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Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

ABSTRACT: 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.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 33P gammaATP-labeled PCR protocol was used to analyze dinucleotide repeats.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, Fisher's 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 CA repeats had the shortest median PFS of 3.4 months; patients with at least one allele > 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).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.

SUBMITTER: Schultheis AM

PROVIDER: S-EPMC2586993 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

Schultheis Anne M AM Lurje Georg G Rhodes Katrin E KE Zhang Wu W Yang Dongyun D Garcia Agustin A AA Morgan Robert R Gandara David D Scudder Sidney S Oza Amit A Hirte Hal H Fleming Gini G Roman Lynda L Lenz Heinz-Josef HJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 22

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 33P gammaATP-labeled PCR protocol was ...[more]

PMID: 19010874

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Project description:ImportanceTreatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.ObjectiveTo assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.Design, setting, and participantsThis open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.InterventionsPatients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.Main outcomes and measuresPrimary outcomes were objective response rate (ORR) and progression-free survival (PFS).ResultsOf the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).Conclusions and relevanceIn this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.Trial registrationClinicalTrials.gov Identifier: NCT02853318.

Project description:BACKGROUND:The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. METHODS/DESIGN:This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). DISCUSSION:The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer.

Project description:ObjectiveChildren and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses.MethodsElectronic medical records of patients with refractory or recurrent solid tumors who received ANGIO1 therapy were reviewed. Treatment cycles lasted 21 days and included bevacizumab, sorafenib, and cyclophosphamide. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v5.0. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1).ResultsThirty-nine patients (22 male, 17 female; median age 15 years; range 1-22 years) received the treatment regimen. The most common diagnoses included bone sarcomas (n=21; 14 Ewing sarcoma, 7 osteosarcoma) and soft tissue sarcomas (n=9; 2 rhabdomyosarcoma, 3 synovial sarcoma, 2 desmoplastic small round cell tumors, and 2 high-grade sarcoma). The most common Grade 3 non-hematologic toxicities included hypertension (2, 5.4%) and hematuria (2, 5.4%). Five patients (13.5%) had a pneumothorax (3 at progressive disease, 1 post lung biopsy, and 1 spontaneous). Common Grade 3/4 hematologic toxicities were lymphopenia (19, 51%) and leukopenia (13, 35%). Sixteen patients (43.2%) developed palmar-plantar erythrodysesthesia Grade 2 or less. A total of 297 cycles were administered. Twenty-three patients required a dose reduction of cyclophosphamide, sorafenib or bevacizumab during therapy, all of whom continued to have clinical benefit following dose modification. One patient (Ewing sarcoma) achieved a complete response after 11 cycles; 2 patients (Ewing sarcoma, high grade sarcoma) achieved a partial response following cycles 2 and 4, respectively and 20 patients had stable disease as a best response.ConclusionsIntravenous bevacizumab combined with oral sorafenib and metronomic cyclophosphamide was tolerated and required minimal supportive care or additional clinic visits. Disease stabilization for prolonged time periods was observed in greater than half of the treated patients. Patients with bone sarcoma demonstrated a signal of activity suggesting possible benefit from incorporation of the therapy as a maintenance regimen in upfront setting, or as a palliative regimen.

Project description:Background and aimsThis retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real-world setting.MethodsAdult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan-Meier estimator was used to describe overall survival (OS), progression-free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.ResultsSeventy-four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5-58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3-13.4) and 6.4 months (95% CI, 3.9-8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8-∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6-16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8-12.5) in those who did (P = 0.0382, log-rank), while median PFS values were 8.6 months (95% CI, 4.6-9.7) and 3.7 months (95% CI, 2.7-6.6), respectively (P = 0.0243, log-rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.ConclusionsTreatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real-world setting were comparable with those reported in prospective clinical trials.

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Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

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Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

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