Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer

Schlumberger, Martin; Elisei, Rossella; Bastholt, Lars; Wirth, Lori J.; Martins, Renato; Locati, Laura D.; Jarząb, Barbara; Pacini, Furio; Daumerie, Chantal; Droz, Jean Pierre; Eschenberg, Michael; Sun, Yu; Juan, Todd; Stepan, Daniel E.; Sherman, Steven I.

doi:10.1200/jco.2008.18.7815

Cited by 320 publications

(183 citation statements)

References 33 publications

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“…Clinical development of motesanib was later taken up by Takeda. In phase II studies, the drug showed modest activity in MTC (2% PR, 81% SD) as well as in DTC (14% PR, 67% SD) patients (Sherman et al 2008, Schlumberger et al 2009). Moreover, pharmacokinetic analyses indicated that motesanib trough concentrations were lower in MTC compared to DTC patients.…”

Section: Investigational Drugsmentioning

confidence: 99%

“…Moreover, pharmacokinetic analyses indicated that motesanib trough concentrations were lower in MTC compared to DTC patients. The vast majority of patients (88%) experienced AEs, with a significant proportion (38%) of grade 3 AEs (Schlumberger et al 2009). Currently, motesanib is mostly undergoing clinical evaluation as a VEGFR, PDGFR and c-Kit inhibitor (Raghav & Blumenschein 2011).…”

Section: Investigational Drugsmentioning

confidence: 99%

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Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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Section: Investigational Drugsmentioning

confidence: 99%

Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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“…37 Of 91 patients with progressive or symptomatic MTC who initiated therapy, only 2% had confirmed partial response but another 47% experienced stable disease for at least 24 weeks. 36 Unexpectedly, the maximum and trough plasma concentrations of the drug in MTC patients were lower than reported with other solid tumor patients, and these differing pharmacokinetics may have contributed to the lower response rate. In an analysis of biomarkers, a greater than 5.3-fold increase in concentration of placental growth factor after 3 weeks of therapy was predictive of an increased likelihood of objective response across the two cohorts.…”

Section: Motesanibmentioning

confidence: 90%

“…On the basis of this phase I experience, a multicenter, open-label phase II trial was initiated, testing the efficacy of motesanib in separate cohorts of patients with progressive DTC 35 and patients with progressive or symptomatic MTC, 36 starting at 125 mg daily. The eligibility criterion of progression was based upon serial radiographic imaging studies within the preceding 6 months, applying RECIST response assessment.…”

Section: Motesanibmentioning

confidence: 99%

Targeted therapies for thyroid tumors

Sherman

2011

Modern Pathology

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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. 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 observed. 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. At least one randomized, placebo-controlled phase III trial has been successfully completed, showing improved progression-free survival in patients with advanced or metastatic medullary thyroid carcinoma treated with vandetanib. Randomized trials for other agents are currently underway. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

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“…Motesanib demonstrated activity against metastatic medullary thyroid cancer, with 81% of disease stabilizations [54], and in GIST [55]. In advanced NSCLC patients, motesanib combined with carboplatin/paclitaxel resulted in modest clinical benefit in terms of PFR and ORR, and in increased toxicity leading to study discontinuation in patients with squamous histology [56].…”

Section: Motesanibmentioning

confidence: 99%