Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

• Published in: British journal of cancer Vol. 112; no. 10; pp. 1636 - 1643
• Main Authors: Sarduy, M R, García, I, Coca, M A, Perera, A, Torres, L A, Valenzuela, C M, Baladrón, I, Solares, M, Reyes, V, Hernández, I, Perera, Y, Martínez, Y M, Molina, L, González, Y M, Ancízar, J A, Prats, A, González, L, Casacó, C A, Acevedo, B E, López-Saura, P A, Alonso, D F, Gómez, R, Perea-Rodríguez, S E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-05-2015; Nature Publishing Group
• Subjects: 631/154/436/108; 692/699/67/1059; 692/699/67/1517/1371; Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cervical cancer; Clinical Study; Double-Blind Method; Down-Regulation - drug effects; Drug Resistance; Epidemiology; Female; Half-Life; Humans; Injections, Intralesional - methods; Middle Aged; Molecular Medicine; Nuclear Proteins - metabolism; Nucleophosmin; Oncology; Peptides, Cyclic - administration & dosage; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - metabolism; tumour uptake; CIGB-300; cervical cancer; B23/nucleophosmin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.137

Background:
We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose.
Methods:
Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using
99
Tc-radiolabelled peptide.
In situ
B23/nucleophosmin was determined by immunohistochemistry.
Results:
Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1±8.9
vs
31.3±12.9 mg (
P
=0.01). Both, AUC
24h
and biological half-life were also significantly higher using 70 mg of CIGB-300 (
P
<0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (
P
=0.03) in tumour specimens.
Conclusion:
Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.