SatisfACtion: A Phase I/II, open-label, multi-center study of [225Ac]Ac-PSMA-R2 in men with metastatic hormone sensitive prostate cancer (mHSPC) and in men with heavily pre-treated PSMA positive metastatic castration resistant prostate cancer (mCRPC) with or without prior 177Lu-labelled PSMA-targeted radioligand therapy

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

7 Nov 2023 → ongoing

Decision date (initial)

2024-01-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507672-52-00

EudraCT number

2021-003478-30

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Dose response, Therapy, Safety

● Primary objectives for dose escalation
To characterize the safety and tolerability of 225Ac-PSMA-R2 and to the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in:
Group-1: PSMA-positive mCRPC participants previously treated with 177Lu-labelled PSMA-targeted RLT (post-177Lu).
Group-2: PSMA-positive mCRPC participants not previously treated with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).
Group 3: PSMA-positive mHSPC participants not previously treated with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).
● Primary objectives for dose expansion
To evaluate the anti-tumor activity for 225Ac-PSMA-R2 in mCRPC post-177Lu and pre-177Lu treatment (naïve) and mHSPC (pre-177Lu treatment) participants.

Secondary objectives 4

1. ● Secondary objectives for dose escalation: To assess the clinical anti-tumor activity of 225Ac-PSMA-R2 in Group 1, Group 2, and Group 3 ● Secondary objectives for dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs: To assess the clinical anti-tumor activity of 225Ac-PSMA-R2.
2. ● Secondary objectives for dose escalation To characterize the PK of 225Ac-PSMA-R2 post-secular equilibrium. ● Secondary objectives for dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs: To characterize the safety and tolerability of 225Ac-PSMA-R2.
3. ● Secondary objectives for dose escalation: To characterize the PK of 225Ac-PSMA-R2 post-secular equilibrium. ● Secondary objectives for dose expansion in post-177Lu-labelled PSMA-targeted RLTs: To characterize the PK of 225Ac-PSMA-R2 pre- and post-secular equilibrium.
4. • Secondary objectives for dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs: To assess the impact of treatment with 225Ac-PSMA-R2 on the health-related quality of life (HRQoL).

Conditions and MedDRA coding

PSMA-positive metastatic hormone sensitive prostate cancer (mHSPC) and metastatic Castration-resistant Prostate Cancer (mCRPC) with or without prior 177Lu-PSMA radioligand therapy.

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Ability to understand and sign an approved Informed Consent Form (ICF), and to understand and comply with all protocol requirements
2. For mCRPC participants: Prior orchiectomy or ongoing ADT and meet the following criteria in terms of previous 177Lu-labelled PSMA-targeted RLTs in both dose escalation and dose expansion: • Group 1 (dose escalation) and Group 1 (dose expansion): (post-ARPI, post-taxane-based chemotherapy, post-177Lu-PSMA-RLT): participants must have received previous treatment with 177Lu-labelled PSMA-targeted RLTs. • Group 2 (dose escalation) and Group 2 (dose expansion): (post ARPI, pre-177Lu-PSMA-RLT): participants must have never received previous treatment with 177Lu-labelled PSMA-targeted RLTs. Prior taxane-based chemotherapy is not required.
3. Adequate organ function: • Bone marrow reserve: • White blood cell (WBC) count ≥ 3.0 x 109/L and absolute neutrophil count (ANC) ≥ 1.5 x 109/L. • Platelets ≥ 75 x 109/L. • Hemoglobin ≥ 8 g/dL (8 g/dL is equivalent to 80 g/L. • Hepatic function: • Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted. • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases. • Albumin > 3.0 g/dL (3.0 g/dL is equivalent to 30 g/L. • Renal function: • Creatinine clearance ≥ 60 mL/min. Note that participants with hydronephrosis or findings indicating blockage of urinary outflow are not eligible
4. Human immunodeficiency virus (HIV)-infected participants who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes are eligible.
5. For participants who have partners of childbearing potential, the use a method of birth control with adequate barrier protection, deemed acceptable by the Investigator during the study and for 6 months after last study drug administration.
6. Adults ≥ 18 years of age
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) : ECOG 0-1 for participants in dose escalation ECOG 0-2 for participants in dose expansion
8. Histological, pathological, and/or cytological confirmation of prostate cancer
9. Have ≥ 1 metastatic lesion that is present on a baseline CT, Magnetic Resonance Imaging (MRI), or bone scan imaging according to baseline scan imaging as defined in protocol Section 8.3.1.
10. Evidence of PSMA-positive disease by 68Ga-PSMA-R11 PET/CT and eligible as determined by central reading
11. Recovered or stabilized to ≤ Grade 1 from all clinically significant toxicities related to prior PCa therapy with an exception for neuropathy to ≤ Grade 2 and alopecia any grade
12. A documented progressive mHSPC or mCRPC based on at least 1 of the following criteria: • Serum or plasma PSA progression defined as an increase in in PSA ≥ 25% and > 2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL. • Soft-tissue progression defined as an increase ≥ 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. • Progression of bone disease defined as evaluable disease or new bone lesions(s) by bone scan (2 + 2 PCWG3 criteria, Scher et al 2016).
13. A castrate level of serum or plasma testosterone (<50 ng/dL or < 1.7 nmol/L) for mCRPC patients at screening. Monitoring of testosterone level is not mandated for participants with mHSPC who are receiving SoC treatment.
14. For mHSPC participants: treatment naïve OR minimally treated with: • Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of study therapy or after 45 days, whichever happens first. If received, prior LHRH agonist/antagonist with or without first generation antiandrogen use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy. Temporarily ADT adjuvant to EBRT in the curative setting is allowed; however, this must have been discontinued > 3 months prior to inclusion. • Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. • Prior chemotherapy is not required.

Exclusion criteria 14

1. Previous treatment with any of the following within 6 weeks of IRT cohort enrollment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation.
2. History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to ICF signature and/or clinically active significant cardiac disease defined as any of the following: • NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3, left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO), uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg with or without antihypertensive medication. • History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study, primarily mean resting corrected QT interval (QTc) > 470 millisecond (msec), obtained from average value 3 ECG recordings taken approximately 2-3 minutes apart as per Investigator assessment and/or others such as: concomitant clinically significant cardiac arrhythmias e.g. sustained ventricular tachycardia, complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g. bifascicular block). • Mobitz type II, long AT syndrome, known family history and/or current condition of Torsade de Pointes and third-degree AV block, or any factor increasing the risk of QTc prolongation(e.g. hypokalemia).
3. Diagnosis of other malignancies expected to alter life expectancy or may interfere with disease assessment. Prior history of malignancy who have been disease free for more than 3 years are eligible
4. A superscan as seen in the baseline bone scan
5. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 6 months after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF
6. Previous treatment with PSMA-targeted RLT for Group 2 and Group 3
7. Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy.
8. Any systemic anti-cancer therapy (e.g. other concurrent chemotherapy, radioligand therapy, immunotherapy or biological therapy including monoclonal antibodies) within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy. Patients on stable bisphosphonate or denosumab for ≥ 15 days prior to study start are not excluded (with the exception of the drugs listed on inclusion criteria #14 for mHSPC patients).
9. Uncontrolled pain or incompatibility that may result in participant’s lack of ability to comply with imaging procedures
10. Transfusion for the sole purpose of eligibility into the study.
11. History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression are NOT eligible, except: • Previous therapy (surgery, radiotherapy, gamma knife) and are neurologically stable, asymptomatic, and are not receiving corticosteroids for the purposes of maintaining neurologic integrity. • Epidural disease, canal disease and prior cord involvement if those areas have been treated, are stable, and not neurologically impaired.
12. Concurrent serious (as determined by investigator) medical conditions, including, but not limited to, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation
13. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters
14. Known hypersensitivity to components of the imaging product or investigational therapy or its analogues.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Primary endpoint for dose escalation: Incidence and severity of DLTs during the DLT observation period (first 42 days of treatment).Incidence and severity of AEs and SAEs including changes in laboratory values, ECGs and vital signs by group and frequency schedule (Q6W and Q4W).Primary endpoint for dose expansion: Overall Response Rate (ORR) per in soft tissue according to PCWG3 modified RECIST v1.1 in absence of bone progression (as per PCWG3), by central assessment and (PSA50) response rate.
2. Primary endpoint for dose escalation: Tolerability: Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group.

Secondary endpoints 5

1. Secondary endpoint for dose escalation: Secondary endpoint for dose expansion : ● Safety: Incidence and severity of AEs and serious adverse events (SAEs) including changes in laboratory values, electrocardiograms (ECGs) and vital signs by group.
2. Secondary endpoint for dose escalation: Secondary endpoint for dose expansion : ● Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by group.
3. Escalation:ORR,DCR,BOR,rPFS,OS,DoR per PCWG3 (investigator), Time to 1st SSE, responses measured by PSA (response rate, duration, time to 1st response, time to progression). Change from baseline in ALP/LDH. Expansion:DCR,BOR,DoR in soft tissue only according to PCWG3 absence of bone progression (central). rPFS per PCWG3 (central) and PFS (local), OS, Time to 1st SSE, responses measured by PSA (response rate, duration, time to 1st response, time to progression), change from baseline in ALP/LDH.
4. Radioactivity measurements in blood during Cycle 1 and derived PK parameters (i.e., AUC, Cmax, CL, Tmax, Vz, T1/2) of 225Ac-PSMA-R2 at different measurement times (post-secular equilibrium).
5. Secondary endpoint for dose expansion: Secondary endpoint for dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs:Change from baseline in HRQoL as assessed by XeQoL, EQ-5D-5L, FACT-P and BPI-SF. With the exception of XeQoL, the other HRQoL’s will be assessed in dose expansion only.

Investigational products

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

Test 3

Auxiliary 11

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 12

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 17 files

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

Application history

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