Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer

Edelman, Martin J.; Smith, Roger H.; Hausner, P; Doyle, L. Austin; Kalra, Kavita; Kendall, J.; Bedor, Michelle; Bisaccia, Sonia

doi:10.1200/jco.2005.14.373

Cited by 36 publications

(24 citation statements)

References 10 publications

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“…RXR agonists (rexinoids) activate the RXR/RXR homodimers [58]. One such drug, Targretin (Ligand Pharmaceuticals, San Diego, CA) is used in the treatment of cutaneous T-cell lymphoma [59] and shows promise in certain sub-population of lung cancer patients [60]. Rexinoids have the potential to be used in combinations with other nuclear receptor agonists [61][62][63].…”

Section: Nuclear Retinoic Acid Receptors and Synthetic Retinoidsmentioning

confidence: 99%

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Garattini¹,

Giannı̀²,

Terao

2007

CPD

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Retinoic acid and natural as well as synthetic derivatives (retinoids) are promising anti-neoplastic agents endowed with both therapeutic and chemopreventive potential. Although the treatment of acute promyelocic leukemia with all-trans retinoic acid is an outstanding example, the full potential of retinoids in oncology has not yet been exploited and a more generalized use of these compounds is not yet a reality. This may be the result of issues such as natural and induced resistance as well as local and systemic toxicity. One way to enhance the therapeutic and chemopreventive activity of retinoic acid and derivatives is to identify rational combinations between these compounds and other pharmacological agents. This is now possible given the wealth of information available on the biochemical and molecular mechanisms underlying the biological activity of retinoids. At the cellular level, the anti-leukemia and anti-cancer activity of retinoids is the result of three main actions, cell-differentiation, growth inhibition and apoptosis. At the molecular level, retinoids act through the activation of nuclear-retinoic-acid-receptor-dependent and-independent pathways. The cellular pathways and molecular networks relevant for retinoid activity are modulated by a panoply of other intra-cellular and extra-cellular pathways that may be targeted by known drugs and other experimental therapeutics. The review article aims to summarize and critically discuss the available knowledge in the field and provide a rational framework that may be useful for the design of effective drug combinations with the potential to enhance the therapeutic index of retinoids.

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Section: Nuclear Retinoic Acid Receptors and Synthetic Retinoidsmentioning

confidence: 99%

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Garattini¹,

Giannı̀²,

Terao

2007

CPD

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“…Bexarotene is currently the only rexinoid approved by the FDA, for treatment of cutaneous T-cell lymphoma. Notably, bexarotene, either alone or in combination with erlotinib and various chemotherapeutic agents, has been tested in a variety of clinical trials for lung cancer (4)(5)(6)(7)(8)(9). Although bexarotene failed to increase overall survival as a single agent, subsets of patients responded to the drug, with highgrade hypertriglyceridemia identified as a biomarker of efficacy.…”

Section: Introductionmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1b, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1);

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“…Numerous phase I/II trials investigating the efficacy and tolerability of bexarotene, both as monotherapy and as part of combination therapy to treat NSCLC, have shown mixed results with regard to the effect of bexarotene on time to progression and overall survival [20][21][22] . In order to elucidate the role of bexarotene, two phase III studies examined the use of bexarotene in combination with cisplatin/vinorelbine and in combination with carboplatin/paclitaxel, both in chemotherapy-naïve patients with advanced NSCLC, and found that bexarotene had no effect on time to progression or overall survival.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of Docetaxel and Bexarotene

Wildi¹,

Baggstrom²,

Suresh³

et al. 2008

Chemotherapy

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Background: We conducted a single-arm, dose-escalation, phase 1 clinical trial in order to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of bexarotene in combination with docetaxel. Methods: Patients with solid tumors and no other curative treatment options were eligible. Oral bexarotene was taken daily in combination with docetaxel 25 mg/m² administered intravenously on days 1, 8, and 15 of a 28-day cycle. The dose of bexarotene started at 200 mg/m² and increased by 100 mg/m²/dose level, until either a MTD or the final dose of 400 mg/m² was reached. Results:Fifteen patients were enrolled in the study. Median age was 58 years. The majority had non-small-cell lung cancer. The study went to completion without reaching an MTD. Hematological toxicities were mild. Three patients developed grade 3 hypertriglyceridemia, all occurring during the first cycle of treatment. No objective responses were noted. Four patients had stable disease as a best response, 3 with non-small-cell lung cancer and 1 with angiosarcoma. Conclusions:Treatment was well tolerated and no DLT was seen at docetaxel 25 mg/m² and bexarotene 400 mg/m². Given that stable disease was durable in 4 patients, future studies with this combination may be warranted.

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Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer

Abstract: Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.

Cited by 36 publications

References 10 publications

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

A Phase I Study of Docetaxel and Bexarotene

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