Clinical trial NCT04419402: Enzalutamide With Lu PSMA-617 Versus Enzalutamide Alone in Men With Metastatic Castration-resistant Prostate Cancer
Official title: ENZA-p: A Randomised Phase II Trial Using PSMA as a Therapeutic Agent and Prognostic Indicator in Men With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide (ANZUP 1901)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Castration-Resistant Prostate Cancer
Lead sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Clinical Trials Centre
name: Prostate Cancer Research Alliance
name: Endocyte
name: Astellas Pharma Inc
First posted: 2020-06-05
Enrollment: 162
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase 2 randomised clinical trial will investigate the activity and safety of adding Lu-PSMA to enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC) not previously treated with chemotherapy.

Detailed description: This is an open label, randomised, stratified, 2-arm, multicentre phase 2 clinical trial recruiting 160 participants over 12 months and followed until 150 events occurred (approximately another 18 months). Participants will be randomised to enzalutamide or enzalutamide and Lu-PSMA in a 1:1 ratio. A minimisation approach will be used to minimise chance imbalances across the following stratification factors: study site, volume of disease (\>20 versus ≤20 sites of disease measured on 68Ga-PSMA PET/CT), prior treatment with early docetaxel for castration- sensitive disease (yes vs no), and prior treatment with early abiraterone for castration-sensitive disease (yes vs no).

Eligibility criteria: Inclusion Criteria:

1. Males aged 18 or older with metastatic adenocarcinoma of the prostate defined by:

   * Documented histopathology of prostate adenocarcinoma (no features of neuroendocrine carcinoma) OR
   * Metastatic disease typical of prostate cancer
2. Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist).
3. Progressive disease with rising PSA defined by PCWG3 criteria (sequence of 2 rising values at a minimum of 1-week intervals) AND PSA ≥ 5 ng/mL.
4. At least 2 of the following risk factors for early treatment failure with enzalutamide:

   * LDH ≥ ULN
   * ALP ≥ ULN
   * Albumin \<35 g/L
   * De novo metastatic disease (M1) at initial diagnosis \*
   * \<3 years since initial diagnosis
   * \>5 bone metastases \*
   * Visceral metastases \*
   * PSA doubling time \<84 days
   * Pain requiring opiates for \>14 days
   * Prior treatment with abiraterone \* Based on conventional imaging (CT and/or bone scan)
5. Target or non-target lesions according to RECIST 1.1
6. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined as SUVmax \>15 at a single site (regardless of lesion size) and SUV max \>10 at sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact)
7. ECOG performance status 0-2
8. Adequate renal function:

   - Creatinine clearance ≥ 40mL/ min
9. Adequate liver function:

   * Bilirubin \< 1.5 x upper limit of normal (ULN) (or if bilirubin is between 1.5 - 2x ULN, must have a normal conjugated bilirubin)
   * AST or ALT ≤ 2.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases)
10. Adequate bone marrow function:

    * Platelets ≥ 100 x109/L
    * Haemoglobin ≥ 90g/L (no red blood cell transfusion in last 4 weeks)
    * Neutrophils \> 1.5 x109/L
11. Estimated life expectancy \> 12 weeks
12. Study treatment both planned and able to start within 21 days of randomisation
13. Willing and able to comply with all study requirements (including both treatments: enzalutamide and Lu-PSMA), and all required study assessments
14. Signed, written, informed consent

Exclusion Criteria:

1. Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate
2. 68Ga-PSMA PET/CT SUVmax \< 10 at a site of measurable disease \> 10mm
3. Prior treatment with enzalutamide, darolutamide, or apalutamide. Prior treatment with abiraterone is allowed.
4. Prior treatment with any PSMA-targeted radiotherapy
5. Prior chemotherapy for mCRPC. Prior docetaxel in castration-sensitive setting is permitted
6. History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours)
7. Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety
8. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
9. Men in sexual relationships with women of reproductive potential who are not willing/able to use medically acceptable forms of barrier contraception
10. History of:

    1. seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)
    2. loss of consciousness or transient ischemic attack within 12 months of randomization
    3. significant cardiovascular disease within the last 3 months: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater, see Appendix 4), ongoing arrhythmias of Grade \> 2, thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed

Primary outcomes:
measure: Prostate Specific Antigen (PSA) Progression-Free Survival
timeFrame: Date of randomisation to the date of first evidence of PSA progression - assessed up to study completion, approximately 4 years from recruitment.
Secondary outcomes:
measure: Radiographic Progression-Free Survival
timeFrame: Date of randomisation to the date of first evidence of radiographic progression on imaging. Assessed every 12 weeks through study completion, approximately 4 years from start of recruitment.
measure: Prostate Specific Antigen (PSA) response rate
timeFrame: Date of randomisation through study completion, approximately 4 years from start of recruitment. Early rises in PSA prior to 12 weeks will be disregarded in determining PSA response
measure: Pain response and Progression-Free Survival
timeFrame: Date of randomisation through study completion, approximately 4 years from start of recruitment
measure: Clinical Progression-Free Survival
timeFrame: Date of randomisation to the date of first clinical evidence of disease progression or death from any cause. Assessed up to study completion approximately 4 years from recruitment.
measure: Aspects of Health-related Quality of life (HRQL)
timeFrame: Assessed every 4-6 weeks, through study completion, approximately 4 years from recruitment.
measure: Frequency and Severity of Adverse Events
timeFrame: Through study completion, approximately 4 years from recruitment.
Other outcomes:
measure: Overall Survival
timeFrame: Through study completion, approximately 4 years from recruitment.
measure: Resource Use and Incremental Cost-effectiveness
timeFrame: Through study completion, approximately 4 years from recruitment.
measure: Association between Clinical Outcomes and Imaging Analyses at Baseline and During Treatment
timeFrame: Through study completion, approximately 4 years from recruitment.
measure: Association between Clinical Outcomes and Possible Prognostic/Predictive Biomarkers (tissue and circulating) including CTCs and ctDNA
timeFrame: Through to study completion, approximately 4 years from recruitment.
Locations:
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincents Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Macquarie Park
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Sydney
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
Study officials:
affiliation: St Vincent's Hospital, Sydney
name: Louise Emmett, MBBS, FRACP
role: STUDY_CHAIR
References: