PSMAfore: A phase III, Open-label, Multi-Center, Randomized Study Comparing 177Lu-PSMA-617 vs. a Change of androgen receptor-directed therapy in the Treatment of Taxane Naïve Men with Progressive Metastatic Castrate Resistant Prostate Cancer

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

16 Jun 2021 → ongoing

Decision date (initial)

2024-03-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-507772-50-00

EudraCT number

2020-003969-19

ClinicalTrials.gov

NCT04689828

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Safety, Efficacy

The main objective of the trial is to evaluate whether treatment with 177LuPSMA-617 improves the time to radiographic progression by PCWG3- modified RECIST v1.1 or death in participants with progressive PSMA-positive mCRPC compared to participants treated with ARDT

Secondary objectives 10

1. Key Secondary Objective is to evaluate whether treatment with 177LuPSMA-617 improves the overall survival (OS) in participants with progressive PSMA-positive mCRPC compared to participants treated with ARDT treatment
2. To estimate the time to radiographic progression by BICR or death in participants treated with ARDT who subsequently crossover to 177Lu-PSMA-617 after radiographic progression (rPFS2)
3. To evaluate Progression free survival (PFS) by investigator's assessment
4. To evaluate the second progression Free Survival (PFS2) by investigator's assessment
5. To evaluate whether treatment with 177Lu-PSMA-617 improves the biochemical response as detected by Prostate specific antigen (PSA) halving compared to participants treated with ARDT
6. To evaluate whether treatment with 177Lu-PSMA-617 improves the time to first symptomatic skeletal event (TTSE) compared to participants treated with ARDT
7. To evaluate whether treatment with 177Lu-PSMA-617 improves the time to radiographic soft tissue progression compared to participants treated with ARDT
8. To evaluate whether treatment with 177Lu-PSMA-617 improves the time to chemotherapy compared to participants treated with ARDT
9. To evaluate whether treatment with 177Lu-PSMA-617 improves the health-related quality of life (HRQoL) compared to participants treated with ARDT
10. To evaluate the safety and tolerability of 177Lu-PSMA-617

Conditions and MedDRA coding

PSMA-positive metastatic castration-resistant prostate cancer

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

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

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed informed consent must be obtained prior to participation in the study
2. Participants must be adults ≥ 18 years of age
3. Participants must have an ECOG performance status of 0 to 1
4. Participants must have histological pathological, and/or cytological confirmation of adenocarcinoma of the prostate
5. Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor’s central reader
6. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L)
7. Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide). first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior ARDT therapy • second generation ARDT must be the most recent therapy received
8. Participants must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria: • Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression. • Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)] • Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016))
9. Participants must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained prior to randomization
10. Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia
11. Participants 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 participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted • ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases Renal: • eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
12. Albumin ≥ 2.5 g/dL
13. Candidates for change in ARDT as assessed by the treating physician • Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone.

Exclusion criteria 18

1. 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
2. Any investigational agents within 28 days prior to day of randomization
3. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes
4. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy
5. Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion
6. Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
7. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
8. Any condition that precludes raised arms position
9. Eligible for treatment(s) other than ARDT based on presence of any mutations or biomarkers that are known as predictors of better response (e.g., AR-V7 or BRCA).
10. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
11. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, 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. • HIV-infected participants who are at a low risk of AIDS-related outcomes may participate in this trial. • 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. 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 and treatment free for more than 3 years prior to randomization, are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer
13. 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
14. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: Participant with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
15. History or current diagnosis of the following ECG abnormalities indicating significant risk of safety for study participants: • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade 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 Pointe • Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to starting study treatment
16. Previous PSMA-targeted radioligand therapy
17. Prior treatment with cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy [including monoclonal antibodies]. [Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed]
18. Not able to understand and to comply with study instructions and requirements

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 (BICR) and as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death due to any cause.

Secondary endpoints 10

1. OS: Time from randomization to death due to any cause
2. rPFS2 defined as time from the date of crossover (ARDT to 177Lu-PSMA-617) to the date of radiographic disease progression by BICR or death from any cause [rPFS definition as outlined in PCWG3 guidelines]
3. PFS defined as time from date of randomization to the first documented progression by investigator's assessment (radiographic, clinical, or PSA progression) or death from any cause, whichever occurs first
4. PFS2 defined as time from date of randomization to the first documented progression by investigator's assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first, on next-line of therapy
5. PSA50 defined as proportion of participants who achieved a ≥ 50% decrease from baseline that is confirmed by a second PSA measurement ≥ 4 weeks. PSA50 will be evaluated at 3, 6 and 12 months.
6. 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
7. Time to soft tissue progression (TTSTP) defined as time from randomization to radiographic soft tissue progression per PCWG3-modified RECIST v1.1 (Soft Tissue Rules of Prostate Cancer Working Group modified Response Evaluation Criteria in Solid Tumors Version 1.1) as Assessed by Blinded Independent Central Review (BICR)
8. Time to chemotherapy (TTCT) defined as time from randomization to initiation of the first subsequent chemotherapy or death, whichever occurs first
9. HRQoL as assessed by EQ-5D-5L, FACT-P and BPI-SF
10. Frequency of adverse events, safety laboratory assessments and vital signs

Investigational products

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

Test 2

Comparator 6

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 25

Locations

9 EU/EEA countries · 37 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 1 · 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 84 files

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

Application history

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