Search

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

Introduction: Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation., Areas Covered: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015., Expert Opinion: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naïve, EGFR mutated patients with refractory BM.

Background: Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases., Methods: Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity., Results: Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively., Conclusions: This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients., (© 2015 American Cancer Society.)

Purpose: To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients., Methods and Materials: Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression., Results: The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients., Conclusions: The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS., Methods and Materials: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m(2)/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m(2)/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS., Results: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001)., Conclusion: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ., Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts., Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year., Conclusion: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma., Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients., Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9., Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.

The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.

Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT.

Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.

This article reviews the current status and trends in the treatment of primary gliomas, focusing predominantly on glioblastoma. It also discusses the current standard of care and new targeted agents currently under investigation. Furthermore, the concepts of pseudoprogression and pseudoresponse are introduced, which are new imaging correlates that have significant impact on understanding of the disease.

The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.

Purpose: To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue., Experimental Design: Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis., Results: Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus., Conclusions: Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.

Brain metastases are a frequent sequelae of many solid tumors. Whole-brain radiotherapy (WBRT) has been the standard treatment for decades, with modest long-term complications observed using doses no greater than 3 Gy/fraction. Surgical resection may be beneficial in select populations of patients with single brain metastases, controlled systemic disease, and good performance status. Radiosurgery has demonstrated consistent improvement in local control, with some reports showing a survival benefit when combined with WBRT. However, the role of radiosurgery as a single modality is unclear, particularly given concerns that higher rates of distant brain relapse result in increased risk of neurologic compromise and death from neurologic causes. Increasingly, the importance of neurocognitive assessment with brain metastases is being recognized, and recent data have strongly correlated neurocognitive dysfunction with tumor progression. Systemic agents showing activity in brain metastases including temozolomide, RSR13, motexafin gadolinium, and lapatinib are being explored.

Glioblastoma multiforme (GBM) is the most common central nervous system malignancy. It is rapidly progressive with rare opportunity for cure. After three decades of laboratory and clinical research, a newly evolved chemoradiotherapy approach using the alkylating agent temozolomide during and after radiotherapy has resulted in the first significant impact on this disease. Here we discuss the basis for this positive interaction as well as potential mechanisms of resistance to it. Additionally, in the context of current and planned research, we explore approaches to take advantage of this combination and the use of targeted therapies to exploit cell signaling alterations found in GBM. We anticipate that a multimodality approach directed at tumor-specific biology will result in more meaningful advancements in the treatment of this fatal disease.

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib., Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response., Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages., Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

Purpose: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG)., Patients and Methods: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety., Results: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups., Conclusion: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.

Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug., Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival., Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks., Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

Objectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs., Study Design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria., Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs., Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

Purpose: To study in vitro the effect of carboplatin and/or hyperthermia in relation to etoposide (VP-16) cytotoxicity in L929 cells., Methodology/results: Cell survival assays demonstrated that the addition of 41.8 degrees C (x60 min) hyperthermia and carboplatin to VP-16 produced an antagonistic effect relative to VP-16 cytotoxicity in L929 cells; administering carboplatin and hyperthermia 24 h before VP-16 reduced this drug resistance; administering carboplatin and hyperthermia 48 h before VP-16, however, produced a supra-additive cytotoxicity. In order to gain insight into the molecular basis for these observations, we investigated the effect of hyperthermia and/or carboplatin on the stress protein GRP78, which is known to affect VP-16 cytotoxicity. Results obtained were consistent with the hypothesis that carboplatin and hyperthermia perturbation of NAD + pools results in down-regulation of GRP78 with subsequent modulation of VP-16 cytotoxicity. To further explicate these results we studied G-361 as a control cell line that had significantly higher pretreatment NAD+ levels, which were not affected by carboplatin and/or hyperthermia. This cell line did not exhibit a down-regulation of GRP78 or modulation of VP-16 cytotoxicity as a function of carboplatin and hyperthermia., Conclusions: These data taken collectively, demonstrate a sequence effect (regarding the aforementioned antineoplastic agents), and provide a framework for future studies directed at the therapeutic optimization of the sequential application of carboplatin, hyperthermia, and VP-16.

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

Purpose: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m(2) in a phase I trial., Patients and Methods: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m(2) (n = 3); 300 mg/m(2) (n = 7); 350 mg/m(2) (n = 4); 400 mg/m(2) (n = 3); 480 mg/m(2) (n = 10); and 576 mg/m(2) (n = 5). At the maximum-tolerated dose (480 mg/m(2)), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy., Results: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m(2)-dose level, and disease stabilization (7 months) at the 400-mg/m(2-dose) level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m(2)-dose level., Conclusion: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

Purpose: To determine the response rate, time to treatment failure, and toxicity of phenylacetate in patients with recurrent malignant glioma and to identify plasma concentrations achieved during repeated continuous infusion of this agent., Patients and Methods: Adult patients with recurrent malignant glioma were treated with phenylacetate. The schedule consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off). A starting dose of 400 mg/kg total body weight per day of phenylacetate was initially used and subsequently changed to 400 mg/kg/d based on ideal body weight. Intrapatient dose escalations were allowed to a maximum of 450 mg/kg ideal body weight/d. Tumor response was assessed every 8 weeks. The National Cancer Institute common toxicity criteria were used to assess toxicity. Plasma concentrations achieved during the patients' first two 14-day infusions were assessed., Results: Forty-three patients were enrolled between December 1994 and December 1996. Of these, 40 patients were assessable for toxicity and response to therapy. Reversible symptoms of fatigue and somnolence were the primary toxicities, with only mild hematologic toxicity. Thirty (75%) of the 40 patients failed treatment within 2 months, seven (17.5%) had stable disease, and three (7.5%) had a response defined as more than 50% reduction in the tumor. Median time to treatment failure was 2 months. Thirty-five patients have died, with a median survival of 8 months. Pharmacokinetic data for this dose schedule showed no difference in the mean plasma concentrations of phenylacetate between weeks 1 and 2 or between weeks 5 and 6., Conclusion: Phenylacetate has little activity at this dose schedule in patients with recurrent malignant glioma. Further studies with this drug would necessitate an evaluation of a different dose schedule.

Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4-128 mg/m2. The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels < or = 78 mg/m2, while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m2 and 4/5 patients at 123 mg/m2. Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m2 and the mean elimination half-life (t1/2beta) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m2 is recommended for testing in a patient population with cisplatin-refractory disease.

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.

Purpose: To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide., Methods: In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 degrees C (control), 40.5 degrees C, 41.8 degrees C, 42.5 degrees C, and 43 degrees C) for 65 min., Results: The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in L929 1.7 at 41.8 degrees C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 degrees C., Conclusion: The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia.

Tumor size is a significant prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiation therapy (RT). The addition of weekly chemotherapy was evaluated to improve the efficacy of thermoradiotherapy in poor-prognosis lesions (i.e. > or = 7 cm2 or > or = 14 cm3) which have an expected CR rate of approximately 30 +/- 8%. Patients were entered into a two-arm phase-II study: arm 1 = breast cancer (10 patients), ifosfamide (1.5 g/m2) + epirubicin (20 mg/m2) + HT + RT; arm 2 = sarcoma (7 patients) and head and neck cancer (9 patients), cisplatin (40 mg/m2) + HT + RT. Therapy encompassing 106 triple-modality sessions was generally well tolerated for both arms; 2 instances of grade-3 and 1 of grade-4 (arm 2) local toxicity (WHO criteria) were observed. There were 4 instances of grade-3 myelosuppression (arm 1). The CR rates for arms 1 and 2 were 70 and 19%, respectively, suggesting that the combination of ifosfamide/epirubicin/HT/RT deserves further investigation in the context of localized breast cancer.

Favorable B-cell neoplasms provide an excellent clinical model to evaluate the use of systemic multimodality therapy as an approach to the problem of tumor cell heterogeneity. Inherent in this concept is the use of multiple antineoplastic agents to produce supra-additive cytotoxicity without sacrificing therapeutic index. The results of three completed clinical studies and complementary laboratory investigations are reviewed to illustrate an innovative approach to the nodular lymphomas and chronic lymphocytic leukemia. The clinical trials summarized include: A) the combination of 41.8 degrees C whole body hyperthermia (WBH) and the chemotherapeutic drug lonidamine; B) the use of total body irradiation (TBI) (12.5 cGy twice a week, every other week--total planned dose 150 cGy) and daily oral lonidamine; C) the juxtapositioning of TBI (with the same fraction schema) and 41.8 degrees C WBH x 75 min--initiated 10 min after TBI. Also presented is the laboratory rationale and early clinical results for combining lonidamine, TBI, and WBH.

The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m2. Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.

Thymidine (a nucleoside metabolite) and 41.8 degrees C hyperthermia were used to sensitize C6 glioma cells to carboplatin cytotoxicity in vitro. Clinically achievable thymidine concentrations (0, 200, 400, or 1000 micrograms/ml X 24 hours) significantly enhanced carboplatin killing. Clinically achievable hyperthermia exposures (40.5 or 41.8 degrees C X 1 hour) also enhanced carboplatin killing; 41.8 degrees C was more effective than was 40.5 degrees C. Thymidine and 41.8 degrees C hyperthermia together enhanced carboplatin killing significantly more than did the thymidine-carboplatin or hyperthermia-carboplatin combinations. These results illustrate the concept of 'combination chemosensitization' for simultaneously addressing the divergent drug resistance mechanisms of malignant gliomas.

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Interactions of hyperthermia with carboplatin, cisplatin and etoposide were investigated in vitro in JM, a human, T cell, lymphoblastic cell line. Thermal enhancement ratios (TER) for carboplatin killing increased with temperature (2.3 at 40.5 degrees C, 3.2 at 41.8 degrees C) and were similar to those for cisplatin killing (2.6 at 40.5 degrees C, 3.6 at 41.8 degrees C). In a separate experiment, cytotoxicity was additive when carboplatin and cisplatin were given simultaneously at 37 degrees C and at 41.8 degrees C. Etoposide, which synergizes with platinum agents, did not have supra-additive cytotoxic interactions with hyperthermia. The data presented are relevant to the conduct of clinical hyperthermia trials.

Hyperthermic enhancement of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (carboplatin) cytotoxicity was studied in vitro in JM, a human acute lymphoblastic leukemia cell line. Corrected for direct heat toxicity, hyperthermia enhanced carboplatin killing at the clinically relevant temperatures of 40.5 degrees and 41.8 degrees C. The thermal enhancement ratios at these temperatures were 1.89 and 3.32, respectively. Cell killing increased exponentially with increasing duration of combined treatment (41.8 degrees C, carboplatin 30 micrograms/ml) for at least 3.5 h. Hyperthermic enhancement was maximal when heat was given during or immediately before carboplatin; enhancement was diminished when heat preceded carboplatin by more than an hour and was not apparent when heat followed drug treatment. As carboplatin is associated with different clinical toxicity than is cis-diamminedichloroplatinum(II), carboplatin may represent an ideal drug in its class of anticancer agents to use in clinical whole body hyperthermia trials.

Using JM and MOLT3, two human T-cell acute lymphoblastic leukemia cell lines, we investigated the ability of 24-h thymidine exposures to enhance the cytotoxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin). Clinically achievable thymidine concentrations (for 24 h) significantly enhanced carboplatin killing. Unexpectedly, thymidine-carboplatin enhancement was as great at a relatively low 200-micrograms thymidine/ml as at the clinically much more toxic range of 1000 micrograms/ml. For a constant thymidine concentration (500 micrograms/ml), thymidine-carboplatin interaction increased with longer thymidine exposures until about 16 to 24 h. Thymidine and 41.8 degrees C hyperthermia (for 1 h) together enhanced carboplatin killing significantly more than did hyperthermia-carboplatin or thymidine-carboplatin combinations. These results show that relatively brief, presumptively nonmyelosuppressive thymidine exposures can significantly increase carboplatin killing. Carboplatin-thymidine killing can then be further augmented by 41.8 degrees C hyperthermia.

Lonidamine is a dechlorinated derivative of indazole-3-carboxylic acid which preclinically synergizes with hyperthermia. Clinically, this nonmyelosuppressive drug (given p.o. daily) is active as a single agent in a variety of malignancies. On this basis, a Phase I study which incorporates a drug escalation schema as well as an escalation in temperature, i.e., 41.0 degrees C for 85 min to 41.8 degrees C for 75 min, was executed. Induction therapy included seven whole-body hyperthermia treatments. Whole-body hyperthermia was delivered using a radiant heat system. Twenty-four patients were entered on study. Of these, 20 were evaluable for response. Group A (60 mg/m2) had three patients with three no responses. Group B (180 mg/m2) consisted of three patients: one lymphoma, partial response; two gastrointestinal adenocarcinomas, one partial response and one improvement, i.e., less than a partial response. Group C (360 mg/m2) had 17 patients: two lung cancers, one complete response and one improvement; one melanoma, improvement; one ovarian, disease stabilization (greater than 100 days); two adenocarcinomas of the gastrointestinal tract, two disease stabilizations; 11 patients, no responses; one patient entered at this level was ineligible for study and did not receive lonidamine. Therapy was well tolerated. Of 16 patients reporting myalgias, two required a lonidamine dose reduction; one patient required dose reduction for central nervous system toxicity. Results obtained encourage Phase II clinical trials.