Clinical trial NCT05939414: An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC.
Official 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Oligometastatic Prostate Cancer (OMPC)
Keywords: Lutetium (177Lu) vipivotide tetraxetan
Oligometastatic Prostate Cancer (OMPC)
Metastasis Free Survival (MFS)
gallium (68Ga) gozetotide
piflufolastat (18F)
prostate-specific membrane antigen (PSMA)
Delay Castration
Stereotactic Body Radiation Therapy (SBRT)
metastasis-directed therapy
Androgen Deprivation Therapy (ADT)-free survival.
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-07-11
Enrollment: 450
Sex: MALE
Minimum age (years): 18
Maximum age (years): 100
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 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).

Detailed description: All participants will be assessed for eligibility and will undergo baseline disease assessments including a mandatory gallium (68Ga) gozetotide (also known as \[68Ga\]Ga-PSMA-11) or piflufolastat (18F) ( also known as\[18F\]DCFPyL) PET/CT scan and conventional imaging (i.e., CT/MRI and bone scans).

Piflufolastat (18F) PET/CT scan will be performed in countries where it is approved.

Stereotactic Body Radiation Therapy (SBRT) will be administered to all metastatic Prostate Cancer (PC) lesions after randomization and before the start of treatment with AAA617 or observation.

* The duration of SBRT procedures is approximately 3 weeks.
* For participants randomized to the investigational arm (AAA617), the treatment duration will be up to 4 cycles of AAA617. For participants randomized to the control arm (observation) the treatment duration will end at the last fraction of SBRT administration.
* The visit frequency will be every week 1 and 3 of each of the 4 cycles and every 16 weeks thereafter (for both arms) until first event of disease progression (RECIST 1.1)
* The study duration is approximately 6.5 years.

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 (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-α 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 de Pointe
8. Participants in immediate need of ADT as assessed by the investigator.

Other protocol defined Inclusion/Exclusion may apply.

Primary outcomes:
measure: Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS)
timeFrame: 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:
measure: Key secondary endpoint: Time to Hormonal Therapy (TTHT)
timeFrame: From date of randomization until date of Androgen Deprivation Therapy (ADT), assessed up to approximately 74 months
measure: Investigator assessed Metastasis Free Survival (MFS)
timeFrame: 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
measure: Time to prostate specific antigen (PSA) progression (TTPSAP)
timeFrame: From date of randomization until date of first PSA progression, assessed up to approximately 74 months
measure: Radiographic Progression Free Survival (rPFS)
timeFrame: 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
measure: Time to next therapy (local or systemic)
timeFrame: From date of randomization until initiation of the next line of therapy (local or systemic), assessed up to approximately 74 months
measure: 24-month prostate-specific antigen (PSA) progression free survival (PFS)
timeFrame: From date of randomization until date of first documented PSA progression 2 or death from any cause, whichever occurs first, assessed up to approximately 74 months
measure: Time to symptomatic progression
timeFrame: From date of randomization until date of first documented symptomatic progression, assessed up to approximately 74 months
measure: Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire
timeFrame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months
measure: Functional Assessment of Cancer Therapy - Radionuclide Therapy (FACT-RNT) Questionnaire
timeFrame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months
measure: Brief Pain Inventory - Short Form (BPI-SF) Questionnaire
timeFrame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months
measure: European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L)
timeFrame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months
measure: Time to First Symptomatic Skeletal Event (TTSE)
timeFrame: From date of randomization till end of treatment (EOT) or death, whichever happens first, assessed up to approximately 74 months
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months
measure: Dose modifications and intensity for AAA617
timeFrame: From date of randomization until end of treatment (EOT), assessed up to approximately 30 months
measure: Overall survival (OS)
timeFrame: From date of randomization until date of death from any cause, assessed up to approximately 74 months
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Pensacola
country: United States
facility: Woodlands Medical Specialists
state: Florida
city: Atlanta
country: United States
facility: Piedmont Cancer Institute P C
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Elk Grove
country: United States
facility: The Cancer Institute of Alexian Brothers
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Ctr
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Com Cancer Ctr
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Grand Rapids
country: United States
facility: BAMF Health
state: Michigan
city: Royal Oak
country: United States
facility: Profound Research LLC
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: VA St Louis Health Care System
state: Missouri
city: Saint Louis
country: United States
facility: Wash U School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloane Ketterin Cancer Ctr
state: New York
city: Kettering
country: United States
facility: Dayton Physicians
state: Ohio
city: Springfield
country: United States
facility: Oregon Urology Institute
state: Oregon
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center, LLC
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Univ of Texas Southwest Med Center
state: Texas
city: El Paso
country: United States
facility: Rio Grande Urology
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Wytheville
country: United States
facility: Blue Ridge Cancer Center
state: Virginia
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
city: Darlinghurst
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Malvern
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facility: Novartis Investigative Site
state: Victoria
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Aalst
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
state: Poruba
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Saint-Cloud
country: France
facility: Novartis Investigative Site
state: Hauts De Seine
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Bron
country: France
facility: Novartis Investigative Site
city: Clermont-Ferrand
country: France
facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Rostock
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Beer-Sheva
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Cona
country: Italy
facility: Novartis Investigative Site
state: FE
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Negrar
country: Italy
facility: Novartis Investigative Site
state: VR
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Kobe
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Kanazawa
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Fukuoka
country: Japan
facility: Novartis Investigative Site
city: Fukuoka
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Petaling Jaya
country: Malaysia
facility: Novartis Investigative Site
state: Selangor
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Nitra
country: Slovakia
facility: Novartis Investigative Site
city: Trencin
country: Slovakia
facility: Novartis Investigative Site
city: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: Luzern
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Bristol
country: United Kingdom
facility: Novartis Investigative Site
state: Avon
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Coventry
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: