Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies

Hammond, Lisa A.; Eckardt, John R.; Baker, Sharyn D.; Eckhardt, S. Gail; Dugan, Margaret; Forral, Kelly; Reidenberg, Pascale; Statkevich, Paul; Weiss, Geoffrey R.; Rinaldi, David; Hoff, Daniel D. Von; Rowinsky, Eric K.

doi:10.1200/jco.1999.17.8.2604

Cited by 116 publications

(89 citation statements)

References 14 publications

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“…The results of our pharmacokinetic analysis are similar to those observed in studies of adults with advanced solid tumors who received the same temozolomide regimen at doses of 100 -200 mg/m 2 per day. 18 In the current study, the apparent oral clearance of temozolomide was 4.5 L/m 2 per hour, whereas the clearance was 6.9 L/m 2 per hour in adult patients receiving equivalent dosages in the study conducted by Hammond et al 18 . In addition, the mean temozolomide AUC reported in adults was 30 g/mL per hour, compared with 41 g/mL per hour for patients in the current study who were treated at the same dose.…”

Section: Discussionmentioning

confidence: 45%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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BACKGROUNDThe role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.METHODSPatients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.RESULTSThirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).CONCLUSIONSThe administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.

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Section: Discussionmentioning

confidence: 45%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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“…2b). Considering that the median serum concentration measured in patients treated with TMZ at 150 mg/m 2 in clinical settings corresponds to 50 lM (Hammond et al 1999), it becomes clear how this gain in MGMT levels may confer acquired resistance. Depletion of MGMT with O 6 -BG largely restored TMZ sensitivity, although the resistance of LN-18_R remained slightly above that of parental cells, underlining that chemoresistance is multimodal and involves more than one pathway.…”

Section: Discussionmentioning

confidence: 99%

Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells

Happold

Roth

Wick

et al. 2012

Journal of Neurochemistry

129

136

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Despite recent therapeutic advances, the prognosis of patients afflicted by glioblastoma remains poor, with a progression-free survival in the range of months, even with multimodal therapy including surgery, radio-and chemotherapy. Temozolomide (TMZ), an oral alkylating agent, has demonstrated activity against recurrent and newly diagnosed glioblastoma (Yung et al. 2000;Stupp et al. 2005), and is being used as the standard of care for newly diagnosed glioblastoma since 2005.The DNA repair protein O 6 -methylguanine methyltransferase (MGMT) removes O 6 -alkyl-guanine adducts from DNA through irreversible binding and degradation, thereby minimizing the DNA-damaging effects of alkylating agent chemotherapy (Wang et al. 1996;Phillips et al. 1997 Abstract Temozolomide (TMZ) is an alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma. Clinical benefit is more prominent in patients with methylation of the O 6 -methyl-guanine DNA methyltransferase (MGMT) promoter. However, all patients eventually suffer from tumor progression because their tumors become resistant to TMZ. Here, we modeled acquired TMZ resistance in glioma cells in vitro to identify underlying molecular mechanisms. To this end, the glioma cell lines LNT-229, LN-308, and LN-18 were exposed repetitively to increasing concentrations of TMZ to induce a stable resistant phenotype (R) defined by clonogenic survival assays. The molecular mechanisms mediating acquired resistance were assessed by immunoblot, PCR, and flow cytometry. Rescue experiments were performed with siRNA-mediated candidate gene silencing. We found in LN-18 cells constitutively expressing MGMT a strong up-regulation of MGMT levels in TMZ-resistant cells. TMZ resistance in the MGMT-negative cell lines LNT-229 and LN-308 was not associated with de novo expression of MGMT. Instead, we found a down-regulation of several DNA mismatchrepair proteins in resistant LNT-229 cells. A TMZ-resistant phenotype was also achieved by silencing selected DNA mismatch repair proteins in parental LNT-229 cells. No obvious mechanism of resistance was identified in the third cell line, LN-308, except for reduced methylation of LINE-1 repetitive elements. In conclusion, we demonstrate that different molecular mechanisms may contribute to the development of acquired TMZ resistance in glioma cells, indicating the need to develop distinct strategies to overcome resistance.

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“…The highest dose (250 mg m À2 Â 5) caused grade 3 -4 thrombocytopenia in nine out of 18 patients (50%) vs three out of 50 patients (6%) starting with 200 mg m À2 . Several phase I trials of TMZ in patients with advanced cancer also demonstrated myelosuppression, especially thrombocytopenia, as the DLT (Dhodapkar et al, 1997;Hammond et al, 1999;Newlands et al, 1992;O'Reilly et al, 1993). The thrombocytopenia was always transient and bleeding was not observed.…”

Section: Discussionmentioning

confidence: 99%

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

et al. 2003

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The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) lowdose interleukin-2 (IL2), granulocyte -monocyte colony stimulating factor (GM-CSF) and interferon-a 2b (IFNa) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150 -250 mg m À2 ) for 5 days followed by s.c. IL2 (4 MIU m À2 ), GM-CSF (2.5 mg kg À1 ) and IFNa (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12 -30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8 -42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose-and patientdependent. Lymphocytopenia (grade 3 -4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.

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Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies

Cited by 116 publications

References 14 publications

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

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