| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10076506 | | E.1.2 | Term | Castration-resistant prostate cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the efficacy of Lutetium (177Lu) rhPSMA-10.1 injection | |
| E.2.2 | Secondary objectives of the trial | To evaluate the efficacy of Lutetium (177Lu) rhPSMA-10.1 injection.
To further evaluate the safety profile of Lutetium (177Lu) rhPSMA-10.1 injection using the dosing regimen (RP2D) recommended by the Phase 1 results.
To further characterise the whole-body distribution and dosimetry of Lutetium (177Lu) rhPSMA-10.1 injection.
To describe the influence of Lutetium (177Lu) rhPSMA-10.1 injection on the health-related quality of life of treated subjects. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Male subjects, 18 years of age or older.
2. Willing to provide signed and dated written informed consent form (ICF) prior to any study-specific procedures.
3. Willing to comply with required lifestyle restrictions following administration of the IMP per local regulations.
4. Histologically confirmed adenocarcinoma of the prostate.
5. Serum testosterone levels <50 ng/dL (1.73 nmol/L) after surgical or continued chemical castration.
6. Meets respective cohort-specific inclusion criterion for Phase 2 only.
7. Presence of disease target or non-target lesions (per RECIST v1.1) on CT/MRI and/or full body 99mTc bone scan performed within 28 days of screening.
8. Positive disease expression of PSMA as confirmed on rhPSMA-7.3 (18F) PET/CT scan. Note: For Phase 1, LOCAMETZ® or a positive PSMA PET/CT scan which has already been obtained within 4 weeks (28 days) prior to screening may be used for subject selection in Phase 1.
Note: Positive disease is defined as having at least 1 PSMA-positive lesion of any size with higher uptake than normal liver using visual assessment. The lesion can be bone, lymph node or viscera. At least one PSMA-positive lesion should be visible on the CT/MRI and ≥1.5 cm in the short axis (Phase 1 only). Further details regarding the interpretation of the diagnostic images can be found in the Image Acquisition Guidelines.
9. At least 28 days or 5 half-lives (whichever is longer) elapsed between last anti-cancer treatment administration and the initiation of study treatment (except for Luteinising Hormone-releasing Hormone or GnRH).
10. Resolution of all previous treatment-related toxicities to CTCAE version 5.0 grade of ≤1 (except for chemotherapy-induced alopecia and grade 2 peripheral neuropathy or grade 2 urinary frequency which are allowed).
11. Prior major surgery must be at least 12 weeks prior to study entry.
12. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with a life expectancy ≥6 months.
13. Adequate bone marrow reserve and organ function as demonstrated by blood count, and serum biochemistry at baseline:
− Platelet count ≥ 150 × 109/L
− WBC count ≥ 3.0 × 109/L
− Neutrophil count of ≥ 1.5 × 109/L
− Haemoglobin ≥ 10 g/dL
− Estimated glomerular filtration rate (using Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation [2009]) (Levey 2009) ≥60 mL/min
− Total bilirubin <1.5× ULN (except if confirmed history of Gilbert's disease)
− Serum albumin ≥30 g/L
− AST <2× the ULN
− ALT <2× the ULN
14. Male subjects must not father children or donate sperm during the study and for at least 6 months after the last study treatment. In addition, they must agree to use effective contraception for this same period to protect partners from any exposure to the IMP. For males with partners who are of childbearing potential, effective contraception is a combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods). A man is only considered to be infertile if he has had bilateral orchidectomy or successful vasectomy with laboratory confirmed aspermia.
15. Cohort-specific inclusion criteria:
a) Phase 1 and Phase 2 mCRPC: Subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide), and at least 1 course (but no more than 2 courses) of taxane-based chemotherapy.
b) Phase 2 mCRPC: Subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide), but have not received previous taxane-based chemotherapy. | |
| E.4 | Principal exclusion criteria | 1. Known hypersensitivity to the therapeutic or diagnostic IMP or any of its constituents.
2. Presence of PSMA-negative disease: PSMA-negative disease defined as any large PSMA-negative lymph node >1 cm in the short axis and/or a PSMA-negative bone metastasis which has a significant soft tissue component suggesting ongoing disease activity and/or a PSMA-negative solid organ metastasis >1 cm in the long axis. In addition, subjects with significant low PSMA-expressing disease should be excluded. Further details are provided in the Image Acquisition Guidelines.
3. Diffuse marrow infiltration of disease (‘superscan’ appearance on full body 99mTc bone scan). A superscan is defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake in relation to soft tissues along with absent or faint activity in the genitourinary tract and soft tissues due to diffuse bone/bone marrow metastases. Further details regarding this appearance are provided in the Image Acquisition Guidelines.
4. Symptomatic spinal cord compression, or clinical or radiological findings that are indicative of impending spinal cord compression.
5. Known history of haematological malignancy.
6. Known history of central nervous system (CNS) metastases.
Exception: Subjects with a history of CNS metastases who have received and completed therapy (e.g. surgery, radiotherapy), and are neurologically stable, asymptomatic and do not require corticosteroids or anti-convulsants to control neurological symptoms will be eligible. Discrete dural metastases are permitted but diffuse leptomeningeal disease is not. For subjects with a history of CNS metastases, baseline imaging and subsequent radiological imaging for assessing treatment response must include MRI or ceCT evaluation of the brain.
7. Histological findings consistent with neuroendocrine phenotype of prostate cancer.
8. Known history of other solid malignancy that may reduce life expectancy and/or may interfere with disease assessment.
Exception: Subjects with histopathologically confirmed prior malignancy that has been treated, and who have been disease-free for >3 years. Subjects with treated non-melanoma skin cancer and non-muscle invasive bladder cancer will be eligible.
9. Unresolved urinary tract obstruction defined as radiographic evidence of hydronephrosis with or without ureteric stent/nephrostomy. Where the clinical team judges that the subject’s hydronephrosis is not obstructing, and renal function meets the inclusion criteria, the subject may undergo 99mTc mercaptoacetyltriglycerine scanning during the screening period and if the result is non-obstructed, the subject can be eligible for the study.
10. Any uncontrolled significant medical, psychiatric, or surgical condition or laboratory finding that would pose a risk to subject safety or interfere with study participation or interpretation of individual subject results. For cardiac conditions, this includes, but is not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, and myocardial infarction diagnosed within 6 months prior to enrolment.
11. Ongoing treatment with bisphosphonates for bone-targeted therapy.
Exception: Subjects will be eligible if they have received a stable dose of zoledronic acid for at least 8 weeks prior to enrolment. These subjects must have had renal function monitored since initiation of bisphosphonate therapy, with a stable pattern observed, and must have an eGFR ≥ 60 mL/min.
12. Severe urinary incontinence that would preclude safe disposal of radioactive urine.
13. Single kidney or renal transplant or any concomitant nephrotoxic therapy that might put the subject at high risk of renal toxicity during the study in the judgement of the investigator.
14. Clinically significant abnormalities on a single 12-lead electrocardiogram (ECG) at screening.
15. Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidneys.
16. Sponsor employees or investigator site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
17. Previous treatment with any of the following: PSMA-targeted radionuclide therapy, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation.
18. Subjects with bilateral hip replacements or any significant metallic implants or objects, which may in the opinion of the investigator, affect image quality and/or dosimetry calculations.
19. Transfusion of blood products for the sole purpose of meeting the eligibility criteria for this clinical study.
20. Participation in other studies involving IMP(s) within 28 days or 5 half-lives (whichever is longer) prior to study entry and/or during study participation. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Number of subjects with an anti-tumour response defined as ≥50% reduction in PSA level from baseline and at any time during the treatment period of the study which is defined as 6 weeks after the final cycle of therapeutic IMP is received. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | at 12 weekly intervals throughout the study | |
| E.5.2 | Secondary end point(s) | • Number of subjects with ≥50% reduction in PSA level from baseline at 12 weeks after first therapeutic IMP administration.
• PSA Progression-free survival: Time interval from first therapeutic IMP administration to PSA progression as defined by PCWG3 criteria.
• Number of subjects who remain PSA progression-free at fixed 6-month intervals throughout the study.
• Duration of response as defined by time interval from achieving a ≥50% reduction in PSA compared to baseline and the PSA returning to baseline or evidence of radiological progression, as defined by PCWG3.
• Radiographic PFS (rPFS): Time interval from first therapeutic IMP administration to the date when the first site of disease is found to progress radiographically, or death, whichever occurs first, as defined by PCWG3.
• Number of subjects who remain radiographic progression-free at fixed 6-month intervals throughout the study.
• Number of subjects with confirmed CR or PR based on PCWG3-recommended application of RECIST v1.1.
• Evaluation of PSMA PET/CT defined disease response after 2 treatment cycles.
• Overall survival at fixed 6-month intervals throughout the study.
• Frequency and nature of TEAEs.
• Specific absorbed dose to the tumour lesions (Gy/GBq), specific absorbed dose per organ (Gy/GBq).
• Changes in patient-reported outcomes (PROs) assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-PR25, Functional Assessment of Chronic Illness Therapy (FACT-P), EORTC QLQ-C30, European Quality of Life Five Dimension (EQ-5D), and specific domains of the PRO-Common Terminology Criteria for Adverse Events (CTCAE) relating to salivary gland assessment. PROs will be measured from baseline up to the end of treatment.
• Time to PSA Progression: Time interval from first cycle of therapeutic IMP administration to PSA progression as defined by PCWG3 criteria.
• Time to Radiographic Progression: Time interval from first therapeutic IMP administration to the date when the first site of disease is found to
progress radiographically as defined by PCWG3. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | as per the timepoints specified in the respective end point and per appendix 1 Study Schedule in the study protocol | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | United States | | Belgium | | France | | Germany | | Netherlands | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | When the last subject in the Phase 2 portion of the study has completed the 6-week follow-up period after their final cycle | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
