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.
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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
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
Crossover
Injection, 161Tb-SibuDAB,1GBq
DrugIntravenous injection via peripheral venous catheter of \~1GBq 161Tb-SibuDAB (\~200 μg / \~125 nM) in saline
Injection, 177Lu-PSMA-I&T, 1GBq
DrugIntravenous injection via peripheral venous catheter of \~1GBq 161Tb-SibuDAB (\~100 μg / \~65 nM) in saline
Injection, 161Tb-SibuDAB, Dose Escalation
DrugIntravenous injection via peripheral venous catheter of 161Tb-SibuDAB in saline. The intervention comprises 4 cycles at 6-week intervals. The 161Tb-SibuDAB entry activity will be calculated based on dosimetry and toxicity data from the first 3 patients in Phase Ia of the study. The escalated or de-escalated 161Tb-SibuDAB activity for the subsequent 3-patient cohorts will be determined based on the clinical and biochemical safety information and on organ dosimetry results of the entry/previous cohort. Up to 4 escalation or de-escalation steps will be performed.
Phase Ia: Tumour absorbed dose
Comparison of median tumour absorbed dose, in Gy, after sequential injections of non-therapeutic test activity of 161Tb-SibuDAB and 177Lu-PSMA I\&T in the same patients. Tumour absorbed dose is obtained by SPECT/CT of head, thorax, abdomen and pelvis and represents the time integrated tumour activity (3 tumours per patient). To avoid carry-over effects, a period of at least 21 days will be allowed between the two consecutive test injections.
Phase Ib: Identification of the optimal biological dose of 161Tb-SibuDAB for mCRPC RLT
Identification of the optimal biological dose of 161Tb-SibuDAB, in GBq, for mCRPC RLT. The optimal maximum tolerated dose / biological dose will be the highest 161Tb-SibuDAB injected activity which elicits a clinically relevant adverse event grade G3 (according to CTCAE 5.0, ranging from G1 to G5 where G1 corresponds to mild AE and and G5 corresponds to AE related death) in maximal 1 patient per cohort / 1 patient in two cohorts.
Phase Ia: Estimation of critical organ median absorbed doses
Estimation of critical organ (bone marrow, kidney, salivary gland) median absorbed doses after injection of a non-therapeutic test activity of 161Tb-SibuDAB and 177Lu-PSMA I\&T in the same patients. Critical organ absorbed dose is obtained by SPECT/CT of head, thorax, abdomen and pelvis and represents the time integrated tumour activity (3 tumours per patient). Blood samples are collected at each timepoint to enable bone marrow dosimetry.
Phase Ia: Estimation of the median tumour-to-critical organ absorbed dose ratios
Estimation of the median tumour-to-critical organ absorbed dose ratios after test activity injections of 161Tb-SibuDAB and 177Lu-PSMA-I\&T in same patient. The potential therapeutic index will be calculated by take the simple ratio between the median tumour doses (Outcome 1) and the corresponding critical organ doses (Outcome 3) in each patient.
Phase Ib: Cumulative median tumour and organ absorbed doses after 4 cycles of 161Tb-SibuDAB RLT
The median cumulative tumour absorbed dose will represent the 4-cycle summation of the median tumour absorbed dose after receiving the therapeutic injected activity of 161Tb-SibuDAB. This will be normalized to the injected activity (expressed as Gy/GBq).
Phase Ib: Estimation of the "therapy index" for 161Tb-SibuDAB RLT.
Simple radios will be calculated between the cumulative median tumour absorbed dose and the cumulative median doses of different critical organs following completion of 161Tb-SibuDAB RLT. The "therapy index" will be identified as the lowest value for the calculated ratios.
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