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

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jul 2024 → ongoing

Decision date (initial)

2023-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novartis Pharma AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the Blinded Independent Review Committee (BIRC) assessed metastasis free survival (MFS) by conventional imaging (CI)in adult participants with OMPC defined by PSMA Positron Emission Tomography (PET) receiving AAA617 vs observation

Secondary objectives 11

1. To evaluate time to hormonal therapy (TTHT) for castration in adult participants with OMPC defined by PSMA PET receiving AAA617 vs observation
2. To evaluate the Investigator assessed MFS by CI in adult participants with OMPC defined by PSMA PET receiving AAA617 vs observation
3. To evaluate the effect of AAA617 on time to prostate specific antigen (PSA) progression
4. To evaluate the effect of AAA617 on time to radiographic progression free survival (rPFS) by BIRC and Investigator
5. To evaluate the effect of AAA617 on time to next therapy (local or systemic)
6. To evaluate the effect of AAA617 on 24-month PSA PFS (≥ 0.5 ng/mL)
7. To evaluate the impact of AAA617 on the time to symptomatic progression
8. To assess the effect of AAA617 on Patient Reported Outcomes (Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory - Short From (BPI-SF), Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) and European Quality of Life (EuroQoL) 5 Domain 5 Level scale (EQ-5D-5L)
9. To evaluate the effect of AAA617 on time to symptomatic skeletal event (SSE)
10. To evaluate safety and tolerability of AAA617 Common Terminology Criteria for Adverse Events (CTCAE)
11. To evaluate the effect of AAA617 on overall survival (OS)

Conditions and MedDRA coding

Oligometastatic prostate cancer (OMPC)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-002419-PIP02-18, EMEA-002577-PIP01-19

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Histologically confirmed prostate cancer prior to randomization
2. Participants must have biochemically recurrent disease after definitive treatment to prostate by RP, (alone or with post-operative radiation to prostate bed/pelvic nodes) or 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 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 the definition of PSMA PET positivity of a lesion, please refer to Section 8.1 and 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 scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Readers 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/CT 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 are 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

Exclusion criteria 8

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: a. ADT (including bilateral orchiectomy) and ARPIs used for metastatic prostate cancer treatment • Participants who received AR-directed therapy, whether ADT or an AARPI 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., CRPC participants) b. Other hormonal therapy. e.g., • Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) 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 ≥3 months before randomization. c. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy) d. Immunotherapy (e.g., sipuleucel-T) e. Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization f. Any other investigational or systemic agents for metastatic disease
4. 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), 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 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MFS is defined as the time from randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by CI (i.e., CT/MRI and bone scans) as assessed by BIRC using RECIST 1.1 or death from any cause, whichever occurs first

Secondary endpoints 11

1. TTHT is defined as the time from randomization to the time to ADT for castration. The type of hormonal therapy will be at the discretion of the Investigator
2. Investigator assessed MFS is defined as the time from randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by CI (i.e., CT/MRI and bone scans) as assessed by Investigator using RECIST 1.1 or death from any cause, whichever occurs first
3. Time to PSA progression is defined as time from randomization to first PSA progression 1. PSA progression 1 is defined as a rising PSA confirmed on repeated measurement at least 3 weeks later, and at least greater than 25% and ≥2 ng/mL above nadir or baseline, whichever is lower
4. rPFS is defined as the time from randomization to first documentation of confirmed radiographic progressive disease by CI(i.e., CT/MRI and bone scans) using RECIST 1.1 or death due to any cause (whichever occurs first)
5. Time to next therapy is defined as time from randomization to initiation of the next line of therapy (local or systemic)
6. 24-month PSA PFS (≥ 0.5 ng/mL) is defined as PSA PFS at 24 months. PSA PFS is defined as the time from date of randomization to the date of first documented PSA progression 2 or death from any cause, whichever occurs first. PSA progression 2 is defined as a PSA concentration above the nadir (or baseline if lower) of ≥ 0.5 ng/mL, confirmed by repeated measurement at least 3 weeks later
7. Time to symptomatic progression is defined as time from randomization to the date of first documented event for any of the following, whichever occurs first. • Development of a symptomatic skeletal event (SSE), • Escalation in cancer-related pain or worsening of disease-related symptoms leading to the initiation of a new systemic anticancer therapy • Development of clinically significant symptoms due to local or regional tumor progression leading to surgery or radiation therapy
8. HRQoL as assessed by FACT-P, BPI-SF, FACT-RNT and EQ-5D-5L
9. Time to SSE (TTSSE) is defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first
10. Safety: incidence and severity of AEs and serious adverse event (SAEs), changes in laboratory values, vital signs and ECGs. Any clinically significant lab, vital signs, ECG abnormalities will be captured as an AE. Tolerability: dose interruptions, reductions and dose intensity
11. OS is defined as the time from the date of randomization to the date of death due to any cause

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 29

Locations

11 EU/EEA countries · 52 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 2 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 130 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications