Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449.

PURPOSE: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal. METHODS: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal. RESULTS: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1). CONCLUSIONS: GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.

Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma.

Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.

A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors.

Venous thromboembolism (VTE) is a common complication in patients with high-grade gliomas. The purpose of this prospective multicenter study was to determine the hazard rate of first symptomatic VTE in newly-diagnosed glioma patients and identify clinical and laboratory risk factors. On enrollment, demographic and clinical information were recorded and a comprehensive coagulation evaluation was performed. Patients were followed until death. The study end point was objectively-documented symptomatic VTE. One hundred seven patients were enrolled with a median age of 57 years (range 29-85) between June 2005 and April 2008. Ninety-one (85 %) had glioblastoma multiforme (GBM). During an average survival of 17.7 months, 26 patients (24 %) (95 % CI 17-34 %) developed VTE (hazard rate 0.15 per person-year) and 94 patients (88 %) died. Median time to VTE was 14.2 weeks post-operation (range 3-126). Patients with an initial tumor biopsy were 3.0 fold more likely to suffer VTE (p = 0.02). Patients with an elevated factor VIII activity (>147 %) were 2.1-fold more likely to develop VTE. ABO blood group, D dimer and thrombin generation were not associated with VTE. No fatal VTE occurred. VTE is a common complication in patients with newly-diagnosed high grade gliomas, particularly in the first six months after diagnosis. Patients with an initial tumor biopsy and elevated factor VIII levels are at increased risk. However, VTE was not judged to be primarily responsible for any patient deaths. Therefore, outpatient primary VTE prophylaxis remains investigational until more effective primary prophylaxis strategies and therapies for glioma are identified.

Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas.

Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤5% of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing.

Clinical trials of R-(-)-gossypol (AT-101) in newly diagnosed and recurrent glioblastoma: NABTT 0602 and NABTT 0702.

PURPOSE: AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma. METHODS: In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS). RESULTS: A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM. CONCLUSIONS: AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas.

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m(2), in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m(2) for patients not taking EIAEDs and 9.6 mg/m(2) for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0-8.6) months and 6-month PFS rate was 4% (95% CI, 0-22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m(2)) than those not (24 ± 9.2 l/h/m(2)). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.

Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma.

Bortezomib selectively binds and inhibits the 20S proteasome enzyme's active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/-EIASD). The starting dose in both groups was 0.9 mg/m(2) intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the -EIASD group was 1.70 mg/m(2) based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m(2) without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m(2) suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m(2) of bortezomib at 77 ± 12% and in -EIASD patients treated with a dose of 1.7 mg/m(2) at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.

Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). RESULTS: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17-24] and the HR was 0.44 (95% CI, 0.35-0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. CONCLUSIONS: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease.

Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM.

Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma.

Atrasentan is an oral selective endothelin-A receptor antagonist that may inhibit cell proliferation and interfere with angiogenesis during glioma growth. We conducted a dose-finding study to assess atrasentan's safety and toxicity and to gather preliminary evidence of efficacy. Patients with recurrent malignant glioma received oral atrasentan at >or=10 mg/day. We increased the dose among cohorts until the maximum tolerated dose (MTD) was defined. Patients were evaluated for response every 8 weeks and remained on the study until the tumor progressed or toxicities occurred. Twenty-five patients were enrolled, with a median age of 53 years (range, 25-70) and a median KPS of 90% (range, 60-100%). Twenty-two patients had glioblastoma multiforme (GBM), 2 had anaplastic astrocytoma, and 1 had an anaplastic oliogodendroglioma; 24 patients had received one prior chemo therapy regimen before being enrolled in the study. The most common atrasentan-related toxicities were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed grade 3 hypoxia and peripheral edema at a dose of 90 mg/day. We observed no dose-limiting toxicities in an expanded cohort of 10 patients at 70 mg/day, which was declared the MTD. Two partial responses (8%) were seen in patients with GBM at the 70- and 90-mg/day dose levels, and 4 patients had stable disease before progressing. Nineteen patients have died, and median survival was 6.0 months (95% confidence interval, 4.2-9.5 months). We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day. Further study of atrasentan with radiation therapy and temozolomide in newly diagnosed GBM is warranted to evaluate the efficacy of this novel agent.

Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma.

Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies. Celecoxib, a selective COX-2 inhibitor, is predominantly eliminated by hepatic metabolism. This study was conducted to determine the effects of hepatic enzyme-inducing antiseizure drugs (EIASDs) on the pharmacokinetics of celecoxib. The safety of celecoxib administered with radiation for glioblastoma and the effect of the combined treatment on survival were also evaluated. Patients were stratified based on concomitant use of EIASDs. Celecoxib (400) mg was administered orally twice a day until tumor progression or dose-limiting toxicity. Standard radiation was administered without adjuvant chemotherapy. Sampling was performed to define the plasma concentration/time profile for the initial dose of celecoxib and steady-state trough concentrations. Thirty-five patients (22 +EIASD, 13 -EIASD) were enrolled. There were no significant differences in age, performance status, extent of surgery, or Mini Mental State Exam scores between the two cohorts. The treatment was well tolerated. All patients in the +EIASD arm were taking phenytoin. There were no significant differences in any celecoxib pharmacokinetic parameters between 15 +EIASD and 12 -EIASD patients. With 31 of 35 patients deceased, estimated median survival time for all patients was 12 months (+EIASD, 11.5 months; - EIASD, 16 months; p = 0.11). The pharmacokinetics of celecoxib is not significantly affected by the concomitant administration of phenytoin. Celecoxib administered during and after radiation is well tolerated. The potential difference in survival between the +EIASD and -EIASD groups deserves further evaluation.

Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-ß tyrosine kinase inhibitor, in patients with recurrent glioblastoma.

Background: Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-ß is expressed on most endothelial cells in glioblastoma specimens. Methods: We report the results of feasibility, phase I, and phase II studies of tandutinib (MLN518), an orally bioavailable inhibitor of type III receptor tyrosine kinases including PDGF receptor-ß, Fms-like tyrosine kinase 3, and c-Kit in patients with recurrent glioblastoma. Results: In an initial feasibility study, 6 patients underwent resection for recurrent glioblastoma after receiving tandutinib 500mg twice daily for 7 days. The mean ratio of tandutinib concentration in brain tumor-to-plasma was 13.1±8.9 in 4 of the 6 patients. In the phase I study, 19 patients were treated at 500, 600, and 700mg twice daily dose levels. The maximum tolerated dose was found to be 600mg twice daily, and 30 patients were treated with this dose in the phase II study. The trial was closed after interim analysis, as the prespecified goal of patients alive and progression-free survival at 6 months was not achieved. Biomarker studies suggested that tandutinib treatment could lead to vascular disruption rather than normalization, which was associated with rapid progression. Conclusions: Tandutinib readily distributed into the brain following oral administration and achieved concentrations within the tumor that exceed the corresponding concentration in plasma. The phase II study was closed at interim analysis due to lack of efficacy, although this study was not enriched for glioblastomas with alterations of the PDGF pathway.

Repeatability of 18F-FLT PET in a Multicenter Study of Patients with High-Grade Glioma.

Quantitative 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of 18F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. Methods:18F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after 18F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUVmean_30%), gradient-based segmentation (SUVmean_gradient), the maximum pixel (SUVmax), and a 1-mL sphere at the region of highest uptake (SUVpeak). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. Results: RCs for tumor SUVs were 22.5% (SUVmean_30%), 23.8% (SUVmean_gradient), 23.2% (SUVmax), and 18.5% (SUVpeak) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUVpeak (RC, 16.5%). Conclusion: SUV quantification of 18F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after 18F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUVpeak Although changes in 18F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.

Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.

Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods: Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors.

PURPOSE: Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. PATIENT AND METHODS: Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. RESULTS: Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range,

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Phase I study of terameprocol in patients with recurrent high-grade glioma.

Terameprocol is a global transcription inhibitor that affects cell division apoptosis, drug resistance, hypoxia responsive genes, and radiation resistance in hypoxia. A multicenter, dose-escalation study was conducted in heavily pretreated patients with recurrent, measurable, high-grade gliomas. Terameprocol was administered intravenously for 5 consecutive days each month and discontinued for toxicity or progression. Patients taking enzyme-inducing antiseizure drugs (EIASDs) were escalated independently. Thirty-five patients with a median Karnofsky performance status of 80, median age of 46 years, and median of 2 prior treatment regimens were accrued. Doses of 750, 1100, 1700, and 2200 mg/day were administered. Terameprocol was reformulated to avoid acidosis related to the excipient and was well tolerated at 1700 mg/day. Hypoxia and interstitial nephritis were noted at 2200 mg/day. Concurrent administration of EIASD did not significantly affect the serum pharmacokinetics of the terameprocol. Although no responses were seen, stable disease was noted in 9 (28%) of 32 evaluable patients, with 5 (13%) continuing treatment for >6 months (≥6, 8, 10, 10, and ≥21 months). The overall median survival was 5.9 months. This phase I study defined the toxicity of terameprocol, determined that EIASDs do not affect its pharmacokinetics, and identified 1700 mg/day as the dose for future studies. Preclinical and human data suggest that this novel transcription inhibitor is worthy of further study. The long-term stability noted in some patients and the lack of associated myelosuppression suggest that terameprocol could be safely combined with radiation and temozolomide in newly diagnosed high-grade gliomas.

Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03.

PURPOSE: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). EXPERIMENTAL DESIGN: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles. RESULTS: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. CONCLUSION: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.