ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With mCRPC (PRESERVE-006)

Randomized Study of ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Progressed on Androgen Receptor (AR) Pathway Inhibition

In this Phase 2 study, mCRPC patients with PSMA positive scans who progressed on prior ARTA and up to 2 lines of taxanes, and are naïve to lutetium Lu 177 vipivotide tetraxetan, will be enrolled. The study is open-label, randomized with active control, multi-center study.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: ONC-392 low; Drug: lutetium Lu 177 vipivotide tetraxetan; Drug: ONC-392 high

Detailed Description

The goal of this clinical trial is to examine the safety and efficacy of ONC-392 in combination with lutetium Lu 177 vipivotide tetraxetan in metastatic castration resistant prostate cancer patient who have disease progressed on androgen receptor pathway inhibition. The main questions it aims to answer are (1) whether it is safe to combine ONC-392 with lutetium Lu 177 vipivotide tetraxetan, (2) whether the combination increases the radiographic progression free survival (rPFS).

In Phase 1 of the trial, participates will be randomized to experimental arm and control arm in 2:1 ratio. In experimental arm, they will be given ONC-392 IV infusion for up to 9 cycles or approximately one year, together with lutetium Lu 177 vipivotide tetraxetan for up to 6 cycles. In Phase 2 of the trial, participants will be randomized to three arms in 1:1:1 ratio. There will be two experimental arms, one with low dose of ONC-392 and one with high dose ONC-392, to be given in IV infusion for up to 9 or 13 cycles or approximately one year, together with lutetium Lu 177 vipivotide tetraxetan for up to 6 cycles. In active control arm for both Phase 1 and Phase 2, participants will be given standard of care treatment with lutetium Lu 177 vipivotide tetraxetan for up to 6 cycles.

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers USOR
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Cancer
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Winship Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Towson, Maryland, United States, 21204
      • Chesapeake Urology Research Associates
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital & Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • XCancer/GU Research Network
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • New Mexico Oncology Hematology Consultants
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Health, Laura & Isaac Perlmutter Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC North Carolina Comprehensive Cancer Care Center
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97210
      • OHSU Knight Cancer Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists USOR
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates USOR
    • Norton, Virginia, United States, 24273
      • Oncology and Hematology Associates Of Southwest Virginia USOR
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be ≥ 18 years of age and have the ability to understand and sign an approved informed consent form (ICF).
2. Patients must have an ECOG performance status of 0 or 1.
3. Patients must have a life expectancy > 6 months.
4. Patients must have histological or cytological confirmation of prostate adenocarcinoma.
5. Patients must have a positive PSMA in an FDA-approved PSMA PET scan. A positive PSMA is defined as at least one tumor lesion with PSMA uptake greater than normal liver.
6. Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L).
7. Patients must have received at least one second generation AR-targeting agents (such as apalutamide, darolutamide, enzalutamide and/or abiraterone).
8. Patients should have prior treatment of up to two taxane regimens, or are unfit for, or refuse taxane chemotherapy. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. Note: Taxane chemotherapy administered in the Castration Sensitive Prostate Cancer (CSPC) or Castration Resistant Prostate Cancer (CRPC) setting is allowed.

9. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:

   1. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 1.0 ng/mL.
   2. RECIST v1.1 soft-tissue progression
   3. Progression of bone disease: 2 or more new metastatic bone lesions by bone scan per PCWG3 criteria.
10. Patients must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained ≤ 42 days prior to beginning study therapy.
11. Patients must have adequate organ function.
12. Patients with or without concomitant bisphosphonate or denosumab regimen for ≥ 30 days prior to randomization are eligible.
13. For patients who have partners of childbearing potential: Partner and/or patient must use adequate methods of birth control with barrier protection, deemed acceptable by the principal investigator during the study and for 3 months after last study drug administration.

Exclusion Criteria:

1. Patients who have not recovered to NCI CTCAE grade ≤ 1 from an adverse event (AE) due to prior cancer therapeutics except neuropathy or endocrinopathy with Gr 2 or less.
2. Any systemic anti-cancer therapy within 5 half-lives or 14 days, whichever is shorter (small molecule drugs) or within 28 days for antibody based therapy, prior to starting study treatment.
3. Known hypersensitivity to the components of the study therapy or its analogs.
4. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
5. Transfusion within 14 days of first day of study treatment
6. PSMA-negative lesions are defined as lesions with PSMA uptake equal to or lower than that of liver parenchyma. Patients with PSMA-negative lesions in any lymph node with a short axis of ≥ 2.5 cm, in any metastatic solid-organ lesions with a short axis of ≥ 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of ≥ 1.0 cm in the short axis are ineligible.
7. Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation within 6 months prior to randomization. Previous PSMA-targeted radioligand therapy is not allowed.
8. Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).
9. A superscan as seen in the baseline bone scan.
10. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
11. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, myocardial infarction within 6 months, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, or unstable arrhythmia within 3 months, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
12. Active concurrent malignancy (with the exception of non-melanomatous skin cancer). Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and/or whose likelihood of recurrence is very low per investigator's judgment are eligible for this study.
13. Receiving systemic steroid therapy with > 10 mg/day prednisone or equivalent within 7 days prior to the first dose of study treatment or receiving any other form of immunosuppressive medication.
14. Active GI disease, including peptic ulcer disease, pancreatitis, diverticulitis, or inflammatory bowel disease.
15. Active or previously documented autoimmune disease and/or current use of immunosuppressive agents. Use of endocrine replacement therapy (e.g., thyroxine, insulin, low dose of steroid, etc.) is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: ONC-392 low dose plus lutetium Lu 177 vipivotide tetraxetan; Arm 1 receives ONC-392 3 mg/kg, IV infusion, Q4W for up to 13 doses, plus lutetium Lu 177 vipivotide tetraxetan IV infusion, Q6W for up to 6 doses.	Drug: ONC-392 low; ONC-392 will be given as IV infusion, Q4W for up to 13 doses.; Other Names: A humanized anti-CTLA4 IgG1 monoclonal antibody; Gotistobart; Drug: lutetium Lu 177 vipivotide tetraxetan; lutetium Lu 177 vipivotide tetraxetan will be given as IV infusion, Q6W, for up to 6 doses.; Other Names: Pluvicto
Experimental: Arm 2: ONC-392 high dose plus lutetium Lu 177 vipivotide tetraxetan; Arm 2 receives ONC-392 6 mg/kg, IV infusion, Q6W for up to 9 doses, plus lutetium Lu 177 vipivotide tetraxetan IV infusion, Q6W for up to 6 doses.	Drug: lutetium Lu 177 vipivotide tetraxetan; lutetium Lu 177 vipivotide tetraxetan will be given as IV infusion, Q6W, for up to 6 doses.; Other Names: Pluvicto; Drug: ONC-392 high; ONC-392 will be given as IV infusion, Q6W for up to 9 doses.; Other Names: A humanized anti-CTLA4 IgG1 monoclonal antibody; Gotistobart
Active Comparator: Arm 3: lutetium Lu 177 vipivotide tetraxetan; Arm 3 receives lutetium Lu 177 vipivotide tetraxetan, IV infusion, Q6W for up to 6 doses.	Drug: lutetium Lu 177 vipivotide tetraxetan; lutetium Lu 177 vipivotide tetraxetan will be given as IV infusion, Q6W, for up to 6 doses.; Other Names: Pluvicto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT (Dose escalation Phase 1)	Incidence of dose-limiting toxicity (DLT).	40 months
PSA50 (Dose Expansion Phase 2)	Dual primary endpoints: PSA50 and rPFS assessed by investigators.	40 months
rPFS (Dose Expansion Phase 2)	Dual primary endpoints: PSA50 and rPFS assessed by investigators.	40 months
TEAEs and irAEs (Dose Expansion Phase 2)	Incidence of TEAEs, irAEs, and TEAEs leading to study treatment discontinuation.	40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA progression free survival	PSA progression free survival as defined by PCWG3 guideline.	40 months
Composite progression-free survival (PFS)	The PFS event is defined as either radiographic progression, or PSA increase by PCWG3 guideline, or death, whichever comes first.	40 months
Overall survival (OS)	The length of time patients live after starting treatment.	40 months
Response rate	Response rate based on radiographic evaluation of PCWG3.	40 months

Collaborators and Investigators

• Sponsor: OncoC4, Inc.
• Collaborators: Prostate Cancer Clinical Trials Consortium
• Investigators: Principal Investigator: David Wise, MD, NYU Langone Health; Principal Investigator: Mark Stein, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: December 26, 2022
• First Submitted That Met QC Criteria: December 27, 2022
• First Posted (Actual): January 12, 2023

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Pluvicto
• Other Study ID Numbers: PRESERVE-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No