Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors

Mita, Monica; Gordon, Michael; Rosen, Lee S.; Kapoor, Nirmal; Choy, Gavin; Redkar, Sanjeev; Taverna, Pietro; Oganesian, Aram; Sahai, Amarpal; Azab, Mohammad; Bristow, Robert G.; Tolcher, Anthony W.

doi:10.1007/s00280-014-2481-1

Cited by 23 publications

(20 citation statements)

References 15 publications

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“…c-Met, Ret, c-Kit) and to suppress the induction of the DNA repair protein RAD51 in cell lines [99]. Results from a phase I trial suggested that the compound is well tolerated [100]. Interestingly, Amuvatinib displays the capability to inhibit also Axl, its potency towards the target being in the micromolar range [25].…”

Section: Development Of Axl Inhibitors 41 From Chemistry To Pharmacmentioning

confidence: 99%

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno

Gatti

Lanzi

et al. 2016

CMC

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Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.

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Section: Development Of Axl Inhibitors 41 From Chemistry To Pharmacmentioning

confidence: 99%

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno

Gatti

Lanzi

et al. 2016

CMC

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“…Amuvatinib is an orally administered small molecule drug that targets c-KIT, PDGFRA, and RAD51 [61]. A ‘kinase switch’ from KIT-dependent to AXL-dependent receptor tyrosine kinase activity was observed in GIST cell lines when the cells acquired IM resistance [62].…”

Section: Kit and Pdgfra Inhibitorsmentioning

confidence: 99%

“…In another phase I dose-escalation study of amuvatinib, it was noted that 2 of 4 refractory GIST patients showed SD despite the low and variable plasma levels of amuvatinib, suggesting further investigation of this drug as a single agent in refractory GIST [65]. An additional phase I trial demonstrated that amuvatinib has an antitumor activity in neuroendocrine, non-small cell and small cell lung cancers when combined with either paclitaxel/carboplatin or carboplatin/etoposide [61]. There was no report of increased frequency of the adverse effects commonly seen in the abovementioned chemotherapeutic agent.…”

Section: Kit and Pdgfra Inhibitorsmentioning

confidence: 99%

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Alturkmani

Pessetto

Godwin

2015

Expert Opinion on Investigational Drugs

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Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later PDGFRA gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. Areas covered This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. Expert opinion It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.

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“…Proposed mechanisms include: (1) reducing the primary tumour's vascularity and vascular permeability, thereby reducing metastatic shedding, (2) contributing to a micromolecularly unfavourable metastatic niche, (3) primary and secondary tumour hypoxia and (4) somewhat counter‐intuitively improving tumour vascular patency, thereby enhancing delivery of the cytotoxic chemotherapeutic to the tumour . In the human field, combination therapy with an anti‐angiogenic agent and conventional MTD chemotherapy has demonstrated benefit in the treatment of non‐small cell lung cancer, colorectal cancer, breast cancer, urogenital carcinomas, malignant melanoma and several advanced stage diseases . However, benefit is not replicated in all clinical scenarios, and further elucidation of the ideal agents and combinations, tumour targets, optimal doses and scheduling regimens is required …”

Section: Introductionmentioning

confidence: 99%

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour‐bearing dogs: A phase I dose finding study

Wouda

Hocker

Higginbotham

2017

Vet Comparative Oncology

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Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m IV every 21 days and approximately 2.75 mg kg PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials.

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Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors

Abstract: Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

Cited by 23 publications

References 15 publications

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour‐bearing dogs: A phase I dose finding study

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