A Multi-Center, Open-Label, Randomized Phase 3 Trial Comparing the Safety and Efficacy of 177Lu-PSMA-I&T Versus Hormone Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Official Summary

A Multi-Center, Open-Label, Randomized Phase 3 Trial Comparing the Safety and Efficacy of 177Lu-PSMA-I\&T versus Hormone Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

Eligibility Requirements

• Minimum Age: 18 Years
• Sex: MALE

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: CROSSOVER
• Masking: NONE
• Enrollment: 439 participants

Study Arms

• Standard Of Care Hormone Therapy (ACTIVE_COMPARATOR)
  Abiraterone with Prednisone or Enzalutamide
• Investigational Drug (EXPERIMENTAL)
  177Lu-PSMA-I\&T

Interventions

• DRUG: 177Lu-PSMA-I&T — Radioligand therapy
• DRUG: Abiraterone with Prednisone or Enzalutamide — Hormone Therapy

Primary Outcomes

• Radiographic Progression Free Survival (34 weeks)

Secondary Outcomes

• Overall Survival (OS) (156 weeks)
• Second Radiographic Progression Free Survival (rPFS 2) (156 weeks)
• Progression Free Survival (156 weeks)
• Second Progression-Free Survival (156 weeks)
• PSA50 Response Rate (156 weeks)

Eligibility Criteria

Inclusion Criteria:

1. Male 18 years or older able to understand and provide signed written informed consent.
2. Histologically or pathologically confirmed prostate adenocarcinoma without predominant small cell component.
3. Progressive disease by one or more of the following criteria:

   1. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week apart with a minimum start value of \>2 ng/mL.
   2. Progression of measurable disease (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria).
4. Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide, apalutamide, darolutamide).

   1. Must have received no more than one previous AR-directed therapy.
   2. Must have been administered ARAT (abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castration-resistant setting.
   3. Must have progressed while on ARAT.
5. PSMA-PET scan (e.g., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by central reader.
6. Effective castration with serum testosterone level of \<50 ng/dL and plan to continue with chronic medical or surgical castration.
7. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
8. Patients with HIV that are healthy and with a low risk of acquired immune deficiency syndrome related outcomes may participate in the trial at the investigators' discretion.
9. Patients with HBV and HCV may also participate if symptoms are sufficiently managed.
10. Life expectancy of at least 6 months as assessed by investigator.
11. Willing to initiate ARAT therapy determined by investigator.
12. For patients who have partners of childbearing potential: The patient and/or partner 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 the last study drug administration.

Exclusion Criteria:

1. Prior treatment with radioligand therapy including other lutetium-labeled compounds.
2. Prior treatment with radium-223 (Xofigo) within the past 12 weeks.
3. Prior chemotherapy treatment for castration-resistant prostate cancer. Prior docetaxel use in the hormone-sensitive setting is permitted, as long as no more than 6 doses were received, the last dose was administered \>1 year prior to consent, and disease progression did not occur during docetaxel treatment.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2
5. Patients with known HRR gene-mutation (BRCA 1/2 encompassing both germline and somatic) who have not been previously treated with olaparib or rucaparib.
6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
7. Inadequate organ and bone marrow function as evidenced by:

   1. Hemoglobin \< 8 g/dL.
   2. Absolute neutrophil count \< 1.5 x 109/L.
   3. Platelet count \< 100 x 109/L.
   4. AST/SGOT and/or ALT/SGPT \> 3.0 x ULN.
   5. Total bilirubin \> 2 x ULN unless patient has known Gilbert's syndrome and then may be 3 x ULN.
   6. Creatinine clearance (CrCl) \< 50 mL/min based on the Cockcroft-Gault equation.
   7. Albumin ≤ 2.75 g/dL
8. Patients who undergo a transfusion for the sole purpose of meeting eligibility for this trial will be excluded.
9. Assessment by the Investigator as unable or unwilling to comply with the requirements of the protocol.
10. Use of an investigational therapeutic drug within the last 4 weeks prior to start of study treatment or scheduled to receive one during the study period.
11. Known CNS metastasis unless received therapy, asymptomatic and neurologically stable.
12. Patients receiving zoledronic acid for bone-targeted therapy must be on stable dose for 4 weeks prior to randomization.
13. Major surgery within 30 days of randomization as determined by the Investigator.
14. Patients with active significant cardiac disease defined by any of the following:

    1. New York Heart Association class 3 or 4 congestive heart failure within 6 months of signing the ICF unless treated with improvement.
    2. Current diagnosis of electrocardiogram abnormalities with significant cardiac arrhythmias
    3. History of long QT syndrome or know history of Torsades de Pointe
    4. History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months of ICF signature
15. Participants with symptomatic cord compression or clinical/radiological findings indicating impending spinal cord compression
16. Patients with a superscan seen on baseline bone scan as determined by investigator.
17. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer
18. Previous use of G-CSF for persistent neutropenia after standard of care treatment.
19. Participants who have a pregnant partner or are capable of fathering a child and who are unwilling to

Trial Locations

• Arizona Institute of Urology, PPLC, Tucson, Arizona, United States
• Providence Medical Foundation, Fullerton, California, United States
• Long Beach Memorial Center, Long Beach, California, United States
• Hoag Memorial Hospital Presbyterian, Newport Beach, California, United States
• San Francisco VA Health Care System, San Francisco, California, United States
• University of California, San Francisco, San Francisco, California, United States
• Providence Saint John's Health Center, Santa Monica, California, United States
• GenesisCare USA, Boca Raton, Florida, United States
• Biogenix Molecular LLC, Miami, Florida, United States
• Orlando Health Cancer Institute, Orlando, Florida, United States
• ...and 10 more locations

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