Enzalutamide With Lu PSMA-617 Versus Enzalutamide Alone in Men With Metastatic Castration-resistant Prostate Cancer (ENZA-p)

• ClinicalTrials.gov Identifier: NCT04419402
• Recruitment Status: Recruiting
• First Posted: June 5, 2020
• Last Update Posted: February 16, 2022
• Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Collaborators: National Health and Medical Research Council, Clinical Trials Centre; Prostate Cancer Research Alliance; Endocyte; Astellas Pharma Inc
• Information provided by (Responsible Party): Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Tracking Information

• First Submitted Date: May 28, 2020
• First Posted Date: June 5, 2020
• Last Update Posted Date: February 16, 2022
• Actual Study Start Date: August 17, 2020
• Estimated Primary Completion Date: June 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

Prostate Specific Antigen (PSA) Progression-Free Survival [ Time Frame: Date of randomisation to the date of first evidence of PSA progression - assessed up to study completion, approximately 4 years from recruitment. ]

PSA progression is defined as a rise in PSA by more than or equal to 25% AND more than or equal to 2 ng/mL above the nadir (lowest PSA point). This needs to be confirmed by a repeat PSA performed at least 3 weeks later.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 19, 2020)

• Radiographic Progression-Free Survival [ Time Frame: 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. ]
  Radiographic progression-free survival is defined as the interval from the date of randomisation to the date of first evidence of radiographic progression on imaging, or the date of last known follow-up without progression.
• Prostate Specific Antigen (PSA) response rate [ Time Frame: 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 ]
  PSA response rate is defined as the proportion of participants in each group with a PSA reduction of 50% or more from baseline.
• Pain response and Progression-Free Survival [ Time Frame: Date of randomisation through study completion, approximately 4 years from start of recruitment ]
  Pain is measured using the McGill-Melzack Present Pain Intensity scale (PPI). Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of 2 or more. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score. Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of 2 or more. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score.
• Clinical Progression-Free Survival [ Time Frame: 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. ]
  Clinical progression is defined by progression on imaging, development of symptoms attributable to cancer progression, the need for radiotherapy to new metastases or initiation of other anticancer treatment for prostate cancer.
• Aspects of Health-related Quality of life (HRQL) [ Time Frame: Assessed every 4-6 weeks, through study completion, approximately 4 years from recruitment. ]
  The European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire includes five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality-of-life scale to assess HRQL in cancer patients. The Patient DATA form is a simple, multi-item quality of life instrument based on 11-point numeric rating scales for a range of relevant symptoms and functions. It combines cancer specific items from the UBQ-C, GLQ-8 and LASA cancer-specific quality of life instruments. The Fear of Cancer Progression form is a short questionnaire assessing possible future concerns related to the participant's illness.
• Frequency and Severity of Adverse Events [ Time Frame: Through study completion, approximately 4 years from recruitment. ]
  The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to classify and grade the intensity of adverse events during study treatment.

Original Secondary Outcome Measures (submitted: June 3, 2020)

• Radiographic Progression-Free Survival [ Time Frame: 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. ]
  Radiographic progression-free survival is defined as the interval from the date of randomisation to the date of first evidence of radiographic progression on imaging, or the date of last known follow-up without progression.
• Prostate Specific Antigen (PSA) response rate [ Time Frame: 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 ]
  PSA response rate is defined as the proportion of participants in each group with a PSA reduction of ≥ 50% from baseline.
• Pain response and Progression-Free Survival [ Time Frame: Date of randomisation through study completion, approximately 4 years from start of recruitment ]
  Pain is measured using the McGill-Melzack Present Pain Intensity scale (PPI). Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of ≥2. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score. Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of ≥2. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score.
• Clinical Progression-Free Survival [ Time Frame: 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. ]
  Clinical progression is defined by progression on imaging, development of symptoms attributable to cancer progression, the need for radiotherapy to new metastases or initiation of other anticancer treatment for prostate cancer.
• Aspects of Health-related Quality of life (HRQL) [ Time Frame: Assessed every 4-6 weeks, through study completion, approximately 4 years from recruitment. ]
  The European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire includes five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality-of-life scale to assess HRQL in cancer patients. The Patient DATA form is a simple, multi-item quality of life instrument based on 11-point numeric rating scales for a range of relevant symptoms and functions. It combines cancer specific items from the UBQ-C, GLQ-8 and LASA cancer-specific quality of life instruments. The Fear of Cancer Progression form is a short questionnaire assessing possible future concerns related to the participant's illness.
• Frequency and Severity of Adverse Events [ Time Frame: Through study completion, approximately 4 years from recruitment. ]
  The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to classify and grade the intensity of adverse events during study treatment.

Current Other Pre-specified Outcome Measures (submitted: June 3, 2020)

• Overall Survival [ Time Frame: Through study completion, approximately 4 years from recruitment. ]
  Overall survival is defined as the interval from date of randomisation to the date of death from any cause, or the date of last known follow-up alive.
• Resource Use and Incremental Cost-effectiveness [ Time Frame: Through study completion, approximately 4 years from recruitment. ]
  Information on health-care resource use will be combined with information on overall survival and quality of life to estimate the value associated with the addition of Lu-PSMA to enzalutamide in terms of the cost per Quality adjusted life year (QALY).
• Association between Clinical Outcomes and Imaging Analyses at Baseline and During Treatment [ Time Frame: Through study completion, approximately 4 years from recruitment. ]
  A variety of methods to develop, validate and compare predictive and prognostic biomarkers for both enzalutamide treatment and enzalutamide and Lu-PSMA therapy. These include but are not limited to analyses of: 1. associations of screening whole body quantitative parameters on 68Ga-PSMA PET/CT and 18F FDG PET/CT; 2. association between the change on whole body quantitative PET parameters; 3. using the 68Ga-PSMA PET/CT at Day 92, assessment of quantitative whole body PET findings will help determine the proportion of men with persistent PSMA avid disease volume in those undergoing either enzalutamide or enzalutamide and Lu-PSMA treatments; 4. a visual scoring system for both 68Ga-PSMA PET/CT and 18F FDG PET/ CT to evaluate and validate its use in treatment response; 5. QTBI (Quantitative total body imaging) heterogeneity assessment.
• Association between Clinical Outcomes and Possible Prognostic/Predictive Biomarkers (tissue and circulating) including CTCs and ctDNA [ Time Frame: Through to study completion, approximately 4 years from recruitment. ]
  Translational research will include identifying tissue and circulating biomarkers that are prognostic and/or predictive of response to treatment, safety and resistance to study treatment (associations of biomarkers with clinical outcomes). These include, but are not limited to analyses of: 1. Liquid biopsies: Liquid biopsies will be collected at molecular imaging time points including at baseline, Day 92 and at first progression; 2. CTC: CTCs may be enumerated and analysed at the above time points for a variety of biomarkers.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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)
• 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).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Castration-Resistant Prostate Cancer

Intervention

• Drug: Lu-PSMA

  Patients will be given 7.5 GBq of Lu-PSMA in 4 doses. Dose 1 and 2 on Days 15 and 57. Doses 3 and 4 (Days 113 and 169) will be given following result of 68Ga-PSMA PET/CT at Day 92.

  Treatment administered every 6 weeks, x 4 cycles.

  Other Name: 177Lutetium -PSMA 617 also referred to as 177Lu-PSMA
• Drug: Enzalutamide
  160 mg (four 40 mg capsules) daily.
  Other Name: Xtandi

Study Arms

• Experimental: Lu-PSMA + Enzalutamide

  Lu-PSMA - 7.5 GBq (± 10%): doses 1 and 2 (Days 15 and 57). Doses 3 and 4 (Days 113 and 169) will be given following result of PSMA PET/CT scans at Day 92.

  Enzalumatide - 160 mg (four 40 mg capsules): daily until participant is no longer clinically benefiting, or experiences unacceptable toxicity.

  Interventions:

  • Drug: Lu-PSMA
  • Drug: Enzalutamide
• Active Comparator: Enzalutamide
  Enzalutamide - 160 mg (four 40 mg capsules): daily until participant is no longer clinically benefiting, or experiences unacceptable toxicity.
  Intervention: Drug: Enzalutamide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 3, 2020): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 1, 2023
• Estimated Primary Completion Date: June 1, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Men with mCRPC not previously treated with docetaxel for castration-resistant disease, suitable for treatment with enzalutamide and Lu-PSMA.

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Margaret McJannett; +6129562 5033; trials@anzup.org.au

Contact: Ailsa Langford; +61295625006; enza-p.study@sydney.edu.au

• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT04419402
• Other Study ID Numbers: ANZUP 1901
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Original Study Sponsor: Same as current

Collaborators

• National Health and Medical Research Council, Clinical Trials Centre
• Prostate Cancer Research Alliance
• Endocyte
• Astellas Pharma Inc

Investigators

• Study Chair: Louise Emmett, MBBS, FRACP; St Vincent's Hospital, Sydney

• PRS Account: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Verification Date: February 2022