Targeted Radionuclide Therapy in Metastatic Prostate Cancer Using a New PSMA Ligand Radiolabelled With Terbium-161 (161Tb-SibuDAB) - Dose Identification/Escalation Phase Ia/b Study

Researchers will test a new treatment for prostate cancer. This treatment uses an antibody tagged with a small amount of radioactive material. Researchers believe the new antibody might work better than those used before.

In the first part of the study researchers will compare the new treatment to the old one on prostate cancer patients using very low doses, not strong enough to treat nor to cause strong adverse reactions. Each patient will eventually receive both treatments, but one at a time.

The aim of the second part of the study is to find the best dose of the new treatment for patients. This means finding the dose that offers the most benefits with the fewest side effects.

The performance of different prostate cancer diagnostic methods is also in scope of the study.

Radioligand therapy (RLT) has emerged as an effective treatment of metastatic, castration resistant prostate cancer (mCRPC) for those patients having, prostate-specific membrane antigen (PSMA)-positive disease. This led to the FDA approval of 177Lu-PSMA-617 (PluvictoTM), a PSMA ligand radiolabelled with the β--particle emitter lutetium-177(177Lu). Despite the success of this treatment modality, the therapeutic response after RLT with 177Lu-based PSMA radioligands is limited and disease relapse inevitable. In addition, approximately 1/3 of the patients does not respond to 177Lu-based RLT despite PSMA-positive mCRPC.

It has been hypothesized that the insufficient absorbed dose delivery to macroscopic tumours and, in particular, to microscopic metastases with currently used 177Lu-based PSMA radioligands is the reason for the treatment failure in these patients. SibuDAB, a novel long-circulating PSMA ligand, was successfully tested in the preclinical setting in combination with terbium-161 (161Tb) that emits not only β--particles but also conversion and Auger electrons and, hence, delivers 2-4 times higher absorbed doses to microscopic tumours than 177Lu.

The researchers, therefore, propose to enhance the efficacy of PSMA-targeting RLT by using the long-circulating ligand (SibuDAB) labelled with 161Tb. The researchers expect 161Tb-SibuDAB to exhibit increased and/or prolonged tumour uptake with a higher deposition of energy (due to short ranged Auger electrons) resulting in a high linear energy transfer (LET) and, hence, relative biological effectiveness. 161Tb-SibuDAB should not only deliver the absorbed dose to the cellular nucleus (via β-- radiation) but also to the cell membrane and organelles (through the emission of conversion and Auger electrons) which, in mathematical models, leads to a 3-4-fold increased absorbed dose to single cancer cells compared to standard RLT.

Eligibility Criteria:
Inclusion Criteria:

* Consent form signed
* Male patients with age \> 18 years
* Clinical indication for RLT with 177Lu-PSMA-I\&T (progressive PSMA-positive mCRPC patients after androgen receptor signalling pathway inhibitor and taxan-based chemotherapy or patient unfit for chemotherapy)
* Patients will be included in Phase Ia while being under active therapy with 177Lu-PSMA-I\&T (SoC) and after they have completed the first two cycles of 177Lu-PSMA-I\&T RLT
* At least 3 measurable tumours on PSMA PET/CT (\>1.5 cm) with sufficiently intense PSMA uptake (SUVmax\>20)
* ECOG Performance status: 0-1
* Blood parameters: a) Leucocytes ≥ 3 G/L; b) Haemoglobin ≥ 100 g/L; c) Thrombocytes ≥ 100 G/L
* Estimated glomerular filtration rate (eGFR) \> 45 ml/min
* Albumin \> 25 g/L
* ALT, AST, AP: ≤ 5 times upper standard value
* Bilirubin ≤ 2 times upper standard value
* For male patients who are not surgically sterilized (orchiectomy or vasectomy), appropriate contraceptive measures must be taken during RLT and until 4 months after completion of RLT. As acceptable contraceptive count sexual abstinence or double contraceptive methods: hormonal contraceptive (oral, transdermal, implants or injections) in combination with barrier methods (spiral, condom, diaphragm)

Exclusion Criteria:

* Prior PSMA-targeted RLT (except for the 2 first cycles in Part Ia)
* PSMA-negative (or PSMA-negative / FDG-positive) disease
* Known intolerance against DOTA, DOTAGA, urea-based analogues or against any of the components/formulation of 177Lu-PSMA-I\&T or 161Tb-SibuDAB solutions.
* Ongoing infection at the screening visit or a serious infection in the past 4 weeks
* Administration of another investigational product in the last 60 days before Visit 1 Day 1
* Prior or planed administration of a therapeutic radiopharmaceutical during 8 half-lives of the used radio-pharmaceutical's radionuclide, also during the ongoing study
* Any extensive radiotherapy involving bone marrow over the last 3 months before inclusion to the study
* Chemotherapy in the last 4 weeks before inclusion
* Any uncontrolled significant medical, psychiatric or surgical condition (active infection, unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension, poorly controlled diabetes mellitus \[HbA1c ≥ 9%\], uncontrolled congestive heart disease, etc.) or laboratory findings that might jeopardize the patient's safety or that would limit compliance with the objectives and assessments of the study. Any mental conditions which prevent the patient from understanding the type, extent and possible consequences of the study and/or an uncooperative attitude from the patient.
* Current history of any malignancy other than prostate cancer within 5 years of enrolment except for fully resected non-melanoma skin cancer