Splash Trial- NCT 04647526
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Study Evaluating metastatic Castration Resistant Prostate Cancer (mCRPC) Treatment Using PSMA [Lu-177]-PNT2002
Therapy After Second-line Hormonal Treatment (SPLASH)
The primary objective of the study is to determine the efficacy of [Lu-177]-PNT2002 ([Lu-177]-PSMA-I&T) versus abiraterone or enzalutamide in delaying radiographic progression in patients with mCRPC. The study consists of 3 phases: Dosimetry, Randomized Treatment, and Long term Follow up. The study will commence with a 25-patient safety and dosimetry lead-in (Part 1) and proceed to a randomization treatment phase in approximately 390 patients (Part 2). Patients in Part 2 will be randomized in a 2:1 ratio to receive either [Lu-177]-PNT2002 (Arm A), or enzalutamide or abiraterone (Arm B). Patients in Arm B who experience radiographic progression per central review and meet protocol defined eligibility, may crossover to receive [Lu-177]-PNT2002. All patients will be followed in long-term follow-up for at least 5 years from the first therapeutic dose, death, or loss to follow up (Part 3). Only patients that meet PSMA PET avidity criteria per central review will be eligible for this study.
Primary Outcome Measures :
1. Radiographic Progression Free Survival (rPFS) [ Time Frame: 32 weeks ] Time in months from the date of randomization to radiological progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) or confirmed progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3) (bone), or death from any cause, as assessed by blinded independent central review (BICR).
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: evaluable disease or one new bone lesion by bone scan
5. 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 ( 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 mmol/L. 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.
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 of childbearing potential: Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after last study drug administration.
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.
Patients are excluded from the study if any of the following criteria apply: 1. Prostate cancer with known significant (>10%) 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) 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 have had 2 or more lines of ARATs.
9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) must be 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 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. Use of opioids for cancer-related pain ≤30 days prior to consent.
16. Known presence of central nervous system metastases.
17. Contraindications to the use of planned ARAT therapy.
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 (see 12.1 Appendix 1), 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.