Clinical trial NCT04647526: Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: PSMA
mCRPC
Prostate cancer
177Lu-PSMA
radioligand therapy
PSMA-I&T
SPLASH
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2020-12-01
Enrollment: 415
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Radiographic Progression Free Survival (rPFS)
timeFrame: 32 weeks
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 32 weeks
measure: Duration of response
timeFrame: 32 weeks
measure: Overall Survival
timeFrame: 5 years
measure: PSA Response
timeFrame: 32 weeks
measure: Biochemical Progression-Free Survival (bPFS)
timeFrame: 32 weeks
Other outcomes:
measure: Safety and Tolerability (AEs)
timeFrame: 5 years
Locations:
city: Tucson
country: United States
facility: Arizona Institute of Urology (AIU) - Tucson
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
state: California
city: Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles, Nuclear Medicine Clinic
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Orange
country: United States
facility: UC Irvine Chao Family Comprehensive Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
city: Towson
country: United States
facility: Chesapeake Urology Associates (CUA) P.A.
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Hospitals
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: VA St. Louis Health Care System
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Urology Cancer Center, PC
state: Nebraska
city: East Brunswick
country: United States
facility: Astera Cancer Care
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology Consultants Ltd., New Mexico Cancer Center
state: New Mexico
city: New York
country: United States
facility: New York Presbyterian Hospital/Weill Cornell Medical Center
state: New York
city: Cincinnati
country: United States
facility: Tri-State Urologic Services
state: Ohio
city: Kettering
country: United States
facility: Greater Dayton Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Dallas VA Medical Center, Nuclear Medicine Service
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Excel Diagnostics & Nuclear Oncology Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute Research
state: Washington
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver
state: British Columbia
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
city: London
country: Canada
facility: London Health Sciences Center - Victoria Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute, Odette Cancer Center
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM - University Hospital of Montreal
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU of Quebec - Laval University
state: Quebec
city: Clermont-Ferrand
country: France
facility: Center Jean Perrin, Department of Medical Oncology
city: Lille
country: France
facility: Claude Huriez Hospital
city: Lyon
country: France
facility: Leon Berard Center
city: Marseille
country: France
facility: La Timone Hospital, Nuclear Medicine Department
city: Montpellier
country: France
facility: Montpellier Cancer Institute, Department of Nuclear Medicine
city: Paris
country: France
facility: Tenon Hospital, Department of Medical Oncology
city: Nieuwegein
country: Netherlands
facility: St. Antonius Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center (Radboudumc)
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center Rotterdam
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Umea
country: Sweden
facility: Norrlands University Hospital, Department of Radiation Sciences, Oncology
city: London
country: United Kingdom
facility: Charing Cross Hospital, Department of Medical Oncology
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust - Institute of Cancer Research
Study officials:
affiliation: Eli Lilly and Company
name: Jessica Jensen
role: STUDY_DIRECTOR
References:
citation: 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.