New Approaches To Brain Tumor Therapy Research Articles

A safety run‐in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306)

Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose.

Survival of Patients with Newly Diagnosed Glioblastoma Treated with Radiation and Temozolomide in Research Studies in the United States

Novel agents are currently combined with radiation and temozolomide (RT + TMZ) in newly diagnosed glioblastoma using overall survival as the primary end point. Results of these phase II studies are typically compared with the phase III European Organization for Research and Treatment of Cancer (EORTC) survival data that resulted in RT + TMZ becoming standard therapy. The New Approaches to Brain Tumor Therapy (NABTT) Consortium assigned 365 patients with glioblastoma to four single-cohort studies with similar eligibility criteria. Patients received RT + TMZ with talampanel (n = 72), poly-ICLC (n = 97), or cilengitide (n = 112) or RT + TMZ alone with monitoring of CD4 counts (n = 84). Overall survival of those ages 18 to 70 years with glioblastoma was compared with published EORTC data. NABTT and EORTC patients had comparable performance status and debulking surgery. Median, 12-month, and 24-month survival rates for the EORTC patients (n = 287) and the comparable NABTT patients receiving RT + TMZ and novel agents (n = 244) are 14.6 versus 19.6 months, 61% versus 81%, and 27% versus 37%, respectively. This represents a 37% reduction in odds of death (P < 0.0001) through 2 years of follow-up. NABTT and EORTC patients receiving only RT + TMZ had similar survival. Newly diagnosed glioblastoma treated recently with RT + TMZ and talampanel, poly-ICLC, or cilengitide had significantly longer survival than similar patients treated with only RT + TMZ accrued internationally from 2000 to 2002. These differences could result from the novel agents or changing patterns of care. Until the reasons for these different survival rates are clarified, comparisons of outcomes from phase II studies with published RT + TMZ survival data should be interpreted with caution.

Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on &gt;90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]

Rituximab monotherapy for relapsed or refractory primary central nervous system lymphoma

2043 Background: Rituximab, a chimeric monoclonal antibody against the CD20 antigen, improves survival when combined with CHOP therapy in patients with systemic diffuse large B-cell lymphoma (DLBCL). Approximately 90% of primary central nervous system lymphomas (PCNSL) are DLBCL and rituximab is now part of combination therapy in some regimens for PCNSL with only anecdotal evidence of efficacy in this patient population. Methods: Adult patients with relapsed or refractory CD20+ PCNSL are being enrolled in a National Cancer Institute-sponsored multicenter phase II trial of rituximab monotherapy in the New Approaches to Brain Tumor Therapy (NABTT) consortium. All patients failed prior methotrexate-based therapy. Rituximab is administered at a dose 375 mg/m2 in weekly intravenous infusions for a maximum of 8 treatments. The primary objectives are to determine the radiographic response proportion, progression-free and overall survival. The study design is a two-stage phase II trial with 15 patients in stage I and 10 additional patients in stage II. Results: Nine patients have been enrolled at the time of this submission. There have been 3 (1 CR, 2 PR) objective radiographic responses in the first 9 patients enrolled. Eight patients have progressed from 3–228 days after treatment and 4 patients have died. The rituximab responses lasted 174 days, 228 days and 324+ days. Four patients have experienced CTC grade 3 or 4 toxicity potentially related to rituximab with adverse events consisting of allergic reaction, fatigue, anxiety and pain. Conclusions: Rituximab monotherapy in patients with relapsed or refractory CD20+ PCNSL results in radiographic regression of tumor in a subset of patients and warrants further study in combination with other chemotherapeutic agents. Enrollment and follow-up are ongoing. No significant financial relationships to disclose.

Phase I study of gadolinium texaphyrin in newly diagnosed glioblastoma

2064 Background: Gadolinium texaphyrin (Gad Tex) is a putative radiosensitizer which inhibits cellular respiration resulting in the production of reactive oxygen species and induces apoptosis (Drugs R D. 2004; 5(1):52–7). Methods: The New Approaches to Brain Tumor Therapy (NABTT) consortium conducted a prospective phase I dose-escalation trial to determine the maximum tolerated dose of Gad Tex along with brain radiation therapy (RT) in newly diagnosed glioblastoma multiforme with KPS &gt; 60. RT was 60 Gy in 30 fractions, 5 days per week over 6 weeks, to localized treatment fields. Two different dosing regimens of Gad Tex were utilized. In regimen A, the initial dose was 2.5 mg/kg with each daily fraction of RT whereas in regimen B it was 5.5 mg/kg with every fraction of RT. Gad Tex was administered 2–5 hours before each radiation treatment. Results: The initial dose in both regimen A and B was found not to be tolerable. Of three patients treated at 2.5 mg/kg/dose on regimen A (daily dosing), one completed planned therapy (30 doses of Gad Tex), one had treatment stopped after 16 doses of Gad Tex when diffuse pulmonary infiltrates with shortness of breath developed and returned after rechallenge with an additional dose of Gad Tex, and one patient developed an allergic reaction after 15 doses of Gad Tex which returned on rechallenge. Of three patients treated at 5.5 mg/kg/dose (qod dosing) on regimen B, one completed planned therapy (15 doses of Gad Tex) after a dose reduction related for skin blisters, and the other two patients discontinued treatment after 9 doses of Gad Tex for debilitating skin blisters. Conclusions: Gad Tex was poorly tolerated as administered in this small phase I study as 4 of 6 patients experienced dose limiting toxicities. As such, NABTT elected not to pursue this drug in subsequent clinical trials. However, similar or more intensive regimens utilizing Gad Tex in combination with brain RT have been successfully administered in patients with newly diagnosed glioblastoma and brain metastases. No significant financial relationships to disclose.

Calculated versus measured creatinine clearance for dosing methotrexate in the treatment of primary central nervous system lymphoma

High-dose methotrexate (HDMTX) (>or=3 g/m2), the cornerstone of therapy for primary CNS lymphoma (PCNSL), is commonly dosed using a measured 24 h creatinine clearance (CrCl) every 2-4 weeks. Because these collections are cumbersome and at times unreliable, the use of a calculated CrCl was evaluated as a potential alternative. A retrospective analysis was performed on data from all 287 treatment cycles from the 25 patients with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. The 25 patients had a median age of 61 years (range 32-75). Seventeen (68%) were men. The patients received a median of 14 (range 2-21) HDMTX treatments. For 256 of 287 treatments (89%), data were available to compare the measured and calculated (using the Cockcroft-Gault equation) CrCl. The average measured CrCl was 93 ml/min (95% CI, 89-96 ml/min), and the average calculated CrCl was 107 ml/min (95% CI, 102-112 ml/min). The Pearson correlation coefficient (r) was 0.49 (P<0.0001) between the measured and calculated CrCl. The average MTX dose determined using measured CrCl was 14.1 g (95% CI, 13.6-14.5 g), and the average MTX dose determined using calculated CrCl was 14.7 g (95% CI, 14.2-15.1 g). MTX doses based on measured and calculated CrCl were significantly correlated (r=0.72, P<0.0001). Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48 h serum MTX levels documented. Forty-seven levels (30%) were within target range (0.3-1 micromol/l), 99 levels (62%) were below target range (<0.3 micromol/l), 12 levels (8%) were in the range associated with mild toxicity range (>1-3 micromol/l), and no levels were in the range associated with severe toxicity (>3 micromol/l). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 48 treatments (30%), a higher MTX dose for 62 treatments (40%), and a lower MTX dose for 48 treatments (30%). This distribution was not significantly different among the subsets of below target, within target range, and above target MTX levels (P=0.87). In this cohort of patients with PCNSL, there is significant correlation between the calculated and measured CrCl. MTX doses determined using calculated and measured CrCl are not significantly different. For these patients, there is no clear association between the method of determining CrCl and serum MTX levels. As a result, calculated CrCl is a reasonable alternative to measured CrCl in this patient population and would avoid the inconvenience and potential inaccuracies associated with measured CrCl.

Calculated versus measured creatinine clearance for the dosing of methotrexate in patients with primary CNS lymphoma

1536 Background: High-dose methotrexate (HDMTX) (8g/m2), the cornerstone of therapy for primary central nervous system lymphoma (PCNSL), is commonly dosed using a measured 24-hour creatinine clearance (CrCl) every 2–4 weeks. Because these collections are cumbersome, costly, and at times unreliable, the use of a calculated CrCl was evaluated. Methods: A retrospective analysis was performed on data from all 25 patients (287 treatments) with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Results: The 25 patients had a median age of 61 years (range 32–75 years). Seventeen patients (68%) were men. The patients received a median of 14 (range 2–21) HDMTX treatments. For 256 of 287 total treatments (89%), data were available to compare the measured and calculated (using the Cockcroft-Gault equation) CrCl. The average measured CrCl was 93±29 ml/min, and the average calculated CrCl was 107±43 ml/min. The correlation coefficient (r) was 0.66 (p&lt;0.001) between the measured and calculated CrCl. Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48-hour serum MTX levels documented. Forty-eight levels (30%) were in the ideal range (0.3–1 μmol/L), 98 levels (62%) were lower (&lt;0.3 μmol/L), 12 levels (8%) were higher (&gt;1–3 μmol/L), and no levels were in the range associated with significant toxicity (&gt;3 μmol/L). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 46 treatments (29%), a higher MTX dose for 62 treatments (39%), and a lower MTX dose for 50 treatments (32%). This distribution was not significantly different among the subsets of low, ideal, and high MTX levels (p=0.13). Conclusions: In this cohort of patients with PCNSL, there is a high correlation between the calculated and measured CrCl. For these patients, there is not a clear association between the method of determining CrCl and serum MTX levels. Therefore, the administered MTX doses using either method are likely to be similar. In this patient population, a calculated CrCl could be used to avoid the cost and inconvenience associated with measured CrCl. No significant financial relationships to disclose.

Prognostic factors for survival in adult patients with recurrent glioma enrolled on New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium phase I and II clinical trials

Prognostic factors for survival in adult patients with recurrent glioma enrolled on New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium phase I and II clinical trials

Updated results from NABTT CNS consortium studies in primary CNS lymphoma

1519 Background: Optimal therapy for patients with newly diagnosed PCNSL has not been defined. Methods: From 6/98–12/99, The New Approaches to Brain Tumor Therapy (NABTT) CNS consortium conducted a phase 2 trial of high dose methotrexate (MTX) without radiation (J Clin Oncol 2003; 21:1044–1049). We now report longer-term follow-up data from this study as well as preliminary results from our ongoing phase 2 study. Results: In the initial study, 25 patients with a median age of 60 and median KPS of 80 were treated with MTX at an intravenous (i.v.) dose of 8 g/m2 for up to 8 induction cycles every 14 days, 2 consolidation cycles every 14 days and 11 maintenance cycles every 28 days. There were 12/23 (52%) complete responses (CR); 5/23 (22%) partial responses; 1/23 (4%) stable disease and 5/23 (22%) progressions during treatment. In the 12 patients who achieved CR the median number of cycles to CR was 6. The median progression free survival was 12.8 months and median overall survival has not been reached at 47.6 months. Based on these promising results a second study was initiated combining MTX (8 g/m2 i.v. every 14 days) with thio-TEPA (2 mg/kg i.v. every 14 days). The first 3 patients treated with this regimen each achieved a CR after a median of 4 cycles of chemotherapy and remain in CR at 280, 313, and 340 days. Myelosuppression was prohibitive and the thio-TEPA dose was reduced to 2 mg/kg every 28 days for subsequent patients. Conclusions: Overall survival with high dose MTX monotherapy compares favorably with results reported with more toxic, chemotherapy plus radiation strategies. Early results from the NABTT protocol using MTX and thio-TEPA suggest that this combination might reduce the time to CR and increase the percentage of patients achieving CR. No significant financial relationships to disclose.

Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96–07

A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Methotrexate (8 g/m(2)) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.

Practical implementation of a modified continual reassessment method for dose-finding trials.

We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting. The continual reassessment method (CRM) was modified for use in phase I trials conducted through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our implementation of the CRM uses (1) a simple dose-toxicity model to guide data interpolation, (2) groups of three patients to minimize calculations and stabilize estimates, (3) investigators' clinical knowledge or opinion in the form of data to make the process easier to understand, and (4) a flexible computer program and interface to facilitate calculations. The modified CRM was used in two dose-finding trials of 9-aminocamptothecin in patients with newly diagnosed and recurrent glioblastoma who were taking anticonvulsant medication. The CRM located the maximum tolerated dose (MTD) efficiently in both trials. Compared to conventional designs, the CRM required slightly more than half the number of patients expected, did not greatly overshoot the MTD (i.e. no patients were treated at dangerously high doses), and did not underestimate the MTD. Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.

The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization, Objectives, and Activities.

BACKGROUND: Despite advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy, limited progress has been made in the treatment of patients with high-grade astrocytomas. The National Cancer Institute has attempted to speed advances in this field by funding CNS consortia to conduct innovative clinical trials in this patient population since 1994. METHODS: The NABTT CNS Consortium is composed of a consortium headquarters and nine member institutions with outstanding multidisciplinary expertise, clinical and laboratory research capabilities, and access to large numbers of patients with brain tumors. RESULTS: The objectives of the NABTT Consortium are to improve the therapeutic outcome for adults with primary brain tumors, to conduct basic science and clinical research, and to improve the care and quality of life of adults with primary brain tumors. NABTT's clinical studies have discovered important drug interactions between anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation strategy for brain tumor trials, and established new protocol "classes" to expedite and standardize clinical research in this field. CONCLUSIONS: Significant progress in the care of patients with primary brain tumors is likely to result from the highly focused and multidisciplinary efforts of the NIH-funded CNS consortia.