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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04647526
Recruitment Status : Active, not recruiting
First Posted : December 1, 2020
Last Update Posted : April 19, 2024
Information provided by (Responsible Party):
POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE November 23, 2020
First Posted Date  ICMJE December 1, 2020
Last Update Posted Date April 19, 2024
Actual Study Start Date  ICMJE February 25, 2021
Actual Primary Completion Date November 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 23, 2020)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 23, 2020)
  • Objective Response Rate (ORR) [ Time Frame: 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).
  • Duration of response [ Time Frame: 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.
  • Overall Survival [ Time Frame: 5 years ]
    Time from the date of randomization until death due to any cause.
  • PSA Response [ Time Frame: 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.
  • Biochemical Progression-Free Survival (bPFS) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 23, 2020)
Safety and Tolerability (AEs) [ Time Frame: 5 years ]
Frequency and severity of AEs, graded and categorized using CTCAE v. 5.0.
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment
Official Title  ICMJE 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)
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).
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castration-Resistant Prostate Cancer
Intervention  ICMJE
  • 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 Name: [Lu-177]-PSMA-I&T
  • 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)
Study Arms  ICMJE
  • Experimental: [Lu-177]-PNT2002 (Arm A)
    [Lu-177]-PNT2002 (6.8 GBq (±10%) every 8 weeks for 4 cycles)
    Intervention: Drug: [Lu-177]-PNT2002
  • 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
    • Drug: Enzalutamide
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.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 23, 2020)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2028
Actual Primary Completion Date November 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Netherlands,   Sweden,   United Kingdom,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04647526
Other Study ID Numbers  ICMJE PBP-301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
Original Responsible Party Same as current
Current Study Sponsor  ICMJE POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jessica Jensen POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
PRS Account POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
Verification Date April 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP