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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

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Studienbeginn:
Juni 2024

Letztes Update:
02.04.2024

Wirkstoff:
Injection, 161Tb-SibuDAB,1GBq, Injection, 177Lu-PSMA-I&T, 1GBq, Injection, 161Tb-SibuDAB, Dose Escalation

Indikation (Clinical Trials):
Prostatic Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
University Hospital, Basel, Switzerland

Collaborator:
-

Studienleiter

Alin Chirindel, MD
Principal Investigator
University Hospital, Basel, Switzerland

Kontakt

Damian Wild, MD
Kontakt:
Phone: +41 61 328 66 83
E-Mail: damian.wild@usb.ch» Kontaktdaten anzeigen

Alin Chirindel, MD
Kontakt:
Phone: +41 61 328 63 75
E-Mail: alin.chirindel@usb.ch» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University Hospital Basel
4031 Basel
Switzerland» Google-Maps
Ansprechpartner:
Alin Chirindel, MD
Phone: +41 61 328 63 75
E-Mail: alin.chirindel@usb.ch

Guillaume Nicolas, MD
Phone: +41 61 265 47 02
E-Mail: guillaume.nicolas@usb.ch» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Phase Ia: Tumour absorbed dose (Time Frame - 3, 24, 48 and 168 hours after each injection):
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.

2. Phase Ib: Identification of the optimal biological dose of 161Tb-SibuDAB for mCRPC RLT (Time Frame - baseline and 1 week, 2 weeks and 4 weeks after each injection. Long term: 6 and 12 months after 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.

Secondary outcome:

1. Phase Ia: Estimation of critical organ median absorbed doses (Time Frame - 3, 24, 48 and 168 hours after each injection):
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.

2. Phase Ia: Estimation of the median tumour-to-critical organ absorbed dose ratios (Time Frame - 3, 24, 48 and 168 hours after each injection):
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.

3. Phase Ib: Cumulative median tumour and organ absorbed doses after 4 cycles of 161Tb-SibuDAB RLT (Time Frame - 3, 24, 48 and 168 hours after each injection):
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).

4. Phase Ib: Estimation of the "therapy index" for 161Tb-SibuDAB RLT. (Time Frame - 3, 24, 48 and 168 hours after each injection):
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.

Studien-Arme

Active Comparator: Cross-Over Group A
Cross-over design (n=10, random allocation at a 1:1 ratio). Event order: Injection of 1 GBq of 161Tb-SibuDAB, 3 weeks washout period, Injection of 1GBq of 177Lu-PSMA-I&T
Active Comparator: Cross-Over Group B
Cross-over design (n=10, random allocation at a 1:1 ratio). Event order: Injection of 1 GBq of 177Lu-PSMA-I&T, 3 weeks washout period, Injection of 1GBq of 161Tb-SibuDAB
Experimental: Dose Escalation Study
Arm composed of 5 patient cohorts each with 3-patients. Treatment consists of 4 cycles of 161Tb-SibuDAB based on the available MTD and DLT findings. Safety and efficacy evaluation performed after each therapy cycle.

Geprüfte Regime

Injection, 161Tb-SibuDAB,1GBq:
Intravenous injection via peripheral venous catheter of ~1GBq 161Tb-SibuDAB (~200 μg / ~125 nM) in saline
Injection, 177Lu-PSMA-I&T, 1GBq:
Intravenous injection via peripheral venous catheter of ~1GBq 161Tb-SibuDAB (~100 μg / ~65 nM) in saline
Injection, 161Tb-SibuDAB, Dose Escalation:
Intravenous 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.

Quelle: ClinicalTrials.gov

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