Study comparing Lutetium (177Lu) Vipivotid-Tetraxetan (AAA617) with observation in PSMA-positive oligometastatic prostate cancer.

Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Hungary, Israel, Italy, Japan, Malaysia, Netherlands, Singapore, Slovakia, Spain, Switzerland, Taiwan, United Kingdom, United States (ICTRP)

ICTRP Trial ID
NCT05939414 (ICTRP)

Official title (approved by ethics committee)
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). (BASEC)

Academic title
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) (ICTRP)

Public title
An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC. (ICTRP)

Disease under investigation
Oligometastatic Prostate Cancer (OMPC) (ICTRP)

Intervention under investigation
Drug: AAA617 (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion 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 (XRT), (prostate
alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy
prior to randomization. Biochemical recurrence 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 =< 5 PSMA-positive metastatic lesions on screening
PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as
visually assessed by BIRC based on the methodology proposed in the Prostate Cancer
Molecular Imaging Standardized Evaluation (PROMISE v2) (Seifert et al 2023) for
further details, 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
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 should be a distant metastasis (M1) per AJCC8
classification at screening. For AJCC M staging, PSMA PET information should be used

5. Participants must have a negative conventional imaging 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 conventional imaging
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 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 conventional imaging 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 should 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

- Participants who had XRT or RP and completed adjuvant ADT (or ADT+ARPI)
prior to recurrence are eligible to participate if the last dose of ADT
(or ADT+ARPI) was before 12 months from randomization. Participants who
had prior SBRT with short term ADT (3-6 months) are also allowed if the
ADT was stopped at least 12 months before randomization.

- Participants who discontinued ADT due to disease progression are not
allowed (i.e., Castration-Resistant Prostate Cancer (CRPC) participants)

2. Other hormonal therapy. e.g.,

- Use of estrogens, 5-a reductase inhibitors (finasteride, dutasteride),
other steroidogenesis inhibitors (aminoglutethimide) if used in the
context of prostate cancer treatment. Same medications are allowed if used
for other indications: e.g., Benign Prostatic Hyperplasia (BPH), if
stopped at least 5 half-lives before randomization.

- First-generation anti-androgens (bicalutamide, flutamide, nilutamide,
cyproterone)

- Second generation anti-androgens (e.g., enzalutamide, apalutamide and
darolutamide)

- CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone,
ketoconazole). Short term ketoconazole treatment (<28 days) is permitted

3. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand
therapy)

4. Immunotherapy (e.g., sipuleucel-T)

5. Chemotherapy, except if administered in the adjuvant/neoadjuvant setting
completed > 12 months before randomization

6. Any other investigational or systemic agents for metastatic disease

4. Radiation therapy external beam radiation therapy (EBRT) and brachytherapy within 28
days before randomization

5. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal
therapy (see ADT initiation guidance in Section 6.8.2), Poly Adenosine
Diphosphate-Ribose Polymerase (PARP) inhibitor, biological therapy or
investigational therapy

6. Diagnosed at screening with other malignancies that are expected to alter life
expectancy or may interfere with disease assessment. However, participants with a
prior history of malignancy that has been adequately treated and who have been
disease/treatment free for more than 3 years are eligible, as are participants with
adequately treated non-melanoma skin cancer and superficial bladder cancer.

7. History or current diagnosis of ECG abnormalities indicating significant risk of
safety for participants participating in the study such as:

- Concomitant clinically significant cardiac arrhythmias, e.g. sustained
ventricular tachycardia, and clinically significant second or third degree
Atrioventricular (AV) block without a pacemaker

- History of familial long QT syndrome or known family history of Torsades (ICTRP)

not available

Primary and secondary end points
Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) (ICTRP)

Key secondary endpoint: Time to Hormonal Therapy (TTHT);Investigator assessed Metastasis Free Survival (MFS);Time to prostate specific antigen (PSA) progression (TTPSAP);Radiographic Progression Free Survival (rPFS);Time to next therapy (local or systemic);24-month prostate-specific antigen (PSA) progression free survival (PFS);Time to symptomatic progression;Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire;Functional Assessment of Cancer Therapy - Radionuclide Therapy (FACT-RNT) Questionnaire;Brief Pain Inventory - Short Form (BPI-SF) Questionnaire;European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L);Time to First Symptomatic Skeletal Event (TTSE);Incidence and severity of adverse events (AEs) and serious adverse events (SAEs);Dose modifications and intensity for AAA617;Overall survival (OS) (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Novartis Pharmaceuticals;Novartis Pharmaceuticals, novartis.email@novartis.com, 1-888-669-6682, Novartis Pharmaceuticals, (ICTRP)

Secondary trial IDs
2022-502956-29-00, CAAA617D12302 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT05939414 (ICTRP)