Abass Alavi. A distinguished physician scientist and a pioneer in molecular imaging.

Abass Alavi is a world renowned physician-scientist and has made substantial contributions to development and translation of modern imaging techniques to the day-to-day practice of medicine. Among his accomplishments, the introduction of fluorine-18-fluorodeoxyglucose ((18)F-FDG )-positron emission tomography (PET) has truly revolutionized the field of medicine worldwide. The impact of using (18)F-FDG -PET along with computed tomography (CT) (and soon magnetic resonance imaging-MRI) in managing so many serious diseases and disorders is unparalleled by any other technique in recent history. He has received many awards for his outstanding contributions to the field of molecular imaging. Currently, he is actively involved in conducting research on a full time basis.

Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas.

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas.

BACKGROUND: The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS: This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS: For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS: Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.

Phase II clinical and pharmacologic study of radiation therapy and carboxyamido-triazole (CAI) in adults with newly diagnosed glioblastoma multiforme.

INTRODUCTION: Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-voltage-gated calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. This study examined the efficacy, safety and pharmacokinetics of oral CAI in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) in an open-label, single arm non-randomized phase 2 trial. METHODS: Eligible patients with histologically confirmed GBM started CAI therapy (250 mg daily) on the first day of radiation (6000 cGy in 30 fractions) and continued until progression, unless side effects became intolerable. The primary outcome was survival compared to historical controls within the NABTT CNS Consortium database. Secondary outcomes included toxicity and pharmacokinetic parameters. RESULTS: Fifty-five patients were enrolled with a median Karnofsky performance status of 90 and age of 56 years. Forty-six (84%) of these patients had debulking surgeries and 52 have died. The median survival was 10.3 months (95% confidence interval (CI), 8.5-12.8) compared to 12.1 months (95% CI, 10.3-13.3) in the NABTT reference group (p = 0.97). Significant toxicities included 2 incidents of reversible vision loss. The mean CAI plasma concentration for patients taking enzyme inducing antiepileptic drugs (EIAED) was 1.35 +/-1.22 compared to 4.06 +/- 1.50 (p < 0.001) for subjects not taking these agents. Overall survival and grade > or = 3 toxicities were comparable by EIAED status. CONCLUSIONS: This study demonstrated that (1) CAI can be administered safely with concomitant cranial irradiation, (2) the pharmacokinetics of CAI are significantly affected by co-administration of EIAED, and (3) the survival of patients with newly diagnosed GBM was not improved with this novel agent, despite achieving adequate drug levels.

The effect of enzyme-inducing antiseizure drugs on the pharmacokinetics and tolerability of procarbazine hydrochloride.

PURPOSE: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). EXPERIMENTAL DESIGN: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. RESULTS: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. CONCLUSIONS: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.

Gefitinib in patients with advanced non-small cell lung cancer (NSCLC): the expanded access protocol experience at the University of Pennsylvania.

Gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with favorable toxicity and antitumor activity in pretreated patients with non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the toxicity and efficacy of gefitinib in patients with advanced NSCLC treated at our institution as part of an expanded access protocol; 112 patients with advanced NSCLC were entered. All patients had failed at least one previous chemotherapy regimen, or were not suitable for any systemic chemotherapy because of poor performance status (PS), or were ineligible for other clinical trials. Therapy consisted of gefitinib 250 mg orally once daily; 10.5% (95% CI 5.3-17.9%) of patients achieved partial/minimal response (PR/MR) and 29.5% (95% CI 21.0-39.2%) had stable disease (SD), resulting in a disease control rate (PR/MR+SD) of 40% (95% CI 31-50%). The median duration of treatment for all patients was 12 weeks (range 2-116 weeks) and for patients achieving disease control 28 weeks (range 8-116). Nine patients received gefitinib for more than 1 year. Median survival was 30 weeks. Symptoms were improved in 36% of evaluable patients, and 64% of patients who achieved disease control experienced improvement of their disease related symptoms. Adverse events were generally mild and consisted mostly of skin rash (48%) and diarrhea (38%). A statistically significant association was observed between disease control and skin rash (p = < 0.001), nonsmoking status (p = 0.048), and symptom improvement (p = 0.001). The disease control rate was not statistically associated with histology, PS, gender, or number of prior treatments. In addition, longer survival was significantly associated with skin rash (p = < 0.001) and symptom improvement (p = < 0.001). Gefitinib demonstrated relevant clinical activity and a favorable toxicity profile in pretreated patients with advanced NSCLC. The development of toxicity was associated with a favorable response. In addition, a history of never having smoked seems to predict a higher efficacy of gefitinib.

Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma.

Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.

Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas.

Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.

Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07.

PURPOSE: A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. METHODS: Methotrexate (8 g/m(2)) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. RESULTS: Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. CONCLUSION: These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.