SPLASH: Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment

• Sponsor: POINT Biopharma (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04647526
• Collaborator: (none)
• Enrollment: 415
• Locations: 48
• Arms: 2
• Anticipated Duration (Months): 84.1
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of [Lu-177]-PNT2002 in patients with metastatic castration-resistant prostate cancer who have progressed following treatment with androgen receptor axis-targeted therapy (ARAT).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-Resistant Prostate Cancer	Drug: [Lu-177]-PNT2002; Drug: Abiraterone; Drug: Enzalutamide	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 415 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-Label, Randomized Study Evaluating Metastatic Castrate Resistant Prostate Cancer Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH)
• Actual Study Start Date: Feb 25, 2021
• Anticipated Primary Completion Date: Mar 1, 2023
• Anticipated Study Completion Date: Mar 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: [Lu-177]-PNT2002 (Arm A) [Lu-177]-PNT2002 (6.8 GBq (±10%) every 8 weeks for 4 cycles)	Drug: [Lu-177]-PNT2002; Participants randomized to Arm A will receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 every 8 weeks for 4 cycles; Other Names: [Lu-177]-PSMA-I&T
Active Comparator: Control Arm (Arm B) Abiraterone (1000 mg orally qd with: 5 mg bid prednisone or 0.5 mg qd dexamethasone) or enzalutamide (160 mg orally qd).	Drug: Abiraterone; Abiraterone (1000 mg orally qd with: 5 mg bid prednisone or 0.5 mg qd dexamethasone); Drug: Enzalutamide; Enzalutamide (160 mg orally qd)

Outcome Measures

Primary Outcome Measures

1. Radiographic Progression Free Survival (rPFS) [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).

Secondary Outcome Measures

1. Objective Response Rate (ORR) [32 weeks]

   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).

2. Duration of response [32 weeks]

   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.

3. Overall Survival [5 years]

   Time from the date of randomization until death due to any cause.

4. PSA Response [32 weeks]

   Proportion of patients achieving a ≥50% decrease in PSA (PCWG3 criteria) from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later.

5. Biochemical Progression-Free Survival (bPFS) [32 weeks]

   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, as per PCWG3.

Other Outcome Measures

1. Safety and Tolerability (AEs) [5 years]

   Frequency and severity of AEs, graded and categorized using CTCAE v. 5.0.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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:

5. 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.

6. 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.

7. Progression of bone disease: evaluable disease or one new bone lesion by bone scan

8. Previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or apalutamide) in either the CSPC or CRPC setting.

9. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the sponsor's central reader.

10. Castrate circulating testosterone levels (<1.7 nmol/L or <50 ng/dL).

11. Adequate organ function, independent of transfusion:

1. Bone marrow reserve: i. White blood cell (WBC) count ≥2.5 × 109/L OR absolute neutrophil count (ANC) ≥1.5 × 109/L.

1. 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.

2. 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.

1. Albumin ≥30 g/L.

1. Human immunodeficiency virus-infected patients who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial.

2. 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.

3. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified by investigator, if randomized to Treatment Arm B.

4. ECOG performance status 0 to 1.

5. Willing and able to comply with all study requirements and treatments (including 177Lu PNT2002) as well as the timing and nature of required assessments.

6. Signed informed consent.

Exclusion Criteria:

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 <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. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Institute of Urology (AIU) - Tucson	Tucson	Arizona	United States	85704
2	Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California	United States	90048
3	VA Greater Los Angeles Healthcare System	Los Angeles	California	United States	90073
4	University of California Los Angeles, Nuclear Medicine Clinic	Los Angeles	California	United States	90095
5	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92663
6	UC Irvine Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
7	Stanford Cancer Institute	Palo Alto	California	United States	94305
8	University of Colorado Hospital	Aurora	Colorado	United States	80045
9	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
10	University of Kentucky Chandler Medical Center	Lexington	Kentucky	United States	40536
11	Tulane University Medical Center	New Orleans	Louisiana	United States	70112
12	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
13	Chesapeake Urology Associates (CUA) P.A.	Towson	Maryland	United States	21204
14	University of Michigan Hospitals	Ann Arbor	Michigan	United States	48109
15	Karmanos Cancer Center	Detroit	Michigan	United States	48201
16	VA St. Louis Health Care System	Saint Louis	Missouri	United States	63106
17	Saint Louis University Hospital	Saint Louis	Missouri	United States	63110
18	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
19	Urology Cancer Center, PC	Omaha	Nebraska	United States	68130
20	Astera Cancer Care	East Brunswick	New Jersey	United States	08816
21	New Mexico Oncology Hematology Consultants Ltd., New Mexico Cancer Center	Albuquerque	New Mexico	United States	87109
22	New York Presbyterian Hospital/Weill Cornell Medical Center	New York	New York	United States	10065
23	Tri-State Urologic Services	Cincinnati	Ohio	United States	45212
24	Greater Dayton Cancer Center	Kettering	Ohio	United States	45409
25	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
26	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
27	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
28	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
29	Dallas VA Medical Center, Nuclear Medicine Service	Dallas	Texas	United States	75216
30	UT Southwestern Medical Center	Dallas	Texas	United States	75390
31	Excel Diagnostics & Nuclear Oncology Center	Houston	Texas	United States	77402
32	Swedish Cancer Institute Research	Seattle	Washington	United States	98104
33	BC Cancer - Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
34	Nova Scotia Health Authority	Halifax	Nova Scotia	Canada	B3H 2Y9
35	London Health Sciences Center - Victoria Hospital	London	Ontario	Canada	N6A 5W9
36	Sunnybrook Research Institute, Odette Cancer Center	Toronto	Ontario	Canada	M4N 3M5
37	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
38	CHUM - University Hospital of Montreal	Montreal	Quebec	Canada	H2X 3E4
39	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
40	CHU of Quebec - Laval University	Quebec City	Quebec	Canada	G1R 2J6
41	Center Jean Perrin, Department of Medical Oncology	Clermont-Ferrand		France	63011
42	Claude Huriez Hospital	Lille		France	59037
43	Leon Berard Center	Lyon		France	69373
44	St. Antonius Hospital	Nieuwegein		Netherlands
45	Radboud University Medical Center (Radboudumc)	Nijmegen		Netherlands
46	Norrlands University Hospital, Department of Radiation Sciences, Oncology	Umea		Sweden
47	Charing Cross Hospital, Department of Medical Oncology	London		United Kingdom
48	Royal Marsden NHS Foundation Trust - Institute of Cancer Research	Sutton		United Kingdom

Sponsors and Collaborators

• POINT Biopharma

Investigators

• Study Director: Jessica Jensen, POINT Biopharma

Study Documents (Full-Text)

None provided.

More Information

Publications

• Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. 2016 Jul;57(7):1006-13. doi: 10.2967/jnumed.115.168443. Epub 2016 Jan 21.

• Responsible Party: POINT Biopharma
• ClinicalTrials.gov Identifier: NCT04647526
• Other Study ID Numbers: PBP-301
• First Posted: Dec 1, 2020
• Last Update Posted: Jun 3, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by POINT Biopharma: PSMA; mCRPC; Prostate cancer; 177Lu-PSMA; radioligand therapy; PSMA-I&T; SPLASH
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

No Results Posted as of Jun 3, 2022