRS administered with bevacizumab for rGBM. A single dose of bevacizumab was given prior to SRS and continued until progression. Dose-limiting toxicity was evaluated in successive cohorts of 3 patients.nnnRESULTSnSeven males and 2 females entered the study. The maximum linear diameter of the enhancing tumor was 2.58 cm (2.04-3.09). Prescription dose was escalated from 18 to 22u2009Gy. The radiosurgery target was chosen before the first dose of bevacizumab, about 1 wk prior to SRS treatment. Pre-SRS bevacizumab treatment was associated with a reduction of the mean volume of the enhancing lesion from 4.7 to 2.86 cm3 on the day of SRS (P = .103). No patient developed an acute side effect related to SRS treatment. The combination of SRS and bevacizumab resulted in a partial response in 3 patients and stable disease in 6 patients. Median progression-free and overall survival were 7.5 and 13 mo, respectively.nnnCONCLUSIONnA single dose of bevacizumab prior to SRS permitted safe prescription dose escalation up to 22 Gy for rGBM. Further evaluation of the efficacy of SRS for rGBM should be performed in the setting of bevacizumab treatment.

First-in-human evaluation of the Cleveland Multiport Catheter for convection-enhanced delivery of topotecan in recurrent high-grade glioma: results of pilot trial 1

OBJECTIVEProgress in management of high-grade gliomas (HGGs) has been hampered by poor access of potential therapeutics to the CNS. The Cleveland Multiport Catheter (CMC), which deploys 4 independent delivery microcatheters, was developed to be a reliable, high-volume delivery device for delivery of therapeutic agents to the brain and other solid organs. The authors undertook this first-in-human clinical trial effort to evaluate the delivery characteristics of the CMC in patients with HGGs.METHODSA series of pilot studies were launched after approval of a sponsor-investigator IND (investigational new drug) application to evaluate the delivery of topotecan and gadolinium-DTPA (Gd-DTPA) via the CMC in patients with recurrent HGG. The first pilot trial evaluated delivery into enhancing tumor and nonenhancing, tumor-infiltrated brain. Two catheters were placed with the use of a conventional frameless stereotactic technique following a biopsy to confirm tumor recurrence, and drug infusion was performed both intraoperatively and postoperatively for a total of 96 hours with the same rate for all microcatheters. Delivery was assessed by intermittent MRI.RESULTSThree patients were enrolled in the first pilot study. MRI demonstrated delivery from all 6 catheters (24 microcatheters). The volume of distribution (Vd) of Gd-DTPA was heavily dependent upon CMC location (enhancing vs nonenhancing) with an approximately 10-fold difference in Vd observed (p = 0.005). There were no hemorrhages related to catheter placement or removal, and all 3 patients completed the protocol-defined treatment.CONCLUSIONSThe CMC is capable of providing backflow-resistant drug delivery to the brain and brain tumors. The volume of distribution is heavily dependent upon the integrity of the blood-brain barrier. Assessment of delivery is essential for development of loco-regionally applied therapeutics in the CNS.Clinical trial registration no.: NCT02278510 (clinicaltrials.gov).

Phase II trial of sunitinib as maintenance therapy after stereotactic radiosurgery in patients with one to three newly diagnosed brain metastases.

TPS148 Background: For patients with 1-3 brain metastases, standard therapy after stereotactic radiosurgery (SRS) is whole brain radiotherapy (WBRT). SRS without WBRT leads to a significantly higher rate of relapse in the brain and local site (Aoyama, JAMA, 2006). Due to concerns about neurologic sequelae of WBRT, however, a substantial number of patients and physicians opt to delay WBRT until the time of CNS progression. This trial offers chemotherapy as an alternative treatment to WBRT for this patient subgroup. Sunitinib targets VEGFR and therefore vasculature. Because this target lies on the abluminal side of the blood brain barrier (BBB), sunitinib should not need to cross the BBB. Sunitinib might be effective in preventing growth of microscopic brain metastases. This trial uses sunitinib after SRS with the goal of preventing recurrent disease in the brain and at the site of SRS and preserving neurocognitive function (NCF). The hypothesis is that sunitinib will provide an effective alternative to WBR...