A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma

Ho, Alan L.; Dunn, Lara; Sherman, Eric J.; Fury, Matthew G.; Baxi, Shrujal S.; Chandramohan, Raghu; Doğan, Snjezana; Morris, Luc G.T.; Cullen, Grace; Haque, Sofia; Sima, Cami S.; Ni, Andy; Antonescu, Cristina; Katabi, Nora; Pfister, David G.

doi:10.1093/annonc/mdw287

Cited by 99 publications

(87 citation statements)

References 22 publications

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“…12 Moreover, an ORR of 9% was reported by Alan Ho in a phase II study including only patients with ACC. 15 In patients with ACC, a comparable activity was observed with chemotherapy (ORR, 5%-15%) 18 with a median OS ranging from 14 to 19 months with single agent to 8 to 67 months with polychemotherapy 18,19 ). On the contrary, in non-ACC histotypes, chemotherapy seems to be more active (ORR, 20%-40%) than antiangiogenic agents 19 ).…”

Section: Discussionmentioning

confidence: 90%

“…Indeed, preclinical data showed that vascular endothelial growth factor receptor (VEGFR) pathway is frequently upregulated in SGCs, [7][8][9] and VEGF expression correlated with worse prognosis. 15 Our aim was to assess the activity of axitinib in patients with SGCs including mainly patients with non-ACC. 12,13 Axitinib is a second-generation antiangiogenic drug, more potent than sorafenib in inhibition of VEGFR-2 (IC 50 nmol/L VEGFR2 inhibition 0.2 vs 90, respectively).…”

Section: Introductionmentioning

confidence: 99%

“…14 Axitinib was tested also in R/M ACC, one of the most common histotypes that we deal with R/M SGCs, obtaining a 9% partial response [PR] and disease stabilization in 75% of cases as best overall response (>6 months in 10/25 [40%] patients with SD as the best response). 15 Our aim was to assess the activity of axitinib in patients with SGCs including mainly patients with non-ACC.…”

Section: Introductionmentioning

confidence: 99%

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Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract

et al. 2019

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Background Patients with prognosis recurrent/metastatic (R/M) salivary gland carcinomas (SGCs) are poor. Activity of axitinib was demonstrated in adenoid cystic carcinoma (ACC). We tested axitinib in a larger cohort of R/M SGCs including non‐ACC. Methods Axitinib was administered at 10 mg daily (dose escalation allowed) until progression or unacceptable toxicity. Null hypothesis would be rejected if more than 3 of 26 responses were observed. Results Twenty‐six patients (50% were male; 6 ACC, 20 non‐ACC) were treated. Response rate was 8% (2 partial responses), 13 stable disease (>6 months in 7 patients) and 11 disease progression. Median progression‐free survival and overall survival were 5.5 and 26.2 months, respectively. All patients had at least one adverse event: stomatitis (69%), fatigue (58%) and hypertension (54%) were the most frequent. Conclusions This trial did not meet its primary endpoint hence axitinib should not be considered for further investigations in SGCs. Safety profile was in line with the scientific literature.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract

et al. 2019

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“…SD duration (SDD) has been described in several trials for patients with ACC [25–31]. It is unclear if SD represents a marker of drug activity or simply the indolent behavior of this tumor.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma

et al. 2017

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PurposeVorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.ResultsThirty patients were enrolled. Median age of patients was 53 years (range 21–73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC. Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

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“…Because OHSV G47∆-IL12 does not only induce anti-tumor immunity but also produce anti-angiogenic activities [30], it is hypothesized that anti-tumor effects of G47∆-IL12 treatment would synergize with anti-vascular drugs. Axitinib (AG-013736) is an FDA approved, orally administered potent small molecule tyrosine kinase inhibitor (TKI), which inhibits VEGF receptor (VEGFR) 1-3, platelet-derived growth factor receptor beta (PDGFR-β) and receptor tyrosine kinase c-KIT (CD117) [115], and shows promising anti-vascular and anti-tumor activity in a variety of advanced stage cancers, including GBM [116][117][118]. In addition to anti-vascular effects, it also induces anti-tumor immune effects [119,120].…”

Section: Inhibition Of Tumor Angiogenesis Enhances Anti-tumor Potentimentioning

confidence: 99%

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Nguyen

Guz-Montgomery

Saha

2020

Cells

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Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono-and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

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A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma

Cited by 99 publications

References 22 publications

Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract

Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

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