Clinical trial NCT04343885: In Men With Metastatic Prostate Cancer, What is the Safety and Benefit of Lutetium-177 PSMA Radionuclide Treatment in Addition to Chemotherapy
Official title: UpFrontPSMA : A Randomised Phase 2 Study of Sequential 177Lu-PSMA617 and Docetaxel Versus Docetaxel in Metastatic Hormone-Naive Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Hormone Naive Prostate Cancer
Lead sponsor: Peter MacCallum Cancer Centre, Australia
Sponsor class: OTHER
Collaborators: name: Movember Foundation
name: Prostate Cancer Research Alliance
name: United States Department of Defense
name: Advanced Accelerator Applications
name: Australia's Nuclear Science and Technology Organisation (ANSTO)
name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Australasian Radiopharmaceutical Trials network (ARTnet)
name: Centre for Biostatistics and Clinical Trials (BaCT)
First posted: 2020-04-13
Enrollment: 130
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 compare the effectiveness of Lu-PSMA therapy followed by docetaxel chemotherapy versus docetaxel chemotherapy on its own in patients with newly-diagnosed high-volume metastatic hormone-naive prostate cancer (mHNPC).

Detailed description: This is an open label, randomised, stratified, 2-Arm, multi-centre, phase 2 clinical trial recruiting 140 newly-diagnosed high-volume mHNPC patients at 11 Australian centres over a period of 18 months. Patients will be randomised to the experimental Arm (177Lu-PSMA followed by docetaxel) or standard-of-care Arm (docetaxel) in a 1:1 ratio. All patients will receive ADT continuously throughout the trial. Patients will be stratified according to disease volume by conventional imaging (low-volume vs. high-volume) and duration of ADT at time of registration (≤ 28 days vs. \> 28 days).

Eligibility criteria: Inclusion Criteria for study registration:

1. Patient has provided written informed consent
2. Male aged 18 years or older at screening
3. Prostate cancer diagnosed within 12 weeks of commencement of screening
4. Histologically or cytologically confirmed adenocarcinoma of the prostate without significant neuroendocrine differentiation or small cell histology OR metastatic disease typical of prostate cancer (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with a rising serum PSA
5. Evidence of metastatic disease on CT and/or bone scan
6. PSA \> 10ng/ml prior to commencement of medical ADT or surgical orchidectomy
7. Adequate haematological, renal and hepatic functions as defined by:

   * Absolute neutrophil count \>1.5 x 109/L
   * Platelet count \>100 x 109/L
   * Haemoglobin ≥ 90g/L (no red blood cell transfusion in 4 weeks prior to randomisation)
   * Creatinine Clearance ≥ 40mL/min (Cockcroft-Gault formula)
   * Total bilirubin \< 1.5 x ULN (unless known or suspected Gilbert syndrome)
   * Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases)
8. Have a performance status of 0-2 on the ECOG Performance Scale (see Appendix 1)
9. Life expectancy greater than 6 months with treatment
10. Assessed by a medical oncologist as suitable for treatment with docetaxel
11. Patients must agree to use an adequate method of contraception
12. Willing and able to comply with all study requirements, including all treatments and required assessments including follow-up

Exclusion Criteria for Registration:

1. Any prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer. The following exceptions are permitted:

   * Up to 4 weeks of ADT with luteinising hormone releasing hormone agonists or antagonists or orchiectomy ± concurrent anti-androgens are permitted prior to commencement of screening. At investigator discretion, patients may start ADT at commencement of protocol therapy
   * Up to one course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 14 days prior to registration
2. Symptomatic cord compression, or clinical or imaging findings concerning for impending cord compression
3. Central nervous system metastases
4. Patients with Sjogren's syndrome
5. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
6. Prior diagnosis of another cancer that was:

   * More than 3 years prior to current diagnosis with subsequent evidence of disease recurrence or clinical expectation of recurrence greater than 10%
   * Within 3 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma or adequately treated non-muscle invasive bladder cancer (Tis, Ta and low grade T1 tumours)

Inclusion Criteria for Randomisation:

1. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined after central review as a minimum uptake of SUVmax 15 at a site of disease
2. High-volume metastatic disease on 68Ga-PSMA PET/CT defined as visceral metastases or ≥ 4 bone metastases with ≥ 1 outside the vertebral column and pelvis (extra-axial skeleton)
3. Patient continues to meet all the inclusion criteria for registration

Exclusion Criteria for Randomisation:

1. Major FDG-PET discordance defined as presence of FDG positive disease with minimal PSMA expression in multiple sites (\>5) or in more than 50% of total disease volume
2. All the exclusion criteria for registration continue to not apply

Primary outcomes:
measure: Undetectable prostate specific antigen (PSA) rate at 12 months after commencement of protocol therapy
timeFrame: Upto 32 months assuming 18 months to complete recruitment, a maximum of 1.6 months from consent to commencement of treatment for last patient and then 12 months from commencement of treatment for last patient.
Secondary outcomes:
measure: Safety of 177Lu-PSMA followed by docetaxel compared to docetaxel alone
timeFrame: Through completion of treatment, maximum 26 months.
measure: Time to development of castration resistance between treatment Arms
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
measure: PSA-progression free survival (PSA-PFS) between treatment Arms
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
measure: Radiographic-PFS (rPFS) between treatment Arms
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
measure: Early PSMA PET response between treatment Arms
timeFrame: Through completion of 3 months after treatment commencement for last patient, maximum 23 months.
measure: Describe and compare health-related QoL within 12 months of treatment commencement between treatment Arms
timeFrame: Through completion of 12 months after treatment commencement of last patient, maximum 32 months.
measure: Describe and compare pain within 12 months of treatment commencement between treatment Arms
timeFrame: Through completion of 12 months after treatment commencement of last patient, maximum 32 months.
measure: Overall survival (OS) between treatment Arms
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
Other outcomes:
measure: Assess the correlation between PSMA and FDG PET/CT parameters and clinical outcomes
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
measure: Identify biomarkers potentially associated with clinical outcomes
timeFrame: Through study completion, up until 2 years after the last patient commences treatment.
Locations:
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Sydney
country: Australia
facility: Chris O'Brien Lifehouse
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: Malvern
country: Australia
facility: Cabrini Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Prahran
country: Australia
facility: Alfred Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
Study officials:
affiliation: Peter MacCallum Cancer Centre, Australia
name: Arun Azad, MBBS PhD FRACP
role: PRINCIPAL_INVESTIGATOR
affiliation: Peter MacCallum Cancer Centre, Australia
name: Michael Hofman, MBBS(Hons),FRACP,FAANMS,FICIS
role: PRINCIPAL_INVESTIGATOR
References: