A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors

Fury, Matthew G.; Solit, David B.; Su, Yungpo Bernard; Rosen, Neal; Sirotnak, Francis M.; Smith, Robert P.; Azzoli, Christopher G.; Gomez, Jorge; Miller, Vincent A.; Kris, Mark G.; Pizzo, Barbara; Henry, R.; Pfister, David G.; Rizvi, Naiyer A.

doi:10.1007/s00280-006-0286-6

Cited by 51 publications

(28 citation statements)

References 29 publications

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“…The observed incidence of grade 3/4 neutropenia (22.6% grade 3, 45.2% grade 4) and febrile neutropenia (19.4%) was higher than would be expected with docetaxel alone, which confirmed the already acknowledged difficulty of combining ErbB family TKIs with docetaxel [25,[32][33][34]. In one Phase I trial of docetaxel and lapatinib, the protocol was amended to include the growth factor pegfilgrastim at all cycles, as frequent DLTs of grade 4 neutropenia were observed at a docetaxel dose of 50 mg/m² [34].…”

Section: Discussionsupporting

confidence: 79%

“…In one Phase I trial of docetaxel and lapatinib, the protocol was amended to include the growth factor pegfilgrastim at all cycles, as frequent DLTs of grade 4 neutropenia were observed at a docetaxel dose of 50 mg/m² [34]. Following the addition of pegfilgrastim, no dose-limiting neutropenia was observed with lapatinib doses in the range of 1250 to 1500 mg/day, combined with 60 to 75 mg/ m 2 docetaxel [32].…”

Section: Discussionmentioning

confidence: 98%

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Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

et al. 2013

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 98%

Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

et al. 2013

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“…There were no complete or partial responses in the 25 evaluable patients, although eight had tumor reduction that did not qualify as partial response. One patient with anaplastic carcinoma had stable disease beyond 12 months of therapy, similar to that reported in a phase I trial of gefitinib and docetaxel (60). Overall, median progression-free survival was just less than 4 months and less than 3 months in the MTC cohort.…”

Section: Gefitinibsupporting

confidence: 58%

Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers

Sherman

2009

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes.Evidence Acquisition: The PubMed and Google Scholar search engines were used to identify publications and peer-reviewed meeting presentations addressing chemotherapy and targeted therapy for differentiated or medullary carcinoma.Evidence Synthesis: Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. thyroid carcinomas have limited effectiveness, with response rates typically 25% or less (1). With such poor outcomes, results from few clinical trials of new therapies for thyroid carcinomas were published during the latter half of the 20th century (2). Plaguing these early trials was the practice of lumping patients with all histologies of thyroid carcinoma (differentiated, medullary, and anaplastic), confounding interpretation of the results. The definitions of response used in these earlier studies varied as well, and none are comparable with the currently used standard RECIST methodology [for detailed description of RECIST, see Refs. 3, 4). Thus, treatment with cytotoxic chemotherapy is generally limited to patients with symptomatic or rapidly progressive metastatic disease unresponsive to or unsuitable for surgery, radioiodine (for tumors derived from differentiated carcinomas), and external beam radiotherapy. ConclusionDuring the past decade, biological discoveries sparked trials testing novel therapies for advanced thyroid carcinomas. Of prime importance has been recognition of key oncogenic mutations in papillary (PTC) and medullary (MTC) carcinomas. BRAF and RAS genes code for kinases that activate signaling through the MAPK pathway, regulating growth and function in many cells both normal and neoplastic. Evidence from various tumor models support the contention that most PTCs arise as a result of single activating somatic mutations in one of three genes: BRAF, RAS, and translocations producing RET/PTC oncogenes (5). The resultant RET/PTC proteins signal upstream from RAS, thus activating the same MAPK pathway. For MTC,

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“…Aufgrund von auch in Schilddrüsenkarzinomen vorhandenen EGFR-Mutationen setzt man dieses Medikament auch in Phase-II-Studien bei differenzierten und medullären fortgeschrittenen Schilddrüsenkarzinomen ein. Die Ansprechrate (medianes progressionsfreies Überleben unter 4 Monate) bei unselektierten Patienten [8] ist jedoch gering. Bemerkenswert ist ein Fallbericht über die Gabe des EGFR-Inhibitors bei einer Patientin, bei der ein anaplastisches Schilddrüsenkarzinom auf 2 Punktmutationen der EGFR-Kinase zurückgeführt werden konnte und klinisch sowie radiologisch ein gutes Ansprechen zeigte.…”

Section: Gefitinibunclassified

Stellenwert neuer Behandlungsansätze mit Targettherapeutika bei malignen Schilddrüsenerkrankungen

Uecker

Laban²,

Knecht³

2012

HNO

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Increasing interest in the treatment of locally advanced and already metastasized thyroid cancer is reflected in the high number of submitted and accepted conference papers at the annual meeting of the American Society of Clinical Oncology (ASCO Congress) 2011. Many patients suffering from differentiated, undifferentiated and medullary thyroid cancer do not respond to established therapeutic procedures, so that new strategies have to be developed. Targeted biological agents are a new and promising therapeutic method that selectively affects complex signaling cascades, especially angiogenesis, of the malignant cells. Clinicians and researchers should understand the potential of these therapeutic strategies and be aware of the typical side effects.

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A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors

Abstract: The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.

Cited by 51 publications

References 29 publications

Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers

Stellenwert neuer Behandlungsansätze mit Targettherapeutika bei malignen Schilddrüsenerkrankungen

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