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)

Overview

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 CI (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.

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 outcome measures

• Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) [Time frame: 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 outcome measures (12)

• Key secondary endpoint: Time to Hormonal Therapy (TTHT) [Time frame: From date of randomization until date of Androgen Deprivation Therapy (ADT), assessed up to approximately 74 months]
• Investigator assessed Metastasis Free Survival (MFS) [Time frame: 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) [Time frame: From date of randomization until date of first PSA progression, assessed up to approximately 74 months]
• Radiographic Progression Free Survival (rPFS) [Time frame: 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) [Time frame: From date of randomization until initiation of the next line of therapy (local or systemic), assessed up to approximately 74 months]
• 24-month prostate-specific antigen (PSA) progression free survival (PFS) [Time frame: 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]
• Time to symptomatic progression [Time frame: From date of randomization until date of first documented symptomatic progression, assessed up to approximately 74 months]
• Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire [Time frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months]
• Functional Assessment of Cancer Therapy - Radionuclide Therapy (FACT-RNT) Questionnaire [Time frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months]
• Brief Pain Inventory - Short Form (BPI-SF) Questionnaire [Time frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months]
• European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L) [Time frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months]
• Time to First Symptomatic Skeletal Event (TTSE) [Time frame: From date of randomization till end of treatment (EOT) or death, whichever happens first, assessed up to approximately 74 months]

Eligibility criteria

Inclusion criteria

• Histologically confirmed prostate cancer prior to randomization
• 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))
• 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)
• 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
• 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.
• All metastatic lesions detected at screening must be amenable to SBRT
• Non-castration testosterone level >100 ng/dL at screening

Exclusion criteria

• Participants with de novo OMPC at screening
• 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
• Prior therapy with:

• 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, nilutamide, cyproterone) for biochemical recurrence or adjuvant/neoadjuvant therapy are eligible provided that they discontinued therapy ≥3 months prior to randomization.
• Participants who have discontinued ADT due to disease progression are not eligible (i.e., Castration-Resistant Prostate Cancer (CRPC) participants)
• 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 ≥3 months before randomization.

• Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy)
• Immunotherapy (e.g., sipuleucel-T)
• Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization
• Any other investigational or systemic agents for metastatic disease
• Radiation therapy external beam radiation therapy (EBRT) and brachytherapy within 28 days before randomization
• 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
• 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.
• 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
• Participants in immediate need of ADT as assessed by the investigator.

Other protocol defined Inclusion/Exclusion may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 39 centers

• Highlands Oncology Group — Fayetteville
• VA Greater LA Healthcare System — Los Angeles
• VA Palo Alto Health Care System — Palo Alto
• Stanford University — Palo Alto
• UCSF — San Francisco
• Rocky Mountain Cancer Centers — Denver
• Cancer Specialists of North Florida — Jacksonville
• Woodlands Medical Specialists — Pensacola
• … and 31 more centers

Japan · 11 centers

Center list to be confirmed — check the primary protocol.

Spain · 9 centers

Center list to be confirmed — check the primary protocol.

Canada · 8 centers

• Novartis Investigative Site — Calgary
• Novartis Investigative Site — Halifax
• Novartis Investigative Site — London
• Novartis Investigative Site — Ottawa
• Novartis Investigative Site — Toronto
• Novartis Investigative Site — Montreal
• Novartis Investigative Site — Montreal
• Novartis Investigative Site — Québec

Germany · 8 centers

• Novartis Investigative Site — Munich
• Novartis Investigative Site — Cologne
• Novartis Investigative Site — Aachen
• Novartis Investigative Site — Augsburg
• Novartis Investigative Site — Berlin
• Novartis Investigative Site — Essen
• … and 2 more centers

Italy · 8 centers

Center list to be confirmed — check the primary protocol.

France · 6 centers

• Novartis Investigative Site — Saint-Cloud
• Novartis Investigative Site — Bordeaux
• Novartis Investigative Site — Bron
• Novartis Investigative Site — Clermont-Ferrand
• Novartis Investigative Site — Rouen
• Novartis Investigative Site — Saint-Herblain

Israel · 5 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 5 centers

Center list to be confirmed — check the primary protocol.

Australia · 4 centers

• Novartis Investigative Site — Darlinghurst
• Novartis Investigative Site — Herston
• Novartis Investigative Site — Adelaide
• Novartis Investigative Site — Malvern

Slovakia · 4 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 4 centers

Center list to be confirmed — check the primary protocol.

Argentina · 3 centers

• Novartis Investigative Site — CABA
• Novartis Investigative Site — CABA
• Novartis Investigative Site — Caba

Belgium · 3 centers

• Novartis Investigative Site — Aalst
• Novartis Investigative Site — Ghent
• Novartis Investigative Site — Wilrijk

China · 3 centers

• Novartis Investigative Site — Beijing
• Novartis Investigative Site — Guangzhou
• Novartis Investigative Site — Shanghai

Czechia · 3 centers

• Novartis Investigative Site — Ostrava
• Novartis Investigative Site — Olomouc
• Novartis Investigative Site — Prague

Hungary · 3 centers

Center list to be confirmed — check the primary protocol.

Switzerland · 3 centers

Center list to be confirmed — check the primary protocol.

Austria · 2 centers

• Novartis Investigative Site — Linz
• Novartis Investigative Site — Vienna

Colombia · 2 centers

• Novartis Investigative Site — Bogota
• Novartis Investigative Site — Bogotá

Greece · 2 centers

Center list to be confirmed — check the primary protocol.

Malaysia · 2 centers

Center list to be confirmed — check the primary protocol.

Mexico · 2 centers

Center list to be confirmed — check the primary protocol.

Singapore · 2 centers

Center list to be confirmed — check the primary protocol.

Brazil · 1 center

• Novartis Investigative Site — São Paulo

Netherlands · 1 center

Center list to be confirmed — check the primary protocol.

Puerto Rico · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT05939414 · CAAA617D12302 · 2022-502956-29-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗