Recurrent Anaplastic Glioma Research Articles

Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma

Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination. Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme-inducing anticonvulsants were enrolled. Treatment was in 6-week cycles with irinotecan at 125 mg/m(2) weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression-free survival rate at 6 months (PFS-6), and the secondary endpoints were overall survival (OS) and response rate (RR). In 39 eligible patients, PFS-6 for the intent-to-treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment-related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment-related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis. The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing.

A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma

The purpose of this study was to evaluate the activity of single-agent bevacizumab in patients with recurrent anaplastic glioma and assess correlative advanced imaging parameters. Patients with recurrent anaplastic glioma were treated with bevacizumab 10 mg/kg every 2 weeks. Complete patient evaluations were repeated every 4 weeks. Correlative dynamic contrast-enhanced MR and (18)fluorodeoxyglucose PET imaging studies were obtained to evaluate physiologic changes in tumor and tumor vasculature at time points including baseline, 96 h after the first dose, and after the first 4 weeks of therapy. Median overall survival was 12 months (95% confidence interval [CI]: 6.08-22.8). Median progression-free survival was 2.93 months (95% CI: 2.01-4.93), and 6-month progression-free survival was 20.9% (95% CI: 10.3%-42.5%). Thirteen (43%) patients achieved a partial response. The most common grade ≥ 3 treatment-related toxicities were hypertension, hypophosphatemia, and thromboembolism. Single-agent bevacizumab produces significant radiographic response in patients with recurrent anaplastic glioma but did not meet the 6-month progression-free survival endpoint. Early change in enhancing tumor volume at 4 days after start of therapy was the most significant prognostic factor for overall and progression-free survival.

Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas

Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression-free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas.

Phase I/II vaccine study targeting novel HLA-A2-restricted CTL epitopes in combination with poly-ICLC in patients with recurrent malignant glioma.

2506 Background: We conducted a phase I/II trial to evaluate the safety and immunogenicity of a novel vaccination with α-type-1-polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma associated antigen (GAA) epitopes and administration of poly-ICLC in HLA-A2+ patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, IL-13Rα2, YKL-40 and gp100. Methods: The study enrolled twenty-two recurrent malignant glioma patients with glioblastoma (GBM) (n = 13), anaplastic astrocytoma (n = 5), anaplastic oligodendroglioma (n = 3), or anaplastic oligoastrocytoma (n = 1). Half the patients had 2nd relapse or greater. Two recurrent GBM patients had prior bevacizumab. Peptide-loaded αDC1 were injected intra/peri-nodally every two weeks for 4 injections with the possibility of boosters. 20 µg/kg poly-ICLC was administered intramuscularly two times per week for 8 weeks. Immunogenicity was assessed by ELISPOT, tetramer, and IL-12 assays. Efficacy was determined by MRI according to McDonald criteria. Results: The regimen was well-tolerated and demonstrated efficacy in heavily pre-treated patients. There were no grade 3 or greater toxicities and no dose limiting toxicities. Injection site reactions, transient fatigues and chills were the most common adverse events. Eighty-one percent (13/16) had ≥ 1 positive immunogenicity assay. Forty-six percent (6/13) of recurrent GBM and sixty-seven percent (6/9) of recurrent anaplastic glioma patients had tumor shrinkage or stable disease. One recurrent GBM patient sustained a complete response (CR) for greater than 14 months, and 2 patients achieved a partial response (PR). In recurrent GBM patients, the median overall survival (OS) was 12 months, 6 month OS was 80%, and 12 month OS was 46%. Conclusions: The novel αDC1-based vaccine in combination with poly-ICLC demonstrated safety, immune-reactivity as well as efficacy in patients with recurrent malignant glioma. Given these promising results, Phase II/III clinical studies are planned in recurrent GBM. Phase I/II trials are also underway with peptide emulsion in adult low-grade and pediatric malignant glioma.

Salvage therapy with single agent bendamustine for recurrent anaplastic glioma.

e12506 Background: A prospective Phase II study of the novel alkylator, bendamustine, in adult patients with recurrent temozolomide-refractory anaplastic gliomas (AG) with a primary objective of evaluating 6-month progression free survival (PFS). Methods: Seven patients (2 men; 5 women) ages 33-59 years (median 37), with recurrent AG were treated. All patients had previously been treated with surgery, involved-field radiotherapy and temozolomide chemotherapy. Two patients were treated at first recurrence (2 following re-operation) and five patients at second recurrence with bendamustine administered intravenously on 2 consecutive days (100mg/m2/day) every 4 weeks (operationally defined as a single cycle). Neurological evaluation was performed every 4 weeks; neuroradiographic evaluation was performed every 8 weeks; laboratory assessments on days 21 and 28 of each cycle. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc. Results: All patients were evaluable. A total of 28 cycles of bendamustine (median 4 cycles; range 2–6) was administered. Grade 3 or higher bendamustine-related toxicity included lymphopenia (5/7 patients, 71%) and thrombocytopenia (1, 14.3 %). One patient required a dose reduction to 75mg/m2/day due to prolonged grade 2 neutropenia. No patient required transfusion or developed neutropenic fever. No treatment-related deaths occurred. No radiographic responses were seen however 3 patients (43%) demonstrated stable disease. Time to tumor progression ranged from 2 – 11+ months (median: 7+ months). Survival ranged from 4 – 11+ months (median: 8+ months). Three patients are alive, off therapy and with continued radiographic stable patterns of disease. 6-month PFS was 43% and according to protocol permits secondary expansion of the study to 24 patients. Conclusions: Bendamustine demonstrated sufficient efficacy with acceptable toxicity in this initial cohort of adult patients with recurrent AG that pre-specified study expansion is planned and actively enrolling.

Convection-enhanced delivery of a transforming growth factor- 2 inhibitor trabedersen for recurrent high-grade gliomas: efficacy real or imagined?, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142)

Dr Bogdahn et al. reported on the convection-enhanced delivery (CED) of the transforming growth factor-β2 (TGF-β2) inhibitor trabedersen for recurrent high-grade glioma.1 The trial was designed as a randomized phase 2b study comparing two doses of trabedersen to chemotherapy, either temozolomide (TMZ) or procabazine-lomustine-vincristine (PCV). Several comments regarding the study I believe are warranted. Firstly, the trial was never properly powered to detect a difference in trabedersen dose vs. best standard chemotherapy. Notwithstanding this serious limitation, the trial was clearly negative with respect to recurrent glioblastoma. Much more problematic are the conclusions with respect to recurrent anaplastic astrocytoma (AA) in which the authors assert there is compelling evidence of trabedersen effectiveness to proceed to a randomized phase 3 trial (SAPPHIRE). Concerning in particular is the remarkably small numbers of recurrent AAs studied (39 randomized to 1 of 3 treatment arms) from which these conclusions are based. Furthermore, efficacy of trabedersen is based upon a secondary endpoint (progression-free survival at 14 months: PFS-14) not the prespecified primary endpoint (progression-free survival at 6 months: PFS-6). To my knowledge, PFS-14 has never been validated as a glioma trial endpoint and, consequently, it is uncertain what this construct represents.2,3 Remarkably, from 1/3 to 2/3 of all patients with recurrent AA had not been treated with chemotherapy before study entry, creating differences in the treatment groups and in effect subdividing an already small group of patients into 2 separable populations (chemotherapy-experienced or -naive). At least in the United States, it would be highly unlikely to find such a chemotherapy-naive population, as TMZ is widely used in the upfront treatment of such tumors. How to assess a study performed in non-traditional neuro-oncology centers where standards of care likely differ from European and U.S. centers are challenging, though admittedly is becoming more common as financial and regulatory considerations shift new drug studies offshore. What was not a study inclusion criteria, prespecifying that all recurrent AA patients had been treated with either PCV or TMZ would have resulted in more comparable subgroups, a design utilized in the German NOA-04 recurrent anaplastic glioma trial.4 Additionally and not stated was the salvage therapy employed after study treatment failure, a highly relevant issue with respect to recurrent AA, as salvage therapy has a significant impact in overall survival. Confusingly, the recurrent AA treatment groups had no significant difference in tumor control at 6 months (presumably though not explicitly stated PFS-6) but did differ with respect to median duration of response favoring trabedersen. There also was an improvement favoring low-dose trabedersen in median time to progression. Notwithstanding the considerable investment in the trial, no central radiology review was performed, a process that is blinded to treatment allocation and without bias (unlike investigator-assessed response determinations). Without specifying endpoint definitions these descriptions appear confusing and contradictory. Not mentioned lastly is the prior lack of success utilizing CED as a means of drug delivery exemplified by the PRECISE and TransMID trials for recurrent glioblastoma. The failure of these trials begs the question of whether CED is a practical or feasible drug delivery system. What appears needed based upon this study is a properly designed and statistically powered phase 2 study of trabedersen in the treatment of recurrent AA that utilizes acceptable endpoints and a similarly pretreated cohort of patients. This critique is not intended to diminish the considerable effort by the study investigators but rather draw attention to prematurely moving investigational agents into randomized phase 3 trials without first establishing robust phase 2 trial results.

Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis.

Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas

Temozolomide-based chemotherapy represents an incremental improvement in the treatment of patients with high-grade gliomas. Notwithstanding a survival benefit in a subset of patients with high-grade gliomas, temozolomide (TMZ; Temodar®, Schering-Plough Pharmaceuticals, NJ, USA) is the primarily palliative treatment for the vast majority of patients. Indeed, for patients with newly diagnosed glioblastoma, the median increase in survival for treatment with TMZ and radiotherapy is only 2.5 months compared with radiotherapy alone. Additionally, recent studies suggest that 60–75% of patients with glioblastoma derive no benefit from treatment with TMZ. For the treatment of recurrent anaplastic gliomas, more than 50% of patients fail TMZ treatment with cancer progression at 6 months, demonstrating that TMZ is only a modestly effective chemotherapy. In addition, 15–20% of patients treated with TMZ develop clinically significant toxicity, which can leave further treatment unsafe. Despite the availability of TMZ, there is still a substantial need for a chemotherapeutic agent that is more effective and safe. In fact, there still remains a significant unmet need for more effective treatments of high-grade gliomas (improved palliation or cure), whether that treatment be by surgery, radiotherapy, chemotherapy or any yet to be developed type of treatment, such as ‘targeted therapies’.

Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas

Despite advances in adjuvant therapy, the prognosis for most patients with high-grade glioma (HGG) is poor, and almost all HGGs have a likelihood of disease recurrence. HGGs are highly vascularized tumors with elevated expression levels of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. A compelling biologic rationale, a pressing need for improved therapeutics and positive results from studies of bevacizumab in other tumor types, led to the evaluation of bevacizumab in the treatment of HGG. It was demonstrated previously that bevacizumab, which is a humanized monoclonal antibody that targets VEGF, improved outcomes when combined with chemotherapy (most commonly irinotecan) in patients with recurrent HGG; and, on the basis of an improved objective response rate in 2 prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration as a single agent in patients with previously treated glioblastoma (GB). Bevacizumab-containing therapy has been associated with manageable, class-specific toxicity; however, severe treatment-related adverse events are observed in a minority of patients. Preliminary data on bevacizumab-based therapy in recurrent anaplastic gliomas, in the frontline treatment of GB, and in additional patient populations are also encouraging. With the goal of addressing unanswered questions regarding the optimal use of bevacizumab, the objective of the current review was to provide a summary of the clinical efficacy and safety data on bevacizumab in patients with HGG, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in additional brain tumor treatment settings.

Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma

We evaluated the efficacy of temozolomide (TMZ) or lomustine (CCNU) in combination with 6-thioguanine, capecitabine, and celecoxib for the treatment of recurrent high-grade glioma. Forty-three patients with recurrent glioblastoma and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-thioguanine, capecitabine, and celecoxib. Endpoints were 12-month progression-free survival (PFS) for patients with AG, 6-month PFS for patients with glioblastoma, duration of PFS, and MRI-based objective response rates. Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. Thirty-eight patients with glioblastoma were treated with the lomustine-based regimen, and five received the TMZ-based regimen. For the 43 glioblastoma patients, the objective response rate was 12 and 33% had stable disease; the 6-month PFS was 14% and median overall survival 32weeks. For the 31 AG patients, the combined objective response rate was 26 and 42% had stable disease; the 12month PFS was 44%. Treatment was reasonably well tolerated with hematological toxicity common and more frequent with CCNU than TMZ. The combination therapy with 6-thioguanine, capecitabine and celecoxib plus CCNU or TMZ does not appear to be more effective than other alkylating agent schedules for patients with recurrent glioblastoma. The combination, however, is promising for patients with recurrent high-grade AG.

Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma.

2057 Background: There is currently no standardized therapy for high-grade gliomas after recurrence. Since chemotherapy for these tumors is still dominated by alkylating agents, we evaluated the efficacy of combination chemotherapy with temozolomide (TMZ) or lomustine (CCNU) and 6-thioguanine (6-TG), capecitabine (CAP), and celecoxib (CEL). Methods: Forty-three patients with recurrent glioblastoma (GBM) and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative, study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-TG, CAP, and CEL. Endpoints were 12-month progression-free survival (PFS) for patients with AG and 6-month PFS for patients with GBM, duration of PFS, and MRI- based objective response rates (OR). Results: Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. 38 patients with GBM were treated with the CCNU-based regimen, and 5 received the TMZ-based regimen. For the 43 GBM patients, the OR rate was 12% and 33% had stable disease. For GBM, the 6 month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined OR rate was 26% and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated; hematologic toxicity was most common and more frequent with CCNU. Conclusions: The combination therapy with 6-TG, CAP, and CEL plus either CCNU or TMZ does not appear to be more effective than conventional alkylating agents for patients with recurrent GBM. The combination, however, is promising for patients with recurrent AG. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Castle Biosciences, Genentech, Merck, Novartis, Pfizer, Schering-Plough Bayer, IMEDEX, Merck, Novartis, Schering-Plough Castle Biosciences, Celgene, Genentech, Lilly, MGI Pharma, Novartis, Pfizer, Schering-Plough Schering-Plough

Temozolomide and MGMT forever?

To the outside world, it may seem that neuro-oncologists involved in the development of novel treatment approaches to gliomas are narrow-minded and very preoccupied with one drug, temozolomide (TMZ), and one enzyme, O6-methylguanylmethyltransferase (MGMT). TMZ was approved for recurrent anaplastic glioma and glioblastoma in 1997 and soon became a standard of care in this setting.1,2 In 2005, the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada trial set a new standard of care for newly diagnosed glioblastoma3 and the role of TMZ in recurrent glioblastoma became questionable because fewer and fewer patients were TMZ-naive at recurrence. In the absence of promising competitor agents, however, it soon became clinical practice to re-expose TMZ-pretreated patients to the same drug (rechallenge) when relapse occurred after a treatment-free interval. Moreover, for patients failing the standard TMZ, various competing alternative TMZ dosing regimens of temozolomide were explored based on various theoretical assumptions, including MGMT depletion in tumor cells and anti-angiogenic, metronomic chemotherapy-like effects of TMZ; such regimens included continuous daily temozolomide (see also: clinicaltrials.gov NCT00392171),4 3 weeks on/1 week off,5 and 1 week on/1 week off.6 In the present issue of Neuro-Oncology, Kong and colleagues7 report another small phase II study of continuous daily TMZ (40–50 mg/m2) in patients with recurrent glioblastoma. Their progression-free survival rate at 6 months of 32.5% confirms to the point what has been reported in this setting.4,8 Because of the small patient numbers and different patterns of prior treatment, it is impossible to select the best of these schedules to carry forward, for example, for combination trials, but it can be assumed that the rate of progression-free survival at 6 months with these regimens will be in the range of 30% even in TMZ-pretreated patients. Two of these regimens are currently being studied in a non-comparative randomized phase II design (DIRECTOR, clinicaltrials.gov NCT00941460). Uniformly all studies report that the MGMT promoter methylation status determined at diagnosis does not correlate with the benefit derived from alternative TMZ regimens given at recurrence.5–7 Although many of the rationales for using alternative TMZ dosing regimens at recurrence center on overcoming MGMT-mediated resistance, surprisingly little is known regarding the MGMT status at recurrence and its prognostic or predictive significance. Also in this issue of Neuro-Oncology, Brandes and colleagues9 assessed the MGMT status in 38 paired samples of primary and recurrent glioblastomas. The MGMT status changed in 14 patients (37%), more often from methylated to unmethylated (8 of 13 patients) than from unmethylated to methylated (6 of 25 patients). Again, only the MGMT status determined at diagnosis was prognostic. While both new reports7,9 advance our understanding of the role of TMZ and MGMT status at recurrence, several questions remain. How can we be sure that pseudoprogression did not contribute to the 30% rate of stable disease at 6 months, particularly patients switched to alternative TMZ regimens during the 6 standard maintenance cycles? Which mechanisms drive changes in the MGMT status from first to recurrent tumor and how reliable are such assessments, and is MGMT status within the recurrent tumor as homogeneous as it presumably is in primary tumors? Answers to these questions are clinically relevant and will shape the standards of care in the diagnosis and treatment of glioblastoma for years, justifying our current apparent preoccupation with temozolomide and MGMT.10

BEVACIZUMAB AND IRINOTECAN FOR RECURRENT OLIGODENDROGLIAL TUMORS

We commend Tallibert et al.1 for their article regarding the efficacy of bevacizumab and irinotecan for recurrent oligodendroglial tumors. Bevacizumab was recently approved for treatment of recurrent glioblastoma by the US Food and Drug Administration. It was approved as a single agent because there are no data showing a survival benefit in combining it with irinotecan. Furthermore, irinotecan adds both cost and toxicity. These issues are relevant to the retrospective study by Tallibert al. because data regarding the added benefit of combining irinotecan with bevacizumab for recurrent anaplastic gliomas (AG) are equally uncertain. We investigated the use of single agent bevacizumab for both recurrent …

Rechallenge with temozolomide in patients with recurrent gliomas

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.

A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas

This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.

Phase II study of POLY-ICLC in recurrent anaplastic glioma–A North American Brain Tumor Consortium study

1550 Background: The goals of this study were to determine the 6-month progression free survival (PFS) for patients with recurrent anaplastic glioma (AG) treated with the immune-modulatory agent POLY-ICLC, and to evaluate toxicity. Low dose Poly-ICLC has a direct immune enhancing action which includes an increased antibody response to antigen and activation of NK-cells, T-cells, macrophages and cytokines. Previously documented side effects include transient flu-like symptoms, which responds to acetaminophen and pain related to the intramuscular administration. Methods: Eligibility included age >18 years, recurrent AG, no more than 2 prior relapses, normal laboratory parameters and informed consent. Poly-ICLC was administered at 20mcg/kg 3x/week by intramuscular injection in 4 week cycles continuously. Dose reductions were allowed for toxicities. Patients were assessed for tumor response every 2 months. Treatment continued until tumor progression, unacceptable toxicity or patient withdrawal. The study had a 2 stage design with the initial assessment of 6 month PFS for the first 22 patients with possible expansion to a total of 46 patients, if more than 7 patients of the 22 had a 6 month PFS. Results: As of 12/05, 46 patients were treated (49% males). Median age was 42 years (range 21–70 years) and median KPS was 90. The agent was well tolerated and the toxicity profile was as previously reported. The response rate and 6 month PFS of the 22 patients in the first stage of the study was 9% and 23% respectively. Based on these findings the cohort was expanded to 46 patients. Of the 15 patients in the second cohort with at least 1 post treatment response assessment available, there is 1PR and 7 SD (47%). Conclusions: 6 month PFS for the entire cohort continues to be assessed but preliminary results suggest antitumor activity of this agent in recurrent anaplastic glioma. No significant financial relationships to disclose.

Phase II study of the combination of thalidomide and irinotecan in patients with recurrent anaplastic gliomas not on enzyme inducing anticonvulsants

1564 Background: Patients with recurrent anaplastic glioma (AG) have few treatment options after initial alkylating agent therapy. In this study, the efficacy of thalidomide and irinotecan against recurrent AG was tested to assess if synergistic activity of cytotoxic and antiangiogenic agents could affect clinical outcome. Methods: Patients with recurrent AG with a KPS≥70 not on enzyme inducing anticonvulsants and with fewer than three relapses after radiation therapy and chemotherapies were eligible; the total planned enrollment is 39 patients. Irinotecan is administered at 125 mg/m2 weekly for 4 weeks followed by 2 weeks rest; thalidomide is initiated at 100 mg daily and escalated weekly up to 400 mg daily. Warfarin (1 mg) is given for prevention of venous thromboembolism (VTE). Patients undergo clinical and radiologic evaluations every 6-weeks. The primary endpoint is progression free survival at 6 months (PFS-6). To determine possible radiologic correlates to treatment effects, DCE- MR perfusion-imaging studies are obtained at baseline and subsequent follow up visits. Results: 17 are evaluable for response; the remainder were inevaluable. All evaluable patients had previously failed temozolomide and 9 had also failed nitrosourea therapy. The median age is 44 yrs and median KPS is 90. Four patients are alive and progression free at 6-months whereas 9 have progressed; the median progression free survival is 23 weeks and the PFS-6 is 34%. The best response was a CR in one patient, PR in 2 and stable disease in 9. Two patients have died of unspecified causes probably related to treatment. Median overall survival has not been reached; the 12-month and 18 month survivals by Kaplan Meier analysis are 73% and 26% respectively. Grade 3 and 4 toxicities included fatigue (29%), leukopenia (29%), nausea/vomitting (24%), and diarrhea (18%) requiring dose reductions. Two patients had VTE. Conclusions: The preliminary results of this ongoing study suggest that the combination of irinotecan and thalidomide has activity in patients with recurrent anaplastic gliomas; the ongoing assessment of this combination in patients with AG will more definitively define whether the combination can be an effective second line therapy for this population. [Table: see text]

Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: A relationship among efficacy, joint toxicity and anticonvulsant status

Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma

The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG). Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum. CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks. The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.

A phase II study of temozolomide plus pegylated interferon alfa-2b for recurrent anaplastic glioma and glioblastoma multiforme

1519 Background: Based on prior studies suggesting promise of interferon alfa-2b and temozolomide (TMZ) in relapsed malignant glioma patients, we are testing this combination with a long acting (pegylated) form of interferon alfa-2b (PIFN) prolonging drug exposure and attempting to increase anti-tumor activity. Methods: We are conducting a prospective phase II trial of TMZ plus PIFN in adult patients with recurrent anaplastic glioma (AG) and glioblastoma multiforme (GBM), after surgery and radiotherapy (and chemotherapy in some cases), with adequate organ function and KPS ≥60. TMZ is administered at 150–200 mg/m2/day on days 1–5 of each 28-day cycle, and PIFN is administered subcutaneously at 0.5 microgram/kg every week. Two 28-day cycles equals one course. Patients are re-evaluated with neurological examinations and neuro-imaging every 56 days. The study is powered to detect an improvement of the historic 6-month progression-free survival (PFS) from 15% to 30% for GBM patients and from 20% to 40% for AG patients.Results: Thirty-five patients have enrolled, 9 with recurrent AG and 26 with recurrent GBM, 15 women, 20 men, median age is 55 years (range 20–67), median KPS is 90 (range 70–100). Grade 3 or 4 toxicity occurred in 29 patients, 10 patients required dose reduction, 2 of TMZ, 8 of both drugs. Common grade 3 or 4 toxicities included leukopenia or thrombocytopenia in 15 patients. Best responses were no change in 23/34 (68%). Kaplan-Meier estimates revealed 38% of GBM patients and 44% of AG patients alive and free from progression at 6 months after enrollment. Conclusions: Preliminary results of TMZ combined with PIFN in recurrent AG and GBM, despite a lack of any objective radiologic responses, produced a 6 month PFS in both subgroups that surpasses the target 6 month PFS. This improved outcome appears to come at a price of increased toxicity. This combination may warrant further investigation in a randomized trial or with other anti-neoplastic agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough