| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate 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 determine the efficacy of 177Lu- PNT2002 versus abiraterone or enzalutamide in delaying radiographic progression in patients with mCRPC who have progressed on ARAT. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy: To assess the radiographic response to 177Lu-PNT2002 versus abiraterone or enzalutamide, the effect of 177 Lu-PNT2002 versus abiraterone or enzalutamide on overall survival in patients who have progressed on ARAT and to determine the effect of 177Lu-PNT2002 versus abiraterone or enzalutamide on developing a symptomatic skeletal-related event, and the effect of 177Lu-PNT2002 versus abiraterone or enzalutamide on PSA kinetics in patients who have progressed on ARAT.
Safety: To evaluate the safety and tolerability of 177Lu-PNT2002 vs abiraterone or enzalutamide.
Exploratory: To evaluate the efficacy of tracer uptake in PSMA-PET for patient selection with 177Lu-PNT2002 therapy, the effect of 177Lu-PNT2002
versus abiraterone or enzalutamide on cancer related pain in patients who have progressed on ARAT and the impact of 177Lu-PNT2002 versus abiraterone or enzalutamide on health related quality of life (HRQoL), the efficacy of 177Lu-PNT2002 versus abiraterone or enzalutamide. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK sub-study (applicable for US/CA only)
Dosimetry sub-study (applicable for US/CA only) |
|
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all of the following criteria apply:
1. Male aged 18 years or older.
2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate.
3. Ineligible or averse to chemotherapeutic treatment options.
4. Patients must have progressive mCRPC at the time of consent based on at least 1 of the following criteria:
a. Serum/plasma PSA progression defined as increase in PSA greater than 25% and >2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart.
b. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or a new lesion.
c. Progression of bone disease: defined as appearance of two or more new lesions by bone scan.
5. Progression on previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or apalutamide) in either the CSPC or CRPC setting.
6. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the sponsor's central reader.
7. Castrate circulating testosterone levels (<1.7 nmol/L or <50 ng/dL).
8. Adequate organ function, independent of transfusion:
a. Bone marrow reserve:
i. White blood cell (WBC) count ≥2.5 × 109/L OR absolute neutrophil count (ANC) ≥1.5 × 109/L.
ii. Platelets ≥100 × 109/L.
iii. Hemoglobin ≥8 g/dL.
b. Liver function:
i. Total bilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with known Gilbert’s syndrome, ≤3 × ULN is permitted.
ii. ALT or AST ≤3.0× ULN.
c. Renal function:
i. Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula. (for patients in France, serum/plasma creatinine ≤1.5 × ULN or CrCl ≥60 mL/min based on Cockcroft-Gault formula).
d. Albumin ≥30 g/L.
9. Human immunodeficiency virus-infected patients who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial.
10. For patients who have partners who are pregnant or of childbearing potential a condom is required along with a highly effective contraceptive method during the study and for 6 months after last study drug administration. Such methods deemed highly effective include
a) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
b) progestogen-only hormonal contraception associated with inhibition of ovulation
c) intrauterine device (IUD), d) intrauterine hormone-releasing system (IUS)
e) bilateral tubal occlusion
f) vasectomy
g) sexual abstinence.
11. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified by investigator, if randomized to Treatment Arm B.
12. ECOG performance status 0 to 1.
13. Willing and able to comply with all study requirements and treatments (including 177Lu-PNT2002) as well as the timing and nature of required assessments.
14. Signed informed consent. |
|
| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria apply:
1. If noted in pathology report, prostate cancer with known significant (>10% present in cells) sarcomatoid or spindle cell or neuroendocrine components. Any small cell component in the cancer should result in exclusion.
2. Prior treatment for prostate cancer ≤28 days prior to randomization, with the exclusion of first line local external beam, ARAT, luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy, or non-radioactive bone-targeted agents.
3. Any prior cytotoxic chemotherapy for CRPC (e.g., cabazitaxel or docetaxel); chemotherapy for hormone-sensitive prostate cancer (HSPC) is allowed if the last dose was administered >1 year prior to consent.
4. Prior treatment with systemic radionuclides (e.g. radium-223, rhenium-186, strontium-89).
5. Prior immuno-therapy, except for sipuleucel-T.
6. Prior PSMA-targeted radioligand therapy, e.g., Lu-177-PSMA-617, I 131-1095.
7. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer.
8. Patients who progressed on 2 or more lines of ARATs.
9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) are excluded if they are not on stable doses for at least 4 weeks prior to randomization.
10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to randomization.
11. Major surgery ≤30 days prior to randomization.
12. Estimated life expectancy <6 months as assessed by the principal investigator.
13. Presence of liver metastases >1 cm on abdominal imaging.
14. A superscan on bone scan defined as a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint genitourinary tract activity71.
15. Dose escalation or initiation of opioids for cancer-related pain ≤30 days prior to consent up to and including randomization.
16. Known presence of central nervous system metastases.
17. Contraindications to the use of planned ARAT therapy, [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002 therapy, including but not limited to the following:
a. Hypersensitivity to [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002 excipients (Diethylenetriaminepentaacetic acid (DTPA), Sodium ascorbate, L-ascorbic acid, Sodium gentisate, HCl, Sodium
hydroxide)
b. Recent myocardial infarction or arterial thrombotic events (in the past 6 months) or unstable angina (in the past 3 months), bradycardia or left ventricular ejection fraction measurement of < 50%
c. History of seizures in patients planned to receive enzalutamide
18. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer.
19. Concurrent illness that may jeopardize the patient’s ability to undergo study procedures.
20. Serious psychological, familial, sociological, or geographical condition that might hamper compliance with the study protocol and follow-up schedule. Patients that travel need to be capable of repeated visits even if they are on the control arm.
21. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
22. Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, unstable ischemia, uncontrolled symptomatic arrhythmia, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study
participation or cooperation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Radiological progression-free survival (rPFS) assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening and every 8 weeks from 1st dose until progression |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate (ORR): proportion of patients with partial or complete response (PR or CR, respectively) by BICR based on RECIST 1.1 criteria (soft tissue) and PCWG3 criteria (bone).
• Duration of response: time from the first date of CR or PR by BICR to the first occurrence of radiographic progression (PD) by BICR based on PCWG3 modified RECIST 1.1, or death in the absence of progression.
• Overall survival (OS): time from randomization to date of death from any cause.
• Time from randomization to first symptomatic skeletal-related event.
• PSA response rate according to PCWG3 criteria (first occurrence of a 50% or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later).
• Biochemical progression-free survival (bPFS): time from randomization to the date of the first PSA increase from baseline ≥25% and ≥2 ng/mL above nadir confirmed by a second PSA measurement defining progression ≥3 weeks later
per PCWG3.
• Frequency and severity of AEs, graded and categorized using CTCAE v. 5.0.
• Changes from baseline in physical exam findings, vital signs, clinical laboratory values, and ECG values.
• Number of patients discontinuing study drug due to AEs.
• PSMA-PET and FDG-PET concordance/discordance with treatment response.
• Correlation of tracer uptake defined by SUVmax and SUVmean at initial screening with treatment response.
• Correlation of tracer uptake defined by SUVmax and mean SUVmean at initial screening with treatment failure.
• Within measurable disease sites, correlation of SUV with individual lesion response.
• Time from randomization to opioid use for cancer-related pain.
• Use of opioids quantified by Analgesic Quantification Algorithm (AQA) score.
• Pain palliation: decrease of ≥2 points in Brief Pain Inventory – Short Form (BPI-SF) item 3 at 12 weeks without a ≥1 point increase in AQA score.
• Absolute and change from baseline scores of pain severity and interference, assessed by BPI-SF.
• Change from baseline in overall and component scores of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.
• Time from randomization to second progression by investigator assessment of radiological or clinical progression or death.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Arm A: every 2 weeks until progression an every 3 months thereafter up to year 5 or death |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Canada |
| United Kingdom |
| United States |
| France |
| Italy |
| Netherlands |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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