Overall, up to 50 subjects will be enrolled to receive an injected activity (IA) of 177Lu-HTK03170. The IA's will be escalated based on personalized dosimetry at subsequent treatments (up to 5 cycles total).
Screening Phase: Subjects will be screened against the inclusion and exclusion criteria. A PSMA PET/CT scan using 68Ga-HTK03149 will be used to confirm PSMA positive disease. Those with confirmed PSMA positive disease with continue to one of the two Treatment Phases. Subjects will be informed which Phase they will be enrolled in.
Subjects will undergo a physical exam, complete a medical history questionnaire, a quality of life questionnaire, blood work, and a diagnostic CT.
Treatment summary per Phase:
The first 3 subjects will receive an initial Initial Acitivity (IA) of 1.1 GBq of 177Lu HTK03170, for the first cycle of treatment, assuming no toxicities occur requiring dose modification. Dosimetry will be performed to obtain absorbed organ dose and effective dose values. The initial IA used for dosimetry will be escalated to improve image quality, radiation dosimetry estimates, and potential efficacy. IA escalation will only occur on the initial dosimetry IA, with an increase of 30% over the initial IA (used for dosimetry) at each subsequent level (1.65 GBq, 2.5 GBq, 3.7 GBq) in up to 12 participants.
IA escalation will cease when a maximum tolerated injected activity (MTIA) is determined or a recommended safe initial IA has been identified based on an integrated assessment of safety, pharmacokinetics (PK), dosimetry, and preliminary antitumour activity data, if available.
Treatment Phase I: During the treatment phase, subjects will undergo up to 5 cycles of treatment. Each treatment cycle will be followed by dosimetry SPECT/CT scans on day 3 (72 +/- 24 hours) after treatment administration, and day 10 (10 days +/- 72 hours) after treatment administration. Additional dosimetry SPECT/CT scans will be completed during Cycle 1, on the day of treatment, and on day 1 (24 hours after treatment). After Cycle 3, a quality of life questionnaire will be completed again.
Treatment Phase II: During the treatment phase, subjects will be treated with an initial IA of 177Lu-HTK03170 at the MTD as determined during Phase I, or 1625 MBq, whichever is lower. Personalized dosimetry will be calculated for each subject as in Phase 1 so that subsequent treatments will be estimated to remain within the absorbed cumulative dose limits of 28Gy and 35Gy for kidneys and salivary glands, respectively, adjusted iteratively over the 3 remaining treatment cycles separated by 8 weeks. Each treatment cycle IA will be further adjusted to ensure a single dose exposure of 2Gy or less to the bone marrow, as needed. Fifteen (15) subjects will be enrolled in the first stage. When 6 or more subjects achieve objective radiographic response based on RECIST v1.1 , the study will proceed to the 2nd stage, where additional 17 subjects will be enrolled to continue efficacy evaluation.
Subjects will undergo up to 5 cycles of treatment. Each treatment cycle will be followed by dosimetry SPECT/CT scans on day 1 (18 - 32 hours after treatment administration) and day 3 (64 - 80h after treatment administration). Additional dosimetry SPECT/CT scans will be completed during Cycle 1, on the day of treatment, and on day 10. A repeat After cycle 5 a quality of life questionnaire will be completed again.
Follow up Phase: At the end of treatment or after discontinuation of any cause, subjects will be followed for 2 years to continue data collection for the other objectives. Objective tumour response will be assessed every 4 months by diagnostic CT according to the RECIST 1.1 criteria. A final quality of life questionnaire will be completed again within 28 days after the last treatment.
