Phase I/II dose escalation trial of patupilone every 3 weeks in patients with non-small cell lung cancer

Østerlind, Kell; Sánchez, Jose M.; Zatloukal, Petr; Hamm, J.; Belani, Chandra P.; Kim, E.; Felip, E.; Johri, A.; Berton, M.; Sklenar, I.

doi:10.1200/jco.2005.23.16_suppl.7110

Cited by 12 publications

(5 citation statements)

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“…Peripheral neuropathy with patupilone was primarily of mild-to-moderate (grade 1/2) severity in phase I and phase II studies in patients with various solid tumors. 67,68 The milder toxicity profile of patupilone compared with other epothilones may be attributable to differences in tissue distribution and metabolism. 7 Sagopilone (ZK-EPO) is a synthetic epothilone with promising antitumor activity.…”

Section: Other Epothilonesmentioning

confidence: 99%

Peripheral Neuropathy with Microtubule-Targeting Agents: Occurrence and Management Approach

Carlson

Ocean

2011

Clinical Breast Cancer

132

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Microtubule-targeting agents (MTAs), which include vinca alkaloids, taxanes, and the recently introduced epothilone, ixabepilone, are widely used chemotherapeutic agents for treatment of patients with cancer. MTAs interfere with the normal structure and function of microtubules, leading to cell-cycle arrest and tumor cell death. Microtubule function is critical to normal neuronal function, thus MTA therapy is commonly associated with some form of neuropathy. There is poor agreement between tools for clinical assessment of MTA-associated peripheral neuropathy, and standardization of grading scales is needed to reduce variability. For a majority of patients, MTA-associated neuropathy is mild to moderate in intensity and reversible, but it can be severe and resolve incompletely. The incidence and severity of MTA-associated neuropathy is drug, dose, and schedule dependent. The first-generation vinca alkaloids (eg, vincristine) are associated with severe mixed sensory and motor neuropathy, whereas the newer vinca alkaloids (eg, vinorelbine, vinflunine) induce a milder sensory neuropathy. Taxane-associated sensory neuropathy occurs more often with standard (polyoxyethylated castor oil-based) and albumin-bound paclitaxel than with docetaxel. The incidence and presentation of peripheral neuropathy with ixabepilone, alone or in combination with capecitabine, are similar to that with taxanes. Management of neuropathy may involve reducing or delaying the MTA dose, or in severe persistent or disabling cases discontinuing treatment. Reversal of neuropathy after dosage intervention appears to be more rapid with ixabepilone than with other MTAs.

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Section: Other Epothilonesmentioning

confidence: 99%

Peripheral Neuropathy with Microtubule-Targeting Agents: Occurrence and Management Approach

Carlson

Ocean

2011

Clinical Breast Cancer

132

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“…The process of rational design and selection of ixabepilone has led to eYcacy and safety in the clinical setting, including promising eYcacy in patients with multidrug-resistant disease. Phase II: activity seen in breast, lung, prostate, ovarian and renal cancers Phase III trials ongoing Diarrhea (DLT), fatigue, nausea, vomiting [58][59][60][61] Epothilone D (KOS-862) Phase II: activity seen in metastatic breast cancer pretreated with or progressing after treatment with anthracycline and taxane Neuropathy (DLT), impaired gait and cognitive/perceptual abnormalities (DLT), chest pain (DLT), fatigue, nausea and vomiting [62,63] ZK-EPO (third generation synthetic epothilone B analog)…”

Section: Discussionmentioning

confidence: 99%

Preclinical discovery of ixabepilone, a highly active antineoplastic agent

Lee

Borzilleri

Fairchild

et al. 2008

Cancer Chemother Pharmacol

106

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The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.

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“…In a phase I/II study, 39 patients with relapsed NSCLC received patupilone. The preliminary results indicated a partial response in four patients, and toxicities included asthenia, diarrhea, abdominal pain, fatigue, and nausea (Table 3) [50]. Ixabepilone (BMS-247550), an epothilone B, was reported in a phase II trial to give a partial response of 12% (Table 2) [51].…”

Section: Epothilonesmentioning

confidence: 99%

Second- and third-line treatments in non-small cell lung cancer

Kumar¹,

Wakelee²

2006

Curr. Treat. Options in Oncol.

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Slow but steady progress has been made in the treatment of advanced non-small cell lung cancer. For first-line therapy, multiple chemotherapy combination therapies can extend survival and improve quality of life. And recently, for the first time ever, a noncytotoxic agent, the antivascular endothelial growth factor antibody bevacizumab, has been shown to improve survival when added to chemotherapy. Striking improvements have also been made in second-line treatment. In August 2004, only one agent was US Food and Drug Administration (FDA) approved in this setting, docetaxel, but by the beginning of 2005, two more were available, pemetrexed and erlotinib. All three of these drugs can significantly benefit patients, with 1-year survival in excess of 30%. Choosing between the three agents can be challenging, and this review focuses on the toxicity differences and predictors of response that can help guide this decision. Docetaxel and pemetrexed, both traditional intravenous cytotoxins, are excellent options for patients who have shown some response to first-line chemotherapy, but at this time, no other means exist to determine likelihood of response. When choosing between the two, pemetrexed causes significantly less neutropenia than does docetaxel, at least on the standard every-3-week regimen. With erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, there are factors that can predict for response, including little or no smoking history, and adenocarcinoma histology. Therefore, patients who fit these characteristics are good candidates for second-line erlotinib. However, the relationship between response to erlotinib and improved survival remains unclear, and several laboratory analyses that may help further, such as evaluation of EGFR gene copy number, are still under development. Although erlotinib is the only FDA-approved option currently available for third-line therapy, many patients with good performance status may benefit from third-line therapy and beyond. In addition to the approved second-line options, other single-agent chemotherapies to consider for treatment beyond second-line are gemcitabine, irinotecan, and oral topotecan. Many new drugs, including bevacizumab, ZD6474 (AstraZeneca, Wilmington, DE), sorafenib, cetuximab, paclitaxel poliglumex, epothilones, and others, alone or in combination with traditional agents, are currently undergoing investigation and hold great promise.

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Phase I/II dose escalation trial of patupilone every 3 weeks in patients with non-small cell lung cancer

Cited by 12 publications

References 0 publications

Peripheral Neuropathy with Microtubule-Targeting Agents: Occurrence and Management Approach

Peripheral Neuropathy with Microtubule-Targeting Agents: Occurrence and Management Approach

Preclinical discovery of ixabepilone, a highly active antineoplastic agent

Second- and third-line treatments in non-small cell lung cancer

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