scholarly journals Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer

2011 ◽  
Vol 29 (19) ◽  
pp. 2660-2666 ◽  
Author(s):  
Razelle Kurzrock ◽  
Steven I. Sherman ◽  
Douglas W. Ball ◽  
Arlene A. Forastiere ◽  
Roger B. Cohen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Benefit ◽  
Medullary Thyroid Cancer ◽  
Phase Iii ◽  
End Points ◽  
Medullary Thyroid ◽  
Measurable Disease

PurposeXL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.Patients and MethodsA phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.ResultsEighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.ConclusionCabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing ( ClinicalTrials.gov number NCT00215605).

scholarly journals A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Aaron S. Mansfield ◽  
David S. Hong ◽  
Christine L. Hann ◽  
Anna F. Farago ◽  
Himisha Beltran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Medullary Thyroid Cancer ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Medullary Thyroid ◽  
Neuroendocrine Prostate Cancer ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Neuroendocrine Carcinomas

AbstractDelta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

scholarly journals Cabozantinib in Progressive Medullary Thyroid Cancer

2013 ◽  
Vol 31 (29) ◽  
pp. 3639-3646 ◽  
Author(s):  
Rossella Elisei ◽  
Martin J. Schlumberger ◽  
Stefan P. Müller ◽  
Patrick Schöffski ◽  
Marcia S. Brose ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Adverse Events ◽  
Medullary Thyroid Cancer ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Mutation Status ◽  
Medullary Thyroid ◽  
Ret Mutation

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Phase I trial of combination sorafenib and tipifarnib: The experience in advanced differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC).

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 5586-5586 ◽  
Author(s):  
M. E. Cabanillas ◽  
R. Kurzrock ◽  
S. I. Sherman ◽  
A. M. Tsimberidou ◽  
S. Waguespack ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Differentiated Thyroid Cancer ◽  
Phase I Trial ◽  
Medullary Thyroid Cancer ◽  
Medullary Thyroid

scholarly journals Multikinase Inhibitors for the Treatment of Progressive, Metastatic Medullary Thyroid Cancer – An Evolving Paradigm

2014 ◽  
Vol 10 (2) ◽  
pp. 145
Author(s):  
Barbara Jarzab ◽  
Jolanta Krajewska ◽  
◽  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Medullary Thyroid ◽  
Modes Of Action ◽  
Phase Iii Trials ◽  
Endothelial Growth Factor

Medullary thyroid cancer (MTC) is an uncommon type of thyroid cancer, representing around 4 % of the all thyroid cancers, and is a challenging malignancy. So far, surgery has been the only curative treatment and until recently there have been no effective medications. Within the past 5 years, multi-targeted kinase inhibitors have emerged that have shown convincing efficacy against such tumours. These drugs have changed the landscape in MTC treatment by providing effective medication for the first time. The modes of action of these drugs differ, but most target RET, a tyrosine kinase shown to play an important role in the pathobiology of MTC, as well as other receptors including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor MET. Two agents in this class, vandetanib and cabozantinib, have demonstrated efficacy and safety in phase III trials and have consequently received regulatory approval. Other therapies for MTC treatment, including some with similar modes of action, are also in early development.

Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA).

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 5503-5503 ◽  
Author(s):  
S. A. Wells ◽  
B. G. Robinson ◽  
R. F. Gagel ◽  
H. Dralle ◽  
J. A. Fagin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Locally Advanced ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Medullary Thyroid
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