Since the beginning of INTACT, significant progress has been made. Desferal (Df)-CriPec® docetaxel labelled with 89Zr and 91Zr (91Zr for analysis and characterisation as radioactive 89Zr cannot be analysed at Cristal Therapeutics) has been successfully manufactured at small scale in very close collaboration between CT and VUMC. The 91Zr-Df-CriPec® docetaxel was shown to have equal pharmaceutical characteristics to non-labelled CriPec® docetaxel and was compliant with the target SPECs set at the beginning of the project. In other words, the conjugation of Zr to the surface of CriPec® does not affect the characteristics of the CriPec® docetaxel particles.
In vivo and ex vivo quantification of 89Zr-Df-CriPec® docetaxel in healthy and tumour bearing SCID mice was performed. In both healthy and tumour bearing mice, the PK profile was comparable to that of CriPec® docetaxel, thus that 89Zr labelling did not affect the biological profile (i.e. so-called bioequivalence). Accumulation of 89Zr-Df-CriPec® docetaxel in tissue could successfully be measured via PET scan, including enhanced tumour accumulation thus providing the preclinical proof of concept.
Based on all promising formulation development and preclinical evaluations, Df-CriPec® docetaxel has successfully been manufactured under GMP conditions at clinical scale compliant with all predetermined SPECs.
For the phase I clinical protocol and all correlated documents were compiled and submitted to the regulatory authorities. The phase I study (Piccolo) received approval and 7 patients were included in the clinical evaluation including PET/CT imaging. Proof of principle of the non-invasive imaging approach has been clearly achieved with long circulation, imaging up to 168 hours after injection and non-invasive quantitative accumulation of 89Zr-Df-CriPec® being observed in in a large fraction of tumours. Meanwhile, several evaluable tumours did not show uptake, which again proves the heterogeneity within or amongst patients and illustrating the need for patient stratification.
At this time, the CINOVA phase II trial has been completed confirming the improved safety profile of CriPec® docetaxel but unfortunately, despite promising early signals, the efficacy endpoint was not met in this patient population. Along with the project preparations were made for the confirmatory phase III trial in metastatic castration resistant prostate cancer including advice from regulatory agencies in Europe and the US. Cristal Therapeutics extensively approached many potential industry partners to license the programme ahead of the start of the phase III trial. However, due to the lack of efficacy data from the phase II CINOVA trial it has not yet been possible to close a deal.
