A Novel Theranostic Trial Design Using 64Cu/67Cu with Fully 3D Pre-Treatment Dosimetry

204 Aim: The main purpose of this trial is to study the first-in-man biodistribution and radiation dosimetry estimates for the beta-- & gamma-emitter Copper-67 (67Cu) (t-half=61.8hrs) radiolabelled to Octreotate and comparison with pre-therapeutic positron-emitting Copper-64 (64Cu) Octreotate using identical radiolabelling methodology enabled by a novel chelator MeCOSar. All imaging (PET and gamma camera) is acquired tomographically with accompanying CT without any planar imaging. The primary endpoint of the trial is to evaluate the safety and tolerability of repeated therapeutic doses of [67Cu]Octreotate. A further aim is to evaluate the radiation exposure levels with time after therapy. Methods: Six subjects with inoperable meningiomas that demonstrate high somatostatin receptor expression on [64Cu]Octreotate PET imaging will be recruited to receive up to 4 cycles of [67Cu]Octreotate therapy. An efficacy assessment will be conducted following cycle 2 to determine whether to continue with 2 further cycles of therapy. Copper-64 (t-half=12.7h) MeCOSar-chelated Octreotate is administered intravenously by bolus followed by imaging at 1 hr, 4 and 24 hrs after injection. No amino acid infusion is given for the pre-therapeutic study. Prior to therapy, radiation dose estimates are determined (OLINDA/EXM) from the PET data for a number of organs and to estimate Effective Dose for both 64Cu and by extrapolation for 67Cu. If the 67Cu dose estimates are acceptable, 5-6 GBq of [67Cu]Octreotate in 30 mL is prepared and administered by infusion pump over 30 mins with accompanying amino acid infusion over 2.5 hours, similar to our [177Lu]Octreotate administration protocol. SPECT/CT imaging follows the therapy at 1 hr, 4, 24 & 96 hrs. Results: At the time of submission, a total of 3 pre-treatment scans and 6 therapy doses have been administered to three subjects (3 to subject 1, 2 to subject 2 and 1 to subject 3). The products have been well tolerated and no significant adverse events have been observed. Some low grade adverse events have been mild and hematologic in nature, as expected. Organ doses per therapy cycle estimated from the 64Cu PET study (without amino acid) for the 67Cu therapy have been consistent in liver (approx.1.1 Gy) and bone marrow (0.25-0.4 Gy) whereas the doses to the kidneys (approx.2.5 Gy) and spleen (1.4-7 Gy) are overestimated in the 64Cu study extrapolations by a factor of twofold or higher. Based on a conservative limit of 30 Gy to kidneys or 2 Gy to bone marrow, early results indicate that subjects could receive up to 5-8 cycles of [67Cu]Octreotate in total. No other organs have significant doses recorded. Conclusions: [67Cu]Octreotate appears to be a safe alternative theranostic agent for subjects with somatostatin expressing tumours. The long half-life of the companion diagnostic imaging radionuclide (64Cu) permits pre-therapeutic estimates of dosimetry in a number of organs, bearing in mind the difference with and without the amino acid infusion. This will be particularly valuable when treating paediatric subjects where no reliable dose scaling for age and size exists.