An International, Prospective, Open-label, Multi-center, Randomized Phase III Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) Versus Observation to Delay Castration or Disease Recurrence in Adult Male Patients With Prostate-specific Membrane Antigen (PSMA) Positive Oligometastatic Prostate Cancer (OMPC)

Official Summary

The purpose of this study is to evaluate the efficacy and safety of lutetium (177Lu) vipivotide tetraxetan (AAA617) in participants with oligometastatic prostate cancer (OMPC) progressing after definitive therapy to their primary tumor. The data generated from this study will provide evidence for the treatment of AAA617 in early-stage prostate cancer patients to control recurrent tumor from progressing to fatal metastatic disease while preserving quality of life by delaying treatment with androgen deprivation therapy (ADT).

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 100 Years
• Sex: MALE

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 450 participants

Study Arms

• Investigational Arm: lutetium (177Lu) vipivotide tetraxetan (AAA617) (EXPERIMENTAL)
  All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by a dose of 7.4 GBq (200 mCi) +/- 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for a planned 4 cycles.
• Control arm: observation (watchful waiting) (NO_INTERVENTION)
  All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by observation only.

Interventions

• DRUG: AAA617 — Stereotactic Body Radiation Therapy (SBRT) followed by AAA617 will be administered once every 6 weeks (1 cycle) for a planned 4 cycles to participants randomized to the Investigational arm

Primary Outcomes

• Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) (From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death due to any cause, whichever occurs first, assessed up to approximately 30 months)

Secondary Outcomes

• Key secondary endpoint: Time to Hormonal Therapy (TTHT) (From date of randomization until date of Androgen Deprivation Therapy (ADT), assessed up to approximately 74 months)
• Investigator assessed Metastasis Free Survival (MFS) (From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 74 months)
• Time to prostate specific antigen (PSA) progression (TTPSAP) (From date of randomization until date of first PSA progression, assessed up to approximately 74 months)
• Radiographic Progression Free Survival (rPFS) (From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 74 months)
• Time to next therapy (local or systemic) (From date of randomization until initiation of the next line of therapy (local or systemic), assessed up to approximately 74 months)

Eligibility Criteria

Key Inclusion criteria:

1. Histologically confirmed prostate cancer prior to randomization
2. Participants must have biochemically recurrent disease after definitive treatment to prostate by Radical Prostatectomy ((RP), (alone or with post-operative radiation to prostate bed/pelvic nodes)) or External beam Radiation Therapy (EBRT), (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence (BCR) is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA \> 0.2 ng/mL and rising post RP (with or without post-operation Radiation Therapy (RT))
3. Participants must have OMPC with 1-5 PSMA -positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC. For definition of PSMA PET positivity, please refer to Section 8.1 and the Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using American Joint Committee on Cancer (AJCC) 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions)
4. At least 1 PSMA-positive lesion must be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET/CT information should be used
5. Participants must have a negative CI for M1 disease at screening.

   Note:
   * For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget's disease in bone lesions). For CI assessments, bone lesions must be assessed by bone scan only and soft tissue lesions must be assessed by CT/MRI scans only at screening.
   * Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET/CT scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Reader should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter
   * MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans
   * Participants with pelvic disease (N1) seen in CI are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease)
   * Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis is not exclusionary irrespective of PSMA PET positivity.
   * If a previously surgically removed lesion was unequivocal for M1 by bone scan or CT, the participant is not eligible.
6. All metastatic lesions detected at screening must be amenable to SBRT
7. Non-castration testosterone level \>100 ng/dL at screening

Key Exclusion criteria:

1. Participants with de novo OMPC at screening
2. Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed
3. Prior therapy with:

   1. ADT (including bilateral orchiectomy) and ARPIs used for metastatic prostate cancer treatment

      * Participants who received AR-directed therapy, whether ADT or an ARPI or both, as neoadjuvant or adjuvant therapy as a component of their primary therapy, are eligible provided that they discontinued therapy ≥12 months prior to randomization for ADT (i.e., 12 months after the last day of the last injection) or ≥3 months if ARPI was given as monotherapy. ARPI's as a term includes both contemporary androgen synthesis inhibitors (e.g., abiraterone, galeterone, and orteneronel), and receptor inhibitors (enzalutamide, apalutamide and darolutamide).
      * Patients who biochemically relapsed after primary therapy may also have had treatment with AR directed therapy and participants who had SBRT with ADT are also eligible provided that the ARPI +/- ADT or ADT alone was terminated

        ≥12 months prior to randomization for ADT (i.e., 12 months after the last day of the last injection) or ≥3 months if ARPI was given as monotherapy.
      * Participants who received first generation anti-androgens (bicalutamide, flutamide, n

Trial Locations

• Highlands Oncology Group, Fayetteville, Arkansas, United States
• VA Greater LA Healthcare System, Los Angeles, California, United States
• VA Palo Alto Health Care System, Palo Alto, California, United States
• Stanford University, Palo Alto, California, United States
• UCSF, San Francisco, California, United States
• Rocky Mountain Cancer Centers, Denver, Colorado, United States
• Cancer Specialists of North Florida, Jacksonville, Florida, United States
• Woodlands Medical Specialists, Pensacola, Florida, United States
• Piedmont Healthcare, Atlanta, Georgia, United States
• University of Chicago, Chicago, Illinois, United States
• ...and 10 more locations

Contact Information

• Novartis Pharmaceuticals — CONTACT
  Phone: 1-888-669-6682
  Email: novartis.email@novartis.com
• Novartis Pharmaceuticals — CONTACT
  Phone: +41613241111
  Email: novartis.email@novartis.com

Study Officials

• Novartis Pharmaceuticals — STUDY_DIRECTOR
  Novartis Pharmaceuticals

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