Randomized Phase III Placebo-Controlled Trial of Carboplatin and Paclitaxel With or Without the Vascular Disrupting Agent Vadimezan (ASA404) in Advanced Non–Small-Cell Lung Cancer

Lara, Primo N.; Douillard, Jean Yves; Nakagawa, Kazuhiko; Pawel, Joachim von; McKeage, Mark J.; Albert, István; Losonczy, György; Reck, Martin; Heo, Dae Seog; Fan, Xiaolin; Fandi, Abderrahim; Scagliotti, Giorgio Vittorio

doi:10.1200/jco.2011.35.0660

Cited by 282 publications

(188 citation statements)

References 17 publications

(5 reference statements)

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“…5,6‐dimethylxanthenone (DMXAA or ASA404), flavone acetic acid analog, is a potent vascular disrupting agent that has completed multiple clinical trials, including a large scale phase III trial of carboplatin and paclitaxel with or without ASA404 in advanced non‐small‐cell lung cancer (NSCLC) 165, 166, 167, 168, 169…”

Section: Combining Phototherapy With Novel Anti‐cancer Agentsmentioning

confidence: 99%

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

et al. 2016

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Near infrared (NIR) light penetrates human tissues with limited depth, thereby providing a method to safely deliver non‐ionizing radiation to well‐defined target tissue volumes. Light‐based therapies including photodynamic therapy (PDT) and laser‐induced thermal therapy have been validated clinically for curative and palliative treatment of solid tumors. However, these monotherapies can suffer from incomplete tumor killing and have not displaced existing ablative modalities. The combination of phototherapy and chemotherapy (chemophototherapy, CPT), when carefully planned, has been shown to be an effective tumor treatment option preclinically and clinically. Chemotherapy can enhance the efficacy of PDT by targeting surviving cancer cells or by inhibiting regrowth of damaged tumor blood vessels. Alternatively, PDT‐mediated vascular permeabilization has been shown to enhance the deposition of nanoparticulate drugs into tumors for enhanced accumulation and efficacy. Integrated nanoparticles have been reported that combine photosensitizers and drugs into a single agent. More recently, light‐activated nanoparticles have been developed that release their payload in response to light irradiation to achieve improved drug bioavailability with superior efficacy. CPT can potently eradicate tumors with precise spatial control, and further clinical testing is warranted.

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Section: Combining Phototherapy With Novel Anti‐cancer Agentsmentioning

confidence: 99%

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

et al. 2016

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“…In addition, mice that completely rejected tumors were protected against a rechallenge with the same tumor cell line, implying the generation of an immunological memory [107]. Although DMXAA failed in a phase III clinical trial of non-small cell lung carcinoma [108], now it is well known that this was due to its inability to bind human STING. New agents are being developed that engage human STING.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

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“…A recent phase III trial of DMXAA in combination with carboplatin-paclitaxel chemotherapy for advanced non small cell lung cancer showed no improvement in progression free survival compared to chemotherapy alone, although DMXAA was well tolerated [178].…”

Section: Dmxaamentioning

confidence: 99%

“…In contrast, DMXAA is a vascular disrupting agent that induces apoptosis in tumour endothelial cells, resulting in collapse of the tumour vasculature and thus tumour hypoxia and necrosis [177]. With DMXAA treatment at 1800mg/m 2 , the dose used in phase III clinical trials in combination with chemotherapy [178], a phase I trial of single agent DMXAA reported an estimated plasma C max of 1000µM [179]. A DMXAA dose range of 0 -300µg/ml was therefore initially studied.…”

Section: Vascular Disrupting Agentmentioning

confidence: 99%