A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1580-1580 ◽  
Author(s):  
D. Reardon ◽  
J. A. Quinn ◽  
J. N. Rich ◽  
J. J. Vredenburgh ◽  
A. Desjardins ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Dose Level ◽  
Dose Escalation ◽  
Treatment Cycle ◽  
Maximum Tolerated Dose ◽  
Recurrent Malignant Glioma ◽  
Organ Function ◽  
Adequate Organ Function ◽  
Orally Bioavailable ◽  
Dose Limiting Toxicity

1580 Background: This study attempts to extend the anti-glioma activity of imatinib mesylate (Gleevec, IM) plus hydroxyurea (H), by adding RAD001 (R), an orally bioavailable inhibitor of mTOR, a critical intracellular mediator of signal transduction and metabolism. Methods: We employ a “3+3” dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IM + H + R administered daily among adult recurrent malignant glioma patients s with ≤ 3 prior recurrences, KPS > 60% and adequate organ function. Patients are stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC), and both strata are independently escalated. Initial dose level for each stratum: IM - 400 mg/day; H - 500 mg bid; R - 2.5 mg/day. Each treatment cycle is 28 days. Response is evaluated every other cycle. Pharmacokinetic (PK) studies are performed on days 1 and 28 of cycle 1. Results: Twenty-two recurrent GBM patients have enrolled. The median age is 53 (range 37 to 75), 41% are male, and 45% are on EIAC. Two DLTs (grade 4 hypercholesterolemia and thrombocytopenia) occurred among 5 patients on dose level one (non-EIAC stratum). No other DLTs have occurred. The dose escalation schema has been amended to include alternate day R dosing. IM PK were consistent with those previously reported for patients on IM and HU. IM clearance on day 1 was 492 ± 247 ml/min in the EIAC stratum and 231 ± 100 ml/min in the non-EIAC stratum. On day 28, IM clearance was decreased in both strata (243 ± 93 ml/min in the EIAC stratum and 116 ± 47 ml/min in the non-EIAC stratum) PK results for HU and R are pending. Nine patients continue on study having received 2–8 cycles of therapy. Four partial responses have been observed and accrual is ongoing. Conclusions: Further accrual is warranted. An update of outcome, toxicity and pharmacokinetic analyses will be presented. [Table: see text]

Phase I combination study of trabectedin (T) and capecitabine (C) in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2079-2079
Author(s):  
L. Gore ◽  
E. Rivera ◽  
K. Lavallee ◽  
S. Holden ◽  
S. Grolnic ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Excision Repair ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2079 Background: T binds to the minor groove of DNA, synergizes with functional nuclease excision repair and targets inducible transcription. T is active in several tumor types and exhibits preclinical synergy with C. The primary objective of this study is to determine the maximum tolerated dose (MTD) of T in combination with C. Secondary objectives include safety and pharmacokinetic (PK) analyses. Methods: Pts with advanced cancer, performance status 0–1 and adequate organ function are eligible. Pts received T starting at 0.4 mg/m2 over 3 hours on day 1 followed by C on days 2 through 15. The initial dose of C was 2000 mg/m2/day and was reduced to 1600 mg/m2/day due to GI dose-limiting toxicity. Dose escalation of T continued. Cycles are repeated every 3 weeks, with PK sampling included. Standard “3+3” dose escalation design, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. Results: To date, 30 patients have received 112 cycles (range 1–12, median 4) of treatment at 7 dose levels. Two of 3 pts at dose level 4 (C 2000 mg/m2/d and T 0.9 mg/m2) and 2/6 pts at dose level 3 (C 2000 mg/m2/d and T 0.75 mg/ m2) developed gastrointestinal DLT (emesis, diarrhea, pancreatitis). C was subsequently reduced to 1600 mg/m2/d and a new T dose escalation was initiated at 0.6 mg/m2. Treatment has been well tolerated with C 1600 mg/m2/d and T up to the current dose of 0.9 mg/m2 (dose level 4a), with 1of 6 subjects experiencing grade 1 alkaline phosphatase. The most frequently reported related grade 3–4 adverse events (AEs) are diarrhea (23%), neutropenia (20%), nausea (16.6%), hand-foot syndrome (16.6%) and vomiting (13%). Anti-tumor activity to date includes a confirmed partial response lasting 8 months (m) in a patient with cholangiocarcinoma, and prolonged stable disease in 2 patients with breast cancer (6 and 7m), ovarian cancer (11m) and chondrosarcoma (9m). Conclusions: The combination of C 1600mg/m2/d and T up to 0.9mg/m2 is tolerable and has promising activity in several tumor types. Dose escalation of T continues at 1.1 mg/m2. Biologic and pharmacokinetic analyses will be presented. [Table: see text]

Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13007-e13007
Author(s):  
J. P. Kirkpatrick ◽  
J. J. Vredenburgh ◽  
A. Desjardins ◽  
S. Gururangan ◽  
K. B. Peters ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Imatinib Mesylate ◽  
Dose Level ◽  
Tyrosine Kinases ◽  
Therapeutic Benefit ◽  
Organ Function ◽  
Once Daily ◽  
Adequate Organ Function ◽  
Level 1 ◽  
Grade 3

e13007 Background: Malignant glioma (MG), an incurable primary CNS tumor, is characterized by frequent aberrant activation of EGFR, VEGFR, and PDGFR. This study will determine the MTD and DLT of vandetanib (V), a once-daily, oral selective inhibitor of VEGFR and EGFR when combined with imatinib mesylate (IM), an inhibitor of multiple tyrosine kinases including PDGFR and hydroxyurea (H). Methods: Adult recurrent MG patients with ≤ 3 prior recurrences, KPS ≥ 60% and adequate organ function were stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC). Both strata were independently escalated using a “3+3” design. H is administered at 500 mg BID while IM is administered at 500 mg BID for patients on EIAC and 400 mg QD for those not on EIAC. V is increased by 100 mg in successive cohorts beginning at 100 mg and 200 mg for patients not on and on EIAC, respectively. Evaluations were after every other 28-day cycle. Pharmacokinetics of V and IM were obtained on days 1 and 28 of cycle 1. Results: Twenty-six patients (grade 4 MG, n = 20; grade 3 MG, n = 6) have enrolled. Only 1 DLT (reversible grade 4 transaminase elevation; dose level 1) occurred among 22 non-EIAC patients and enrollment to this stratum is planned to continue at dose level 4. The MTD of V for patients on EIAC is 200 mg/day due to 2 of 3 patients developing grade 3 thrombocytopenia at the 300 mg/day dose level. Evidence of therapeutic benefit to date includes 1 partial response and 15 patients (58%) with stable disease for at least 4 weeks, including 4 patients for ≥4 months. Conclusions: Combination of V, IM, and H is well-tolerated in recurrent MG patients. Further accrual is ongoing and an update of outcome, toxicity, and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.

Phase I study of paclitaxel in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.

1998 ◽  
Vol 16 (6) ◽  
pp. 2188-2194 ◽  
Author(s):  
S M Chang ◽  
J G Kuhn ◽  
J Rizzo ◽  
H I Robins ◽  
S C Schold ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Phase Ii Study ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Recurrent Malignant Glioma ◽  
Starting Dose ◽  
Dose Levels ◽  
Higher Doses ◽  
Dose Limiting Toxicity ◽  
Unacceptable Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) of paclitaxel administered as a 3-hour infusion in patients with recurrent malignant glioma. PATIENTS AND METHODS Patients were stratified by starting dose of paclitaxel and concurrent anticonvulsant (AC) use and were treated in cohorts of three patients. The starting dose was 240 mg/m2 administered intravenously with escalations of 30 mg/m2 until the MTD was established. Pharmacokinetic data were obtained for each patient for the first infusion. Tumor response was assessed at 6-week intervals and treatment was continued until documented tumor progression, unacceptable toxicity, or a total of 12 paclitaxel infusions. RESULTS From April 1995 to December 1996, 34 patients were treated; 27 patients in the AC group and seven patients in the non-AC group. The MTD for patients who received ACs was established at 360 mg/m2 and the dose-limiting toxicity (DLT) was central neurotoxicity, characterized as transient encephalopathy and seizures. In contrast, the MTD for patients who did not receive ACs was 240 mg/m2, and myelosuppression, gastrointestinal toxicity, and fatigue were the DLTs. Pharmacokinetic data confirmed that the plasma drug levels and clearance rates were similar for patients in both groups at the respective dose levels that produced DLTs. CONCLUSION The pharmacokinetics of paclitaxel are altered by ACs, and significantly larger doses of the drug can be administered to patients with brain tumors on AC therapy. The toxicity profile is different for patients on AC therapy treated at these higher doses. A phase II study has been initiated that uses a dose of 330 mg/m2 for patients on AC therapy and 210 mg/m2 for patients not on AC therapy.

scholarly journals 3D Conformal Radiotherapy and Cisplatin for Recurrent Malignant Glioma

2008 ◽  
Vol 35 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Lauren VanderSpek ◽  
Barbara Fisher ◽  
Glenn Bauman ◽  
David Macdonald
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Conformal Radiotherapy ◽  
Maximum Tolerated Dose ◽  
External Beam Radiation ◽  
Recurrent Malignant Glioma ◽  
Beam Radiation ◽  
Fractionated Radiotherapy ◽  
3D Conformal Radiotherapy ◽  
Grade 3

Purpose:To determine the maximum tolerated dose of 3D conformal radiotherapy in combination with Cisplatin for patients with recurrent malignant gliomas.Methods:From 1999-2003, nine patients with recurrent malignant glioma received fractionated radiotherapy and Cisplatin (20 mg/m2/d IV on days 1-5) in a Phase I radiation dose escalation trial. Three sequential dose levels were evaluated: 25 Gy, 30 Gy, and 35 Gy, using 5 Gy fractions. All patients received prior external beam radiation (median dose 59.4 (20-60) Gy) and five patients received prior chemotherapy.Results:Six male and three female patients were enrolled with a median age of 52 years, and a median Karnofsky performance status score of 70. The median re-irradiated tumor volume was 18.9 (0.1-78.5) cm3 and the median follow-up was 8.8 (3.2-31.2) months. One patient (30 Gy/ 6 fractions) experienced medically reversible acute grade 3 toxicity. A second patient (35 Gy/ 7 fractions) experienced acute grade 2 toxicity and histology showed tumor and radiation effect. A third patient (25 Gy/ 5 fractions) experienced late grade 3 toxicity from radiation necrosis. The radiological responses consisted of complete response (1 patient), partial response (1 patient), and stable disease (2 patients). The median overall survival was 8.8 months (95% CI 8.0-9.9), and the median disease free interval was 2.0 months (95% CI 1.4-4.4). Seven patients received chemotherapy following re-irradiation and Cisplatin.Conclusion:The maximum tolerated dose of 3D conformal fractionated radiotherapy was 30 Gy in 6 fractions with low dose Cisplatin, which was well tolerated in terms of acute toxicity for our patient population. This regimen demonstrated only modest efficacy in the treatment of recurrent malignant glioma. Combinations of conformal re-irradiation and other systemic agents may merit investigation. Currently our recommended dose is 30 Gy in 6 fractions for selected patients.

scholarly journals Phase I and Correlative Biology Study of Cilengitide in Patients With Recurrent Malignant Glioma

2007 ◽  
Vol 25 (13) ◽  
pp. 1651-1657 ◽  
Author(s):  
L. Burt Nabors ◽  
Tom Mikkelsen ◽  
Steven S. Rosenfeld ◽  
Fred Hochberg ◽  
Narasimha S. Akella ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Toxicity Assessment ◽  
Perfusion Magnetic Resonance Imaging ◽  
Hematologic Toxicity ◽  
Recurrent Malignant Glioma ◽  
Time Curve ◽  
Magnetic Resonance Imaging Mri

Purpose This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. Patients and Methods Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. Results A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. Conclusion Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

1995 ◽  
Vol 13 (11) ◽  
pp. 2842-2850 ◽  
Author(s):  
D A Rinaldi ◽  
H A Burris ◽  
F A Dorr ◽  
J R Woodworth ◽  
J G Kuhn ◽  
...  
Keyword(s):  
Dose Level ◽  
Thymidylate Synthase ◽  
Dose Escalation ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Treatment Schedule ◽  
Continual Reassessment Method ◽  
Toxic Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

PURPOSE To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
E. I. Heath ◽  
A. Alousi ◽  
J. P. Eder ◽  
M. Valdivieso ◽  
L. S. Vasist ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 3 ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

Phase I trial of bortezomib in adults with recurrent malignant glioma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1567-1567 ◽  
Author(s):  
S. Phuphanich ◽  
J. Supko ◽  
K. A. Carson ◽  
S. A. Grossman ◽  
L. B. Nabors ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Malignant Glioma ◽  
Dose Level ◽  
Whole Blood ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
20S Proteasome ◽  
Weekly Dose ◽  
Recurrent Malignant Glioma ◽  
Grade 3

1567 Background: Bortezomib is a selective inhibitor of the proteasome that has been approved for the treatment of multiple myeloma and has also shown promising evidence of clinical activity against solid tumors. This study was undertaken to determine the maximum tolerated dose (MTD), toxicity profile, and biologic activity of bortezomib for the treatment of recurrent malignant glioma (MG). Methods: Eligible patients (pts) had supratentorial progressive MG upon radiotherapy and ≤ 1 prior regimen of chemotherapy. Dose escalation was conducted separately for pts taking enzyme inducing antiseizure drugs (EIASD+) and for those not (EIASD-). Bortezomib was given by bolus iv injection on weeks 1 and 2 of each 3 week cycle of therapy. The starting dose in both groups was 0.9 mg/m2. Cohorts of at least 3 patients were evaluated at each dose level. 20S proteasome activity was determined in whole blood lysates before and at 1 and 24 h after the first dose. Results: Fifty-nine evaluable pts (41 male/18 female) with a median age of 51 years and median KPS of 90% have been enrolled. All but 2 pts had received 1 prior chemotherapy regimen. In the EIASD- group, the weekly dose was escalated from 0.9 to 1.9 mg/m2 through 3 intermediate dose levels, with 1.7 mg/m2 established as the MTD. DLT experienced by 2 of 6 pts in the 1.90 mg/m2 dose level were grade 3 thrombocytopenia and grade 3 fatigue plus neurosensory toxicities. In the EIASD+ group, the dose has been escalated to 2.3 mg/m2 without the occurrence of any DLT. Ten additional EIASD- pts were treated at 1.7 mg/m2, with the most common adverse events being thrombocytopenia and peripheral neuropathy. The extent of proteasome inhibition in whole blood increased in a dose-dependent manner in both treatment groups. Mean proteasome inhibition in EIASD+ pts 1 h after receiving 2.1 mg/m2 of bortezomib (77 ± 12%) was similar to the 1.7 mg/m2 dose in EIASD- pts (79 ± 6%). Conclusions: The MTD for the weekly x 2 schedule of bortezomib in EIASD- patients, 1.7 mg/m2, is higher than the approved dose of 1.3 mg/m2 for the treatment of multiple myeloma. The enhanced tolerability of the drug when given together with EIASDs, for which the MTD is at least 2.1 mg/m2, is consistent with the diminished inhibition of 20S proteasome activity in these pts. No significant financial relationships to disclose.

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