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

Metastatic Castration-Resistant Prostate Cancer Clinical Trial

— SPLASH  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04647526
• Other study ID #: PBP-301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 25, 2021
• Est. completion date: March 2028

Study information

• Verified date: April 2024
• Source: POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 415
• Est. completion date: March 2028
• Est. primary completion date: November 1, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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:

1. 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.

2. 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.

3. Progression of bone disease defined as the 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 × 10^9/L OR absolute neutrophil count (ANC) =1.5 × 10^9/L.

ii. Platelets =100 × 10^9/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 (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) true sexual abstinence: when this is in line with the preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of 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.

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) 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) 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 activity.

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:

• Hypersensitivity to [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002 excipients (Diethylenetriaminepentaacetic acid (DTPA), Sodium ascorbate, Lascorbic acid, Sodium gentisate, HCl, Sodium hydroxide).

• 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%.

• 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 (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.

Related Conditions & MeSH terms

• Metastatic Castration-Resistant Prostate Cancer
• Prostatic Neoplasms

Intervention

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
• Abiraterone
Abiraterone (1000 mg orally qd with: 5 mg bid prednisone or 0.5 mg qd dexamethasone)
• Enzalutamide
Enzalutamide (160 mg orally qd)

Locations

Country	Name	City	State
Canada	Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	London Health Sciences Center - Victoria Hospital	London	Ontario
Canada	CHUM - University Hospital of Montreal	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	CHU of Quebec - Laval University	Quebec City	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Sunnybrook Research Institute, Odette Cancer Center	Toronto	Ontario
Canada	BC Cancer - Vancouver	Vancouver	British Columbia
France	Center Jean Perrin, Department of Medical Oncology	Clermont-Ferrand
France	Claude Huriez Hospital	Lille
France	Leon Berard Center	Lyon
France	La Timone Hospital, Nuclear Medicine Department	Marseille
France	Montpellier Cancer Institute, Department of Nuclear Medicine	Montpellier
France	Tenon Hospital, Department of Medical Oncology	Paris
Netherlands	St. Antonius Hospital	Nieuwegein
Netherlands	Radboud University Medical Center (Radboudumc)	Nijmegen
Netherlands	Erasmus University Medical Center Rotterdam	Rotterdam
Sweden	Sahlgrenska University Hospital	Gothenburg
Sweden	Norrlands University Hospital, Department of Radiation Sciences, Oncology	Umea
United Kingdom	Charing Cross Hospital, Department of Medical Oncology	London
United Kingdom	Royal Marsden NHS Foundation Trust - Institute of Cancer Research	Sutton
United States	New Mexico Oncology Hematology Consultants Ltd., New Mexico Cancer Center	Albuquerque	New Mexico
United States	University of Michigan Hospitals	Ann Arbor	Michigan
United States	University of Colorado Hospital	Aurora	Colorado
United States	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland
United States	Tri-State Urologic Services	Cincinnati	Ohio
United States	Dallas VA Medical Center, Nuclear Medicine Service	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Karmanos Cancer Center	Detroit	Michigan
United States	Astera Cancer Care	East Brunswick	New Jersey
United States	Excel Diagnostics & Nuclear Oncology Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California
United States	University of California Los Angeles, Nuclear Medicine Clinic	Los Angeles	California
United States	VA Greater Los Angeles Healthcare System	Los Angeles	California
United States	Carolina Urologic Research Center	Myrtle Beach	South Carolina
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	New York Presbyterian Hospital/Weill Cornell Medical Center	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Urology Cancer Center, PC	Omaha	Nebraska
United States	UC Irvine Chao Family Comprehensive Cancer Center	Orange	California
United States	Stanford Cancer Institute	Palo Alto	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Saint Louis University Hospital	Saint Louis	Missouri
United States	VA St. Louis Health Care System	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Swedish Cancer Institute Research	Seattle	Washington
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida
United States	Chesapeake Urology Associates (CUA) P.A.	Towson	Maryland
United States	Arizona Institute of Urology (AIU) - Tucson	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Canada,  France,  Netherlands,  Sweden,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety and Tolerability (AEs)	Frequency and severity of AEs, graded and categorized using CTCAE v. 5.0.	5 years
Primary	Radiographic Progression Free Survival (rPFS)	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).	32 weeks
Secondary	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).	32 weeks
Secondary	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.	32 weeks
Secondary	Overall Survival	Time from the date of randomization until death due to any cause.	5 years
Secondary	PSA Response	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.	32 weeks
Secondary	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, as per PCWG3.	32 weeks