Phase II study of danusertib (D) in advanced/metastatic non-small cell lung cancers (NSCLC)

Autor:	Armando Santoro, M. G. Jannuzzo, Cristina Davite, Silvia Novello, Ahmad Awada, Jean-Pierre Delord, Wilfried Eberhardt, Maja J.A. de Jonge, Maurizio Nicodemo, Thomas Gauler, Paolo Marchetti, Anna Petroccione, Mariangela Mariani, Pierfranco Conte, Benjamin Besse, Egbert F. Smit, Roberta Ceruti, Carlo Barone, Elizabeth Ruth Plummer
Rok vydání:	2013
Předmět:	Cancer Research Pathology medicine.medical_specialty ABL Lung business.industry Kinase Medizin Phases of clinical research Tropomyosin receptor kinase A Atp competitive stomatognathic diseases medicine.anatomical_structure Oncology Cancer research Medicine Danusertib Non small cell business
Zdroj:	Publons ResearcherID
ISSN:	1527-7755 0732-183X
DOI:	10.1200/jco.2013.31.15_suppl.e19138
Popis:	e19138 Background: D is an ATP competitive pan-aurora kinases inhibitor with activity also against FGFRs, VEGFR, Ret, TrkA, Scr, and Abl. Methods: Eligible pts had NSCLC progressing for advanced/metastatic disease after 1 prior chemotherapy line (CT). Primary endpoint was progression-free survival at 4 months (PFS-4) evaluated in a Simon two-stage design. Number of successes required for not rejecting the alternative hypothesis (40% PFS-4) was ≥4/19 evaluable pts while the number of successes required to reject at the end of stage 2 the null hypothesis (20% PFS-4) was ≥11/36 (α 1-sided = 0.1). D was administered at 500 mg/m² as 24 hr IV infusion q2w. The expression of Aurora A/B, TPX-2, MDR, Scr, Survivin by IHC and the amplification of FGFR1 by FISH on tumor biopsies of consenting pts were evaluated. Results: 3 out of 19 evaluable pts were PFS-4 at the end of the 1st stage, thus precluding passage to the 2nd stage. Interestingly, in pts with squamous (SCC) (n=7), median PFS and OS were 6.4 and 10.6 mos respectively (vs. 2.2 and 7.6 mos, in non-SCC pts), suggesting a possible specific effect in this subtype. Additional pts with SCC were therefore treated under a protocol amendment. At the end of this 2nd stage, 5/31 evaluable SCC pts (80% CI: 0.08-0.28) were PFS-4 indicating that the predefined threshold required to conclude for activity would not have been reached. Overall 56 pts, all histology NSCLC, were treated: median age 62 yrs (39-79), 64% male, 70% SCC, 36% with >1 prior CT. Best response was a PR in 1 pt and SD in 20 pts; median PFS and OS were 2.1 and 8.3 mos respectively. The most frequent drug-related AEs (any Grade, ≥20%) were: uncomplicated and short lasting neutropenia (94%), nausea (39%), fatigue (37%), asthenia (30%), anorexia and diarrhea (29%), alopecia (23%). Histological analyses by IHC and FISH is still ongoing: results will be presented. Conclusions: Limited evidence of activity was observed, insufficient to meet the predefined threshold to call efficacy in NSCLC when D was administered as monotherapy at this dose/schedule. D confirmed to have a manageable safety profile. Clinical trial information: 2006-003772-35.
Databáze:	OpenAIRE
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