Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia

García, Agustin A.; Hirte, Hal W.; Fleming, Gini F.; Yang, Dongyun; Tsao‐Wei, Denice; Roman, Lynda D.; Groshen, Susan; Swenson, Steve; Markland, Frank; Gandara, David R.; Scudder, Sidney A.; Morgan, Robert J.; Chen, Helen; Lenz, Heinz Josef; Oza, Amit M.

doi:10.1200/jco.2007.12.1939

Cited by 495 publications

(325 citation statements)

References 43 publications

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“…Continuous oral thalidomide and celecoxib with alternating oral etoposide and CTX have been also studied in paediatric cancer patients (Kieran et al, 2005). Garcia et al (2008) have recently reported encouraging phase II trial results of metronomic cyclophosphamide, administered daily, in combination with bevacizumab given every 2 weeks, for treatment of recurrent ovarian cancer.…”

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confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C ss ) of SN-38 were between 1 and 3.3 ng ml À1 . From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m À2 day À1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities 4grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

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confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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“…Interestingly, recent data have suggested that this antiangiogenic effect of metronomic chemotherapy may be also mediated by the induction of the expression of the endogenous inhibitor of angiogenesis thrombospondin (TSP)-1 [18]. The objective of this study was to explore whether metronomic chemotherapy, the activity of which has been already observed in other solid tumor types [19][20][21][22][23][24][25][26][27], warrants further investigation in STS. There is accumulating evidence that antitumor activity of angiogenesis inhibitors is better reflected in terms of parameters of disease stabilization rather than by objective response.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, whether the efficacy of metronomic chemotherapy could be increased by combining it with other antiangiogenic agents is a matter of interest. In a phase II clinical trial including ovarian cancer patients, co-administration of metronomic cyclophosphamide, and bevacizumab resulted in superior antitumor activity when compared with historic controls [26]. Promising results have also been recently reported in patients with neuroendocrine tumors treated with metronomic cyclophosphamide in combination with sorafenib [27].…”

Section: Discussionmentioning

confidence: 99%

“Metronomic” chemotherapy in advanced soft tissue sarcomas

Italiano

Toulmonde

Lortal

et al. 2010

Cancer Chemother Pharmacol

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Purpose Angiogenesis plays a crucial role in metastatic progression of soft tissue sarcomas (STS). Endothelial cells are the primary target of metronomic chemotherapy. We report the safety and the efficacy of metronomic chemotherapy in metastatic STS patients. Methods The medical charts of 26 metastatic STS patients treated at Institut Bergonie (Bordeaux, France) with metronomic etoposide (100 mg/day orally for 21 consecutive days, repeated every 4 weeks) were reviewed by two independent investigators. Results Median age was 49. All but three patients received prior treatment with doxorubicin and/or ifosfamide. One patient (4%) had partial response and 11 patients (42%) had stable disease for more than 24 weeks.The 6-month and the 1-year progression-free survival rates were 42% [95% CI: 23; 61] and 23% [95% CI: 7; 39], respectively. The 6-month and the 1-year overall survival rates were 69% [95% CI: 51; 87] and 31% [95% CI: 13; 49], respectively. Two patients experienced grade 4 febrile neutropenia and one of them died of sepsis. Conclusion In this series, metronomic etoposide was associated with significant clinical activity in STS. Further prospective investigations are necessary to identify those patients who are more likely to benefit from this strategy.

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“…These changes are hypothesized to result in improved delivery of oxygen, nutrients, and cytotoxic chemotherapy to the tumor [43]. Table 1 details notable phase 2 studies of anti-angiogenesis therapy in EOC [44][45][46][47][48][49][50][51][52][53][54]. Of the 6 molecules studied, 5 have been advanced to the phase 3 arena.…”

Section: Phase 2 Studiesmentioning

confidence: 99%

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Eskander

Tewari

2014

Gynecologic Oncology

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Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia

Abstract: The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.

Cited by 495 publications

References 43 publications

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

“Metronomic” chemotherapy in advanced soft tissue sarcomas

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

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