Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

BACKGROUND:

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.

METHODS:

All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme‐inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice‐a‐day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.

RESULTS:

A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice‐a‐day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.

CONCLUSIONS:

Vatalanib doses up to 1000 mg twice‐a‐day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet‐derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity. Cancer 2009. © 2009 American Cancer Society.     

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.     

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas

Purpose Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients and method Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Results Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1–7) and the median number of prior treatment regimens was 3 (range, 1–8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Conclusion Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG. Supported by National Institutes of Health grant nos. 1-P50-CA108786-01, NS20023 and CA11898 and by grant no. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.     

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.     

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Background:

We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs).

Methods:

A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS).

Results:

The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%).

Conclusions:

Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.     

A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03

Romidepsin, a potent histone deacetylase inhibitor, has shown activity in preclinical glioma models. The primary objectives of this trial were to determine the pharmacokinetics of romidepsin in patients with recurrent glioma on enzyme-inducing antiepileptic drugs (EIAEDs) and to evaluate the antitumor efficacy of romidepsin in patients with recurrent glioblastoma who were not receiving EIAEDs. Two dose cohorts were studied in the phase I component of the trial (13.3 and 17.7 mg/m(2)/d). Patients in the phase II component were treated with intravenous romidepsin at a dosage of 13.3 mg/m(2)/day on days 1, 8, and 15 of each 28-day cycle. Eight patients were treated on the phase I component. A similar romidepsin pharmacokinetic profile was demonstrated between patients receiving EIAEDs to those not receving EIAEDs. Thirty-five patients with glioblastoma were accrued to the phase II component. There was no objective radiographic response. The median progression-free survival (PFS) was 8 weeks and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). To date, 34 patients (97%) have died, with a median survival duration of 34 weeks. Despite in vitro studies showing that romidepsin is primarily metabolized by CYP3A4, no decrease in exposure to romidepsin was seen in patients receiving potent CYP3A4 inducers. Romidepsin, at its standard dose and schedule, was ineffective for patients with recurrent glioblastomas. ClinicalTrials.gov identifier: NCT00085540.     

A phase I/II trial of vandetanib for patients with recurrent malignant glioma

Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor–2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.     

Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma

BACKGROUND: In the current study, the authors report a Phase II trial of irinotecan (CPT-11), a topoisomerase I inhibitor active against malignant glioma (MG), with celecoxib, a selective COX-2 inhibitor, among MG patients with recurrent disease. METHODS: Patients with MG at any type of recurrence received CPT-11, administered as a 90-minute intravenous infusion on Weeks 1, 2, 4, and 5 of each 6-week cycle plus celecoxib, which was administered continuously at a dose of 400 mg twice a day. CPT-11 was given at a dose of 350 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and at a dose of 125 mg/m(2) for those patients not receiving EIAEDs. Assessments were performed after every cycle. The primary endpoint was radiographic response and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and therapeutic safety. RESULTS: Thirty-four of the 37 patients enrolled in the current study (92%) were diagnosed with recurrent GBM and 3 patients (8%) were diagnosed with recurrent anaplastic astrocytoma (AA). Twenty-one patients were receiving EIAEDs and 16 patients were not. The median follow-up time was 76.9 weeks. Concomitant CPT-11 plus celecoxib was found to be well tolerated and safe. Hematologic toxicities of >/= Grade 3 (according the second version of the Common Toxicity Criteria of the National Cancer Institute) reportedly complicated 8.6% of treatment courses. Grade 3 diarrhea, the most commonly reported nonhematologic toxicity, occurred with equal frequency (8%), regardless of whether the patient was receiving EIAED. Six patients (16%), all whom were diagnosed with recurrent GBM, achieved an objective radiographic response whereas an additional 13 patients (35%) achieved stable disease. The median PFS was 11.0 weeks and the 6-month PFS was reported to be 25.1%. The median OS was 31.5 weeks. CONCLUSIONS: The results of the current study confirm that CPT-11 plus celecoxib can be safely administered concurrently at full dose levels, and that this regimen has encouraging activity among heavily pretreated patients with recurrent MG.     

Temozolomide for recurrent intracranial supratentorial platinum‐refractory ependymoma

BACKGROUND:

To the authors' knowledge, there currently is no standard therapy for platinum‐resistant ependymoma; hence, a need exists for new therapies. In the current study, a retrospective evaluation of temozolomide (TMZ) in adults with recurrent, supratentorial, platinum‐refractory, World Health Organization grade 2 ependymoma was performed, with an objective of determining 6‐month progression‐free survival (PFS).

METHODS:

A total of 25 patients, ages 28 to 63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum‐based chemotherapy (cisplatin in 15 patients and carboplatin in 10 patients). Nine patients underwent repeat surgery. Patients were treated at the time of second recurrence with TMZ (5 consecutive days), once every 4 weeks, which was defined as a single cycle. Neurologic evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks.

RESULTS:

A total of 68 cycles of TMZ (median, 2 cycles; range, 1‐6 cycles) was administered. TMZ‐related toxicity included leukopenia (7 patients; 1 with grade 3 [grade was determine according to National Cancer Institute Common Toxicity Criteria [version 3.0]), constipation (6 patients; none with grade 3), fatigue (5 patients; none with grade 3), anemia (2; none with grade 3), thrombocytopenia (2; none with grade 3), and deep vein thrombosis (2; none with grade 3). One patient (4%) demonstrated a partial radiographic response, 9 (36%) had stable disease, and 15 (60%) developed progressive disease after 2 cycles of TMZ. Time to tumor progression ranged from 1 to 7 months (median, 2 months). Survival ranged from 2 to 8 months (median, 3 months). The 6‐month and 12‐month PFS were 2% and 0%, respectively.

CONCLUSIONS:

TMZ in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent, intracranial, platinum‐refractory ependymoma. Cancer 2009. © 2009 American Cancer Society.     

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.     

Bevacizumab for recurrent alkylator‐refractory anaplastic oligodendroglioma

BACKGROUND:

A retrospective evaluation of single agent bevacizumab was carried out in adults with recurrent alkylator‐refractory 1p19q codeleted anaplastic oligodendrogliomas (AO) with an objective of determining progression‐free survival (PFS). There is no standard therapy for alkylator‐resistant AO, and hence a need exists for new therapies.

METHODS:

Twenty‐two patients aged 24 to 60 years with recurrent AO were treated. All patients had previously been treated with surgery, radiotherapy, adjuvant chemotherapy (temozolomide, 17; carmustine wafers, 4; carmustine, 1), and 1 salvage regimen (procarbazine, lomustine, and vincristine, 15; temozolomide, 6; carmustine wafers, 1). Eleven patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks, and neuroradiographic assessment was made after the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab.

RESULTS:

A total of 391 cycles of bevacizumab (median, 14.5 cycles; range, 2‐39 cycles) were administered. Bevacizumab‐related toxicity included fatigue (14 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (5; 1 grade 3), deep vein thrombosis (4; 1 grade 3), and wound dehiscence (2; 1 grade 3). Fifteen (68%) patients demonstrated a partial radiographic response, 1 (5.0%) demonstrated stable disease, and 6 (27%) demonstrated progressive disease after 2 cycles of bevacizumab. Time to tumor progression ranged from 1 to 18 months (median, 6.75 months). Survival ranged from 3 to 19 months (median, 8.5 months). Six‐month and 12‐month PFS were 68% and 23%, respectively.

CONCLUSIONS:

Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent 1p19q codeleted alkylator‐refractory AO. Cancer 2009. © 2009 American Cancer Society.     

Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas

BACKGROUND.

Intracranial meningiomas are common, they frequently recur after surgery or radiotherapy, and there are limited data regarding the treatment of intracranial meningiomas with chemotherapy. A phase 2 study was designed to estimate the 6‐month progression‐free survival of patients with recurrent, treatment‐refractory, World Health Organization grade 1 meningiomas who were treated with interferon‐α.

METHODS.

Thirty‐five patients with recurrent meningiomas ranging in age from 36 years to 88 years (median age, 61 years) were treated according to a prospective phase 2 study. All patients had received prior surgery, radiotherapy, (involved‐field radiotherapy in 35 patients andstereotactic radiotherapy in 22 patients), and chemotherapy (hydroxyurea in 19 patients and other in 17 patients). On radiographic documentation of progressive disease, interferon‐α (at a dose of 10 million U/m² administered subcutaneously every other day) was initiated. A complete blood count and chemistry panel was obtained before every cycle, and cranial magnetic resonance images were obtained every 3 months.

RESULTS.

The most common grade 3 and 4 toxicities were fatigue (6 patients; 17%), anemia (3 patients; 8.6%), and leukopenia (3 patients; 8.6%) (toxicities were graded according to the National Cancer Institute's Common Toxicity Criteria [version 3.0]). Three patients went off study because of toxicity, and 7 patients required a dose reduction. There were no treatment‐related deaths or delays in therapy reported. All patients were assessable for response. No patient demonstrated a neuroradiographic complete or partial response. Twenty‐six patients demonstrated stable disease after the first 3 cycles of interferon‐α, and 9 patients had progressive disease. The progression‐free survival rate was 54% at 6 months and 31% at 12 months. The median time to tumor progression was 7 months (range, 2‐24 months). The median survival was 8 months (range, 3‐28 months).

CONCLUSIONS.

Treatment with interferon‐α for recurrent meningiomas was found to be tolerated moderately well and was modestly effective. Cancer 2008. © 2008 American Cancer Society.     

Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma

BACKGROUND:

Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination.

METHODS:

Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme‐inducing anticonvulsants were enrolled. Treatment was in 6‐week cycles with irinotecan at 125 mg/m² weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression‐free survival rate at 6 months (PFS‐6), and the secondary endpoints were overall survival (OS) and response rate (RR).

RESULTS:

In 39 eligible patients, PFS‐6 for the intent‐to‐treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment‐related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment‐related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis.

CONCLUSIONS:

The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing. Cancer 2012;3599–3606. © 2011 American Cancer Society.     

Phase II study of belotecan, a camptothecin analogue, in combination with carboplatin for the treatment of recurrent ovarian cancer

BACKGROUND:

Belotecan (CKD602; Camtobell, Chong Keun Dang Corp., Seoul, Korea) is a recently developed camptothecin derivative with antitumor properties. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC).

METHODS:

Thirty‐eight patients with recurrent EOC were treated with belotecan 0.3 mg/m²/day (days 1‐5) and carboplatin AUC 5 (day 5) every 3 weeks for 6 cycles. The primary objective was to determine the response rate as defined by Response Evaluation Criteria in Solid Tumors and CA‐125 response. Other end points included toxicities and progression‐free survival (PFS).

RESULTS:

All 38 patients were assessed for toxicity, and 35 patients were assessed for response. The overall response rate was 57.1%; there were 7 complete responses (20.0%), 13 partial responses (37.1%), 6 patients with stable disease (17.1%), and 9 patients with progressive disease (25.7%). Grades 3 and 4 hematologic toxicities included neutropenia (28.8%), thrombocytopenia (19.8%), and anemia (14.4%), and there were 2 episodes of febrile neutropenia. Median PFS was 7 months, with a median follow‐up of 12 months.

CONCLUSIONS:

The newly developed topoisomerase I inhibitor belotecan (CKD‐602) combined with carboplatin is a well‐tolerated regimen with activity in recurrent EOC. Further testing of this regimen is warranted to further characterize efficacy and indications for use. Cancer 2011. © 2010 American Cancer Society.     

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00671970","term_id":"NCT00671970"}}NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.     

Myelosuppression in patients benefiting from imatinib with hydroxyurea for recurrent malignant gliomas

Reports suggest reasonable efficacy and minimal myelosuppression from combination imatinib and hydroxyurea for recurrent malignant glioma. We retrospectively reviewed 16 patients treated with this regimen who were evaluable for toxicity; 14 were also evaluable for response. The incidence of grade 3–4 hematologic toxicity was 25%. The best radiographic response, by Macdonald criteria, was partial response (PR) in three patients (21%), stable disease (SD) in four (29%), and progressive disease (PD) in seven (50%). One patient with a PR developed therapy-limiting hematologic toxicity on day 19 of treatment, progressing to grade 4 on day 64, and persisting until death on day 127 despite discontinuing both drugs. Another patient with PR and two of four patients with SD also developed grade 3 hematologic toxicity. All patients with grade 3–4 hematologic toxicity had disease control (PR or SD) as best radiographic response, whereas none with PD suffered grade 3–4 hematologic toxicity. Combining imatinib with hydroxyurea is effective in some patients with malignant glioma. However, myelosuppression can persist for months after discontinuing the regimen, precluding further chemotherapy. Disease control may also correlate with hematologic toxicity (p = 0.08), suggesting that glioma and marrow stem cells may share a common sensitivity to this chemotherapy regimen.     

Phase 1 trial of temozolomide plus irinotecan plus O6‐benzylguanine in adults with recurrent malignant glioma

BACKGROUND:

The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT‐11) when administered with temozolomide (TMZ) and O⁶‐benzylguanine (O⁶‐BG).

METHODS:

All 3 drugs, CPT‐11, TMZ, and O⁶‐BG, were administered on Day 1 of a 21‐day treatment. First, patients were treated with a 1‐hour bolus infusion of O⁶‐BG at a dose of 120 mg/m² followed immediately by a 48‐hour continuous infusion of O⁶‐BG at a dose of 30 mg/m²/d. Second, within 60 minutes of the end of the 1‐hour bolus infusion of O⁶‐BG, TMZ was administered orally at a dose of 355 mg/m². Third, 1 hour after administration of TMZ, CPT‐11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1‐ and CYP3A4‐inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata.

RESULTS:

Fifty‐five patients were enrolled. In both strata, the dose‐limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m², the MTD of CPT‐11 was determined to be 120 mg/m². In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m², the MTD of CPT‐11 was determined to be 80 mg/m².

CONCLUSIONS:

The authors believe that the results of the current study provide the foundation for a phase 2 trial of O⁶‐BG in combination with CPT‐11 and TMZ in patients with MG. Cancer 2009. © 2009 American Cancer Society.     

Phase 2 trial of a novel capecitabine dosing schedule in combination with bevacizumab for patients with metastatic breast cancer

BACKGROUND:

Capecitabine has antitumor activity in metastatic breast cancer (MBC); however, its optimal dose and schedule remain unclear. Mathematical modeling predicts that a capecitabine schedule 7 days of treatment followed by 7 days of rest (7—7) will improve efficacy and minimize toxicity. Bevacizumab has demonstrated the ability to improve outcomes when it is added to chemotherapy, including capecitabine, in the first‐line and second‐line settings.

METHODS:

Patients with measurable MBC received oral capecitabine (2000 mg twice daily; 7—7), and intravenous bevacizumab (10 mg/kg every 2 weeks). The primary endpoint was the response rate. Secondary endpoints included toxicity, the clinical benefit rate, and progression‐free survival (PFS).

RESULTS:

Forty‐one patients were treated. After a median of 7 cycles (range, 1‐32 cycles), partial responses were observed in 20% of patients, and stable disease for ≥6 months was noted in 35% patients. The median PFS was 8 months. The most common treatment‐related toxicities were hand‐foot syndrome (49% grade 2, 20% grade 3/4) hypertension (12% grade 2, 10% grade 3/4), and fatigue (12% grade 2, 2% grade 3/4). Diarrhea (5% grade 2, 0% grade 3/4), nausea (0% grade 2‐4), and vomiting (0% grade 2‐4) were rare.

CONCLUSIONS:

Capecitabine administered for 7 days followed by a 7‐day rest in combination with bevacizumab had modest efficacy and an acceptable toxicity profile in patients with MBC. Gastrointestinal toxicity with this schedule was minimal. Cancer 2011;. © 2011 American Cancer Society.     

Bevacizumab and daily temozolomide for recurrent glioblastoma

BACKGROUND:

The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide.

METHODS:

There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty‐two adult patients were enrolled. Patients received temozolomide 50 mg/m² daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks.

RESULTS:

The authors observed a 6‐month progression‐free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%‐33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6‐month OS rate was 62.5% (95% CI, 43.5%‐76.7%), and the 12‐month OS rate was 31.3% (95% CI, 16.4%‐47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia.

CONCLUSIONS:

The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies. Cancer 2012;. © 2011 American Cancer Society.