Showing papers by "Amit M. Oza published in 2008"
TL;DR: The data suggest that the IL-8 A-251T polymorphism may be a molecular predictor of response to bevacizumab-based chemotherapy and the CXCR2 C+785T, VEGF C+936T single nucleotide polymorphisms and the AM 3′ dinucleotide repeat polymorphisms may be molecular markers for PFS in ovarian cancer patients.
Abstract: Purpose: This study was designed to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in ovarian cancer patients treated with low-dose cyclophosphamide and bevacizumab. Experimental Design: Seventy recurrent/metastatic epithelial ovarian cancer patients were enrolled in a phase II clinical trial. Genomic DNA was available from 53 blood samples. Polymorphisms were analyzed using the PCR-RFLP protocol. A 5′ end 33 P γATP-labeled PCR protocol was used to analyze dinucleotide repeats. Results: Patients genotyped A/A or A/T for the IL-8 T-251A gene polymorphism had a statistically significant lower response rate (19%; 0%) than those homozygous T/T (50%; P = 0.006, Fisher9s exact test). Patients carrying a minimum one C allele (C/C; C/T) of the CXCR2 C+785T polymorphism showed a median progression-free survival (PFS) of 7.4 months compared with the PFS of 3.7 months for those homozygous T/T ( P = 0.026, log-rank test). Patients with the VEGF C+936T polymorphism C/T genotype had a longer median PFS of 11.8 months, compared with those with the C/C and T/T genotype, which had median PFS of 5.5 months and 3.2 months, respectively ( P = 0.061, log-rank test). Patients carrying both AM 3′end alleles 14 repeats or both alleles >14 repeats showed a median PFS of 6.4 months and 7.2 months, respectively ( P = 0.008, log-rank test). Conclusion: Our data suggest that the IL-8 A-251T polymorphism may be a molecular predictor of response to bevacizumab-based chemotherapy. The CXCR2 C+785T, VEGF C+936T single nucleotide polymorphisms and the AM 3′ dinucleotide repeat polymorphisms may be molecular markers for PFS in ovarian cancer patients.
181 citations
TL;DR: Cediranib is a novel, orally-administered, highly potent inhibitor of VEGFR1, which is over-expressed in human ovarian tumours and this is associated with a poor prognosis.
Abstract: 5521 Background: VEGF is over-expressed in human ovarian tumours and this is associated with a poor prognosis. Cediranib (AZD2171) is a novel, orally-administered, highly potent inhibitor of VEGFR1...
85 citations
TL;DR: This trial was designed to assess the level of activity in patients who had previously received chemotherapy and demonstrated promising activity inhibition of mTOR with temsirolimus, an ester derivative of rapamycin, in chemotherapy naive endometrial cancer.
Abstract: 5516 Background: Loss of PTEN function occurs in 26–80% of endometrial carcinomas and leads to deregulated PI3K/Akt/mTOR signalling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR with temsirolimus, an ester derivative of rapamycin, has demonstrated promising activity, irrespective of PTEN loss, in chemotherapy naive endometrial cancer with an objective response rate of 21% and prolonged stable disease in 48%. This trial was designed to assess the level of activity in patients who had previously received chemotherapy. Methods: A single stage phase II study of temsirolimus in women with chemotherapy treated, recurrent or metastatic endometrial cancer has been completed, at a dose of 25mg i.v. weekly. 27 eligible patients have been enrolled and archival specimens of tumour have been collected for PTEN immunohistochemistry analysis. Thirteen had received prior radiation and 10 hormonal therapy...
53 citations
TL;DR: Sunitinib as mentioned in this paper is a multi-targeted receptor tyrosine kinase (RTK) inhibitor with potent activity against a number of RTK targets that are implicated in epithelial ovarian cancer (EOC) g...
Abstract: 5522 Background: Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor with potent activity against a number of RTK targets that are implicated in epithelial ovarian cancer (EOC) g...
35 citations
TL;DR: A multi-center phase II trial of SOR in pts with advanced/recurrent UCA or CS with 0–1 prior chemotherapy regimens using Sorafenib, a multitargeted kinase inhibitor with antiangiogenic activity that is approved for use in renal and hepatocellular carcinoma.
Abstract: 5585 Background: There is no effective treatment for UCA/CS pts who have progressed on platinum-taxane therapy. Increased levels of VEGF are frequently seen in UCA and CS, and antiangiogenic therapy has shown activity in a mouse model of UCA. Sorafenib is a multitargeted kinase inhibitor with antiangiogenic activity that is approved for use in renal and hepatocellular carcinoma. Methods: We initiated a multi-center phase II trial of SOR in pts with advanced/recurrent UCA (arm A) or CS (arm B) and 0–1 prior chemotherapy regimens. PS 0–2 and measurable disease were required. The starting SOR dose was 400 mg orally twice daily. The primary endpoint was objective response, which was evaluated every 8 weeks. The trial design required 1 response in the first 12 evaluable pts to proceed to second stage. Results: 55 pts (39 UCA, 16 CS) enrolled between 3/05 and 10/07. Pt characteristics arm A: median age 65 (range 44- 83); PS 0/1/2: 16/19/3. Pt characteristics arm B: median age 64 (range 40- 87); PS 0/1/2: 7/8/1....
23 citations
TL;DR: Assessment of the activity of belinostat in 2 patient populations: metastatic or recurrent platinum resistant EOC and LMP ovarian tumors finds that the drug demonstrates anti tumor activity in ovarian cancer models.
Abstract: 5518 Background: Patients with LMP ovarian tumors represent an understudied population whose tumors are intrinsically resistant to radiation and chemotherapy. Patients with platinum resistant epithelial ovarian cancer (EOC) have low response rates to conventional chemotherapy. Histone deacetylation results in loss of tumor suppressor and pro apoptotic genes in ovarian cancer cell lines. Belinostat is a pan hydroxamate, histone deacetylase inhibitor which demonstrates anti tumor activity in ovarian cancer models Methods: The aim of this phase II study is to assess the activity of belinostat in 2 patient populations: metastatic or recurrent platinum resistant (< 6 mo) EOC and LMP ovarian tumors. 3 prior lines of chemotherapy were allowed. Primary endpoints are objective response with a multinomial stopping rule, secondary endpoints include stable disease (SD) rate, survival, tolerability and assessment of molecular changes with therapy. Belinostat 1,000mg/m2/day was administered iv on days 1–5 of a 21 day c...
19 citations
TL;DR: Vaginal SmCC complicated by EAS is a rare paraneoplastic syndrome, and this case history outlines the management options for patients with this condition and reviews the pertinent literature.
Abstract: Objective To describe ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) to increase awareness of this condition when treating patients with gynecological small cell carcinoma (SmCC). Materials and methods This is a review of a 61-year-old woman with primary vaginal SmCC and an atypical presentation of Cushing syndrome. This case describes the molecular rationale, caveats in clinical presentation, pathological diagnosis, and management options for patients with this rare syndrome. Results After treatment with primary chemotherapy, the patient presented acutely with delirium and metabolic disturbances. This was associated with elevated ACTH and gastrin levels without any tumor staining for ACTH. The patient was initially managed with ketoconazole to control the EAS. Complications developed related to her Cushing syndrome, and she succumbed to complications of her disease. Conclusions Vaginal SmCC complicated by EAS is a rare paraneoplastic syndrome, and this case history outlines the management options for patients with this condition and reviews the pertinent literature.
17 citations
TL;DR: A regression model was constructed that predicts the SAE and SAEatt risk for an individual patient during cycle 1 of phase II trial treatment with moderate to good internal validity.
Abstract: Purpose A tool that quantifies the risk of treatment-related toxicity based on individual patient characteristics can augment the informed consent process and safety monitoring in the setting of phase II cancer treatment trials of molecularly targeted agents (MTAs). Methods A regression model was constructed to predict the risk of a serious adverse event (SAE) with an MTA and presented as a nomogram. Estimation of risk can be performed by integrating risk estimates from the nomogram and from a reference or average patient. Internal validation was performed using bootstrapping techniques. Results A total of 578 patients were treated with one of 14 MTAs given alone or in combination on one of 27 clinical trials performed by the Princess Margaret Hospital Drug Development Program between 2001 and 2006. Approximately 50% and 24% of patients experienced an SAE and an attributable SAE (SAEatt) during cycle 1, respectively. Albumin, lactate dehydrogenase (LDH), number of target lesions, prior radiotherapy, Charl...
17 citations
TL;DR: Current and emerging therapeutic strategies combining CRT with novel molecular agents that specifically target the abnormal tumor microenvironment are reviewed, with the aim of improving local control and survival in patients with locally advanced cervix cancer.
Abstract: Despite improvements in survival after the introduction of chemo-radiotherapy (CRT) in the treatment of patients with cervical cancer, loco-regional control of this disease continues to be a major problem. The present article reviews current and emerging therapeutic strategies combining CRT with novel molecular agents that specifically target the abnormal tumor microenvironment, with the aim of improving local control and survival in patients with locally advanced cervix cancer. The evidence supporting the biological rational to combine novel non-cytotoxic agents with CRT is strong, and drugs targeting different molecular pathways are currently under clinical development (EGFR inhibitors, COX-2 inhibitors, hypoxia targeted agents, etc). Early pre-clinical and clinical strategies also favor the use of vascular-targeted agents with the aim to normalize the abnormal tumor vasculature, increase tumor oxygenation, and reduce interstitial fluid pressure (IFP). The integration of these novel targeted therapies with CRT in clinical trials is discussed, as well as new and promising biomarkers to test drug activity.
11 citations
TL;DR: The maximum tolerated dose (MTD) of 2-weekly cisplatin, infusional 5-FU and concurrent conformal radiotherapy for resected gastric cancer was assessed in this phase I study.
Abstract: 15671 Background: This phase I study assessed the maximum tolerated dose (MTD) of 2-weekly cisplatin, infusional 5-FU and concurrent conformal radiotherapy (RT) for resected gastric cancer. Methods...
1 citations
TL;DR: PEGylated liposomal doxorubicin (PLD) is safe and effective as monotherapy for advanced ovarian cancer and was compared with topotecan in a large Phase III trial and was found to be associated with less severe adverse events.
Abstract: Effective agents with a favorable toxicity profile are needed for women with advanced ovarian cancer. PEGylated liposomal doxorubicin (PLD) is safe and effective as monotherapy for advanced ovarian cancer. It was compared with topotecan in a large Phase III trial in this patient population and was found to be associated with less severe adverse events. In platinum-sensitive patients, PLD was associated with a statistically significant survival advantage over topotecan. PLD is currently under further investigation to expand its role in the treatment of ovarian cancer into combination regimens with carboplatin as first-line treatment, as maintenance therapy as a single-agent, and in combination with molecularly targeted agents in the salvage setting.