Advani Sh

Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study

BACKGROUND Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites. METHODS In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (≤ 2 weeks vs > 2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444. FINDINGS 55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55·1 [SE 7·3] vs 23·3 [7·7] days; difference 31·8 days, 95% CI 10·6-53·1; p=0·0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis). INTERPRETATION This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit-risk balance should be thoroughly discussed for each patient. FUNDING Sanofi Oncology.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral Talactoferrin in Combination with Carboplatin and Paclitaxel in Previously Untreated Locally Advanced or Metastatic Non-small Cell Lung Cancer

Introduction: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. Methods: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29–47%; p = 0.05) and 15% (27–42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. Conclusion: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.

Pediatric Germ Cell Tumor: An Experience with BEP

Purpose This study is an analysis of our experience with bleomycin, etoposide, and cisplatin (BEP) chemotherapy, in pediatric germ cell tumors (GCTs). Patients and Methods The study included all children (age <16 years) who were registered between May 1988 and May 1993 with a histologically confirmed diagnosis of GCT and received BEP chemotherapy. In addition to the clinicopathological features, the response rate, survival rate, and toxicity were analyzed. Results There was a total of 56 patients, of whom 22 had an ovarian tumor and 17 each had a testicular or an extragonadal tumor. Histologically, endodermal sinus tumor was the most common type (62%). Tumor markers were increased in 89% (50 of 56). Complete responses were observed in 89.1% (49 of 55) and partial responses in 10.9% (6 of 55) of the evamable patients. Five-year actuarial survival was 83% and progression free survival was 93%. Median follow-up was 18 months. Median survival is not yet reached. The chemotherapy was well tolerated. Conclusions From the present report, it is apparent that BEP chemotherapy is very effective and well tolerated in children with GCT. The data probably suggests that conservative surgery, when combined with effective chemotherapy, can result in cure of the majority of children with GCTs.

Clinical Experience with Gefitinib in Indian Patients

Introduction: Treatment options are limited in patients with advanced or refractory non-small cell lung cancer and lead to suboptimal outcome and/or benefit. The epidermal growth factor tyrosine kinase inhibitor gefitinib (IRESSA) has been approved in many countries. Increased responsiveness to gefitinib has been demonstrated in particular subsets of patients, for example never smokers and patients of Asian origin. However, to date, little is known of its use specifically in patients from India. Methods: Retrospective ad hoc analysis of clinical data from experience with gefitinib in patients with advanced NSCLC from India enrolled in the IRESSA Survival Evaluation in Lung (ISEL) study (n = 77) or included in the gefitinib expanded-access program in India (n = 133). Results: Among Indian patients enrolled in the ISEL study, median survival was 6.4 months with gefitinib and 5.1 month with placebo. The objective response rate in Indian patients was 14% with gefitinib versus 0% with placebo. In ISEL, tolerability data from Indian patients were consistent with the overall study population. In the Indian gefitinib expanded-access program, median survival was 6 months and gefitinib was well tolerated. Conclusions: Gefitinib seems well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed.

Multifocal Extranodal Lymphomas: An Expression of Homing Phenomenon

The present study analyses 27 patients with primary lymphoma involving multiple extranodal sites. Eight patients were found to have multiple extranodal involvement at presentation while in 19 patients, relapse of disease was noticed at a different extranodal site without any other systemic spread. Malignant lymphomas of Waldeyers ring were frequently associated with involvement of gastrointestinal, gonadal or cutaneous lesion. Primary gonadal lymphoma also showed a high incidence of cutaneous, pleura and bone involvement. The homing pattern of mucosa-associated lymphoid cells explains the multifocal extranodal lymphomas with site-specific tropism.

Post-Therapy Profile of Serum Total Cholesterol, Retinol and Zinc in Pediatric Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma

Objective: To assess serum albumin, total cholesterol, retinol, zinc and hemoglobin in children who had completed treatment for acute lymphoblastic leukemia (ALL) and Non-Hodgkins lymphoma (NHL). Methods: The above parameters were analyzed in 105 ALL and NHL and 108 age and sex-matched controls. Serum albumin, serum cholesterol and hemoglobin were estimated by colorimetric methods. Serum retinol was estimated by HPLC and serum zinc was estimated by atomic emission spectrophotometer (ICP-AES). Comparisons were made to stage of treatment (maintenance 6 with post-therapy), type of treatment (chemotherapy and radiation with only chemotherapy) and type of malignancy (ALL with NHL). Results: Only serum albumin in patients included at Maintenance6 was significantly higher (t = 2.31, p = 0.05) than post-therapy patients. No significant difference in serum values was observed by type of treatment. Only total cholesterol was significantly higher in NHL patients than in ALL patients (t = 1.954, p = 0.05). Patients had comparable serum levels to that of controls. However, in patients and controls more than 75% children had deficient serum retinol levels, (< than 0.6989 μmol/l, or 20 μg/dl). Further, 75% patients and 54.7% controls had serum retinol levels less than 0.3439 μmol/l or 10 μg/dl. Conclusion: The results of the present study indicate that cancer and its treatment did not have any long-lasting effect on serum albumin, total cholesterol, retinol, zinc and hemoglobin. Majority of subjects had low serum retinol suggestive of depleted liver reserves. The deficient serum retinol levels (< than 0.6989 μmol/l, or 20 μg/dl) in at least 75% of the patients and controls probably reflect poor dietary intake. A higher percentage of patients with low serum retinol levels may also be attributed to the possibility of urinary losses of retinol that occur during episodes of infection while on immunosuppressive anti-cancer drug therapy.

A multicenter phase II randomized study of Cremophor-free polymeric nanoparticle formulation of paclitaxel in women with locally advanced and/or metastatic breast cancer after failure of anthracycline.

Paclitaxel is extensively used in the treatment of advanced carcinomas of the breast, ovary and non‐small cell lung cancer. In clinical use it is formulated in the non‐ionic surfactant polyethoxylated castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility. Cremophor adds to toxic effects of paclitaxel by producing or contributing to the well‐described hypersensitivity reactions that commonly occur during its infusion, affecting a large number of patients. This randomized trial was conducted to evaluate efficacy and safety of novel nanoparticle‐based paclitaxel in the treatment of patients with advanced breast cancer.

Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer

CONTEXT Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. AIMS To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). SETTINGS AND DESIGN Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. MATERIALS AND METHODS An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). STATISTICAL ANALYSIS USED All data summaries were descriptive. PK parameters were estimated using compartmental analysis. RESULTS 25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. CONCLUSIONS 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.

Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion

Advanced nonsmall cell lung cancer (NSCLC) treatment is primarily based on platinum-based chemotherapy. Although epidermal growth factor receptor (EGFR) targeting has shifted the treatment paradigm toward personalized tyrosine kinase inhibitors (TKIs), resistance develops inevitably and EGFR T790M is the most common acquired resistance mechanism. Rebiopsy of resistant NSCLC cases can provide additional information on the underlying resistant mechanisms and therefore can help clinicians in taking better management decisions. An expert panel meeting of renowned cancer oncologists was held to discuss the management of advanced-stage NSCLC. The present paper is based on the recommendations made by the expert panel and is supported by an exhaustive literature search. It was suggested that identification of driver mutation leads to better treatment decisions. TKIs have proven to be better treatment option in EGFR-positive patients as compared to chemotherapy. Third-generation TKIs (osimertinib) promise to bring optimal and improved care for NSCLC cases failing first-line TKI treatment.

Abstract 2766: Multicenter pharmacokinetic evaluation of ON 01910. Na, a novel broad-spectrum anticancer agent, in Phase I single agent clinical trials in patients with solid tumors

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: ON 01910. Na is an anti-cancer agent with demonstrated activity against both solid tumors and hematological cancers. The purpose of this research was to evaluate the effect of dose and administration schedule on ON 01910. Na pharmacokinetics (PK) in advanced, heavily pre-treated solid tumor patients. Methods: Data was collected in three Phase I protcols conducted in the US and in India covering a wide range of doses and intraveous infusion schedules: Protocol 1 (50-1375 mg/m2/day over 72 h); Protocol 2 (250 – 4450 mg/m2/day over 24 h) and Protocol 3 (2400-3200 mg over 2, 4 or 8 h). In several patients, pharmacokinetics were evaluated for more than 1 dosing cycle. Plasma samples were collected pre-dose and up to 72 hours post-infusion. ON 01910. Na plasma levels were determined by a validated LC/MS/MS method. Results: Ninety-five data sets from 81 patients were evaluated in this study. ON 01910. Na showed biphasic elimination from the plasma, regardless of dose and administration schedule. The functional half-life of ON 01910. Na, estimated from the initial decline of plasma levels following infusion termination, was less than 2 hours. This was confirmed in data from patients receiving prolonged infusions as ON. 01910. Na approached steady state levels within several hours after dose initiation. As noted in the table below, ON. 01910. Na clearance was lower at higher drug dosing rates. There were no differences in drug pharmacokinetics among the infusion schedules. Conclusion: The pharmacokinetics of ON 01910. Na is dose dependent. A continuous IV infusion would be recommended to treat patients because of its short plasma half-life and rapid clearance. Systemic drug exposure is not affected by type of dosing (flat dosing vs. BSA adjusted). No significant differences were noted between the PK profiles of patients in the US centers and the patients in the India centers. View this table: Effect of Dosing Rate on Clearance of ON 01910. Na Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2766.