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.
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.
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.
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.
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"GBM EGFR Temozolomide 2.0 Gy once daily/30 days Postoperative Efficacy Response determined No additional response I/II 2008  GBM EGFR Temozolomide 1.8–2.0 Gy once daily/30– 33 days Postoperative Efficacy Response determined Significant response II 2009  GBM EGFR Temozolomide 2.0 Gy once daily/30 days Postoperative Safety and efficacy Excessive DLT incidence, trial terminated Significant toxicity and unexpected early disease progression II 2010  GBM RAS Temozolomide or none 2.0 Gy once daily/30 days Postoperative Tolerability MTD determined Well tolerated combination I 2011  GBM mTOR Temozolomide 2.0 Gy once daily/30 days Postoperative Safety and tolerability DLT and MTD determined Significant toxicity I 2010  GBM mTOR Temozolomide 2.0 Gy once daily/30 days Postoperative Safety and tolerability DLT and MTD determined Reasonably well tolerated combination I 2011  Brain metastases EGFR None 2.0 Gy once daily/20 days/ 4 days weekly Local disease control Safety and efficacy Toxicity and response determined Active and generally well tolerated combination II 2009  "
[Show abstract][Hide abstract] ABSTRACT: New strategies to facilitate the improvement of physical and integrated biological optimization of high-precision treatment protocols are an important priority for modern radiation oncology. From a clinical perspective, as knowledge accumulates from molecular radiobiology, there is a complex and exciting opportunity to investigate novel approaches to rational patient treatment stratification based on actionable tumor targets, together with the appropriate design of next-generation early-phase radiotherapy trials utilizing targeted therapeutics, to formally evaluate relevant clinical and biomarker endpoints. A unique aspect in the development pathway of systemic agents with presumed radiosensitizing activity will also be the need for special attention on patient eligibility and the rigorous definition of radiation dose-volume relationships and potential dose-limiting toxicities. Based on recent experience from systematically investigating histone deacetylase inhibitors as radiosensitizing agents, from initial studies in preclinical tumor models through the conduct of a phase I clinical study to evaluate tumor activity of the targeted agent as well as patient safety and tumor response to the combined treatment modality, this communication will summarize principles relating to early clinical evaluation of combining radiotherapy and targeted therapeutics.
Full-text · Article · Jul 2013 · Radiotherapy and Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway.
Patients and methods:
Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome.
For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS.
Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.
No preview · Article · Apr 2013 · European journal of cancer (Oxford, England: 1990)