An Open-label study comparing 177Lu-PSMA-617 plus Standard of Care vs. Standard of Care in the Treatment of mHSPC

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

31 Mar 2021 → ongoing

Decision date (initial)

2024-03-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507970-42-00

EudraCT number

2020-003968-56

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The main objective of the trial is to evaluate radiographic progression free survival (rPFS) as assessed by Blinded Independent Review Committee (BIRC) in patients with mHSPC receiving Standard of Care and 177Lu-PSMA-617 versus patients receiving Standard of Care without 177Lu-PSMA-617.

Secondary objectives 10

1. Key Secondary objective is to evaluate the contribution of 177Lu-PSMA- 617 to Standard of Care in terms of overall survival (OS) in patients with mHSPC.
2. To evaluate PSA90 response at 12, 24 and 48 weeks
3. To evaluate the time to development of metastatic castration resistant prostate cancer (mCRPC) as determined by investigators.
4. To evaluate Progression Free Survival (PFS) by investigator
5. To evaluate the second progression Free Survival (PFS2) by investigator
6. To evaluate the change in the nadir levels of PSA < 0.2 ng/mL at months 12, 24 and 48 weeks
7. To evaluate the overall response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR) and Time to soft tissue progression (TTSTP) based on Prostate Cancer Working Group 3 (PCWG3)-modified Response evaluation criteria in solid tumor (RECIST) 1.1 by Blinded Independent Review Committee (BIRC) assessment
8. To evaluate safety and tolerability of 177Lu-PSMA-617
9. To assess the effect of 177Lu-PSMA-617 on the health-related quality of life (HRQoL)
10. To evaluate the time to first symptomatic skeletal event (SSE).

Conditions and MedDRA coding

PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

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

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Signed informed consent must be obtained prior to participation in the study
2. Patients must be adults ≥18 years of age
3. Patients must have an ECOG performance status of 0 to 2
4. Patients must have a life expectancy >9 months as determined by the study investigator
5. Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site)
6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan, and eligible as determined by the sponsor’s central reader
7. Patients must have at least one metastatic bone and/or soft tissue/visceral lesion documented in the following manners within 28 days prior randomization: a. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans AND/ OR b. Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis AND/ OR c. Visceral metastases of any size or distribution. If a participant has a history of visceral metastases at any time prior to randomization, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes).
8. Patients must have adequate organ function: • Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL • Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN), for patients with known Gilbert’s Syndrome ≤3 x ULN is permitted. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases • Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
9. Albumin ≥2.5 g/dL
10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial
11. Patients must be: 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 antiandrogen must be discontinued prior to start of study therapy or after 45 days whatever 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. • Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. • No CYP17 inhibitor or ARDT exposure for earlier stages of prostate cancer is allowed.

Exclusion criteria 17

1. Patients with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy
2. Any prior systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria 11), including chemotherapy, Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy (including monoclonal antibodies).
3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy
4. Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed
5. Ongoing participation in any other clinical trial
6. Use of other investigational drugs within 30 days prior to day of randomization
7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
8. Transfusion for the sole purpose of making a participant eligible for study inclusion
9. Participant with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participant with epidural disease, canal disease and prior cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired. Patients with parenchymal CNS metastasis (or a history of CNS metastasis), that have received prior therapy and are neurologically stable, asymptomatic and not receiving steroids for CNS metastases, are allowed; baseline and subsequent radiological imaging for them must include evaluation of the brain (magnetic resonance imaging (MRI) preferred or CT with contrast).
10. Diagnosed 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 free, treatment free for more than 3 years prior to randomization, or participants with adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible.
11. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance)
12. Active clinically 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. • History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade atrioventicular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) • History of familial long QT syndrome or known family history of Torsades de Pointes • Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature
13. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
14. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
15. Inability to complete the study imaging procedures due to any reason (e.g., severe claustrophobia, inability to lie still for the entire imaging time, any condition that precludes raised arms position)
16. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: patients with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
17. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks 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 period 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Radiographic progression-free survival (rPFS) is defined as the time from the date of randomization to the date of first documented radiographic disease progression as assessed by blinded independent central review (BIRC) and as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death due to any cause

Secondary endpoints 11

1. Overall survival is defined as the time from the date of randomization to the date of death due to any cause
2. PSA90 response is defined as the proportion of patients who have a ≥90% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement ≥4 weeks later. PSA90 at 12, 24 and 48 weeks will be evaluated.
3. Time to development of mCRPC is defined as the time from date of randomization to disease progression despite androgen deprivation therapy (ADT) presenting as either a continuous rise in serum prostate specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
4. PFS is defined as the time from date of randomization to the date of first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first
5. PFS2 is defined as time from date of randomization to the first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) on next-line therapy or death from any cause, whichever occurs first.
6. Proportion of patients with PSA < 0.2 ng/mL at 12, 24 and 48 weeks
7. ORR, DCR, TTR, DOR, TTSTP based on PCWG3- modified RECIST 1.1 by BIRC.
8. Safety: incidence and severity of AEs and serious adverse event (SAE)s, changes in laboratory values, vital signs and ECGs. Any clinically significant lab, vital signs, ECG abnormalities will be captured as an AE.
9. Tolerability: dose interruptions, reductions and dose intensity
10. HRQoL as assessed by Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory (Short Form (BPI-SF) and European Quality of Life (EuroQol) 5 Domain 5 Level scale (EQ-5D-5L)
11. Time to SSE (TTSSE) 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

Investigational products

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

Test 2

Auxiliary 15

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

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 21

Locations

10 EU/EEA countries · 46 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 80 files

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

Application history

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