Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors

Ganesan, Chitra; Obulareddy, Sri J.; Fischer, James H.; Antonysamy, Mary A.; Jha, Gautam; Bliss, Robin; Dudek, Arkadiusz Z.

doi:10.1097/coc.0000000000000053

Cited by 8 publications

(4 citation statements)

References 22 publications

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“…Cell cycle arrest in S-phase is suggested to increase the susceptibility of tumors to etoposides and cisplatine, chemotherapeutics that are often administered to medulloblastoma patients [ 31 - 32 ]. Moreover, combinations of these chemotherapeutic agents with MKI have either been proven successful or are momentarily under investigation in clinical trials for other cancers [ 33 - 34 ].…”

Section: Discussionmentioning

confidence: 99%

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promisingin vitroandin vivoefficacy

et al. 2014

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Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

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Section: Discussionmentioning

confidence: 99%

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promisingin vitroandin vivoefficacy

et al. 2014

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“…A scientific rationale to combine ixabepilone with pazopanib in patients with uterine leiomyosarcoma may exist, as a recent Phase I study in patients with solid tumors reported at American Association for Cancer Research (AACR) in 2013 has defined a maximally tolerated dose of the combination with a high rate of disease stabilization [46]. Not surprisingly, the main toxicity was myelosuppression.…”

Section: Discussionmentioning

confidence: 99%

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Duska

Blessing

Rotmensch

et al. 2014

Gynecologic Oncology

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Background The combination of gemcitabine and docetaxel is standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy. Methods Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m2 on day one of a 21 day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT). Results Twenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving one cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4 months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over six cycles of treatment. Median PFS for all 23 patients was 1.4 months and overall survival was 7.0 months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), anemia grade 3 (22%). Conclusion Ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.

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“…They are a newer class of microtubuletargeting agents than taxanes. Numerous studies have confirmed the antitumor activity of epothilones in several tumor cell lines, even with high levels of P-glycoprotein (Ganesan et al, 2014;Zhang et al, 2014).…”

Section: Introductionmentioning

confidence: 95%

Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53

Rogalska¹,

Śliwińska²,

Kasznicki³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF-κB and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-κB. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-κB. These findings support the link between NF-κB and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.

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Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors

Abstract: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

Cited by 8 publications

References 22 publications

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promisingin vitroandin vivoefficacy

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promisingin vitroandin vivoefficacy

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53

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