Clinical trial NCT05150236: EVOLUTION: 177Lu-PSMA Therapy Versus 177Lu-PSMA in Combination With Ipilimumab and Nivolumab for Men With mCRPC
Official title: Phase II Study of Radionuclide 177Lu-PSMA Therapy Versus 177Lu-PSMA in Combination With Ipilimumab and Nivolumab for Men With MetastaticCastration Resistant Prostate Cancer (mCRPC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Prostate Cancer
Neoplasms by Site
Neoplasms
Prostatic Disease
Lead sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Sponsor class: OTHER
Collaborators: name: Prostate Cancer Foundation of Australia
name: Bristol-Myers Squibb
name: Advanced Accelerator Applications
name: University of Sydney
First posted: 2021-12-09
Enrollment: 93
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 II study will investigate the activity and safety of radionuclide 177Lu-PSMA therapy versus 177Lu-PSMA in combination with Ipilimumab and Nivolumab in patients with metastatic castrate resistant prostate cancer (mCRPC).

Detailed description: This is an open label, randomised, stratified, multicentre phase 2 clinical trial recruiting 110 participants over 18 months and followed for 12 months. Participants will be randomised to 177Lu-PSMA in combination with Ipilimumab and Nivolumab and 177Lu-PSMA alone in a 2:1 ratio (using minimisation with a random component) stratified by prior exposure to docetaxel.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 years or older, with histologically confirmed adenocarcinoma of the prostate.
2. Castration-resistant metastatic prostate cancer (defined as disease progressing despite castration by orchidectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist).
3. Patients must have progressed on prior novel AR targeted agents for treatment of prostate cancer. Progressive disease defined by at least one of the following:

   * PSA progression, minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screening should be ≥ 5ng/ml
   * Soft tissue or visceral disease progression as per RECIST 1.1
   * Bone progression: ≥ 2 new lesions on bone scan as per PCWG3
4. Target or non-target lesions according to RECIST 1.1 and PCWG3
5. Significant PSMA avidity on PET/CT using 68GaPSMA, defined as SUVmax ≥15 at a site of disease, and SUVmax ≥ 10 at other sites of disease ≥10mm (where there is no impact from partial voluming.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Adequate bone marrow, hepatic and renal function documented within 28 days of registration, defined as:

   * Haemoglobin ≥90 g/L independent of transfusions (no red blood cell transfusion in last 4 weeks)
   * Absolute neutrophil count ≥1.5x109/L
   * Platelets ≥100 x109/L
   * Total bilirubin ≤1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome
   * Aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤2.5 × ULN or ≤5 × ULN for participants with liver metastases
   * Serum creatinine ≤1.5 x ULN or a calculated creatinine clearance \> 50mL/min (Cockcroft-Gault equation)
8. Patients must have a life expectancy ≥ 24 weeks.
9. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
10. Signed, written informed consent.

Exclusion Criteria:

1. Prostate cancer with known significant sarcomatoid, spindle cell or neuroendocrine cell components, or metastasis of other cancers to the prostate.
2. 18F-FDG-PET/CT SUVmax ≥10 at a site of measurable disease with no concurrent PSMA expression \> 10mm
3. Prior treatment with anti-PD1, anti-PD-L1/L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways.
4. Patients must not have had more than one line of chemotherapy. If a patient has had docetaxel chemotherapy for hormone sensitive or castrate resistant setting, this will be considered one line.
5. Prior treatment with 177Lu-PSMA.
6. Patients with active, known, or suspected autoimmune disease. Sjogren's syndrome is considered an autoimmune disease. Exceptions: Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger, may be eligible.
7. Patients with a condition requiring systemic treatment with either corticosteroids (\>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
8. Participants must have recovered from all AE due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.
9. Active malignancies within the previous 2-years with \>30% probability of recurrence within 1 year. Melanoma in situ, basal cell or squamous cell carcinomas of skin, are permitted.
10. Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated.
11. Radiation or surgery within 2 weeks of randomisation.
12. Previous history of interstitial lung disease or non-infectious pneumonitis.
13. Administration of a live vaccine within 30 days prior to the first dose of study drug.
14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
15. Inadequate contraception. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Primary outcomes:
measure: PSA progression free survival (PSA-PFS) at 1 year (PCWG3)
timeFrame: Date of randomisation to the date of first evidence of PSA progression at 53 weeks post randomisation.
Secondary outcomes:
measure: PSA response rate (PSA-RR)
timeFrame: Date of randomisation through to study completion, approximately 3 years from start of recruitment. Early rises in PSA prior to 12 weeks will be disregarded in determining PSA response.
measure: Frequency and severity of adverse events (CTCAE v5.0)
timeFrame: Date of first dose of study treatment until 100 days after cessation of study treatment.
measure: Radiological progression free survival (PCWG3/RECIST1.1)
timeFrame: Date of randomisation to the date of first evidence of progression on imaging (PCWG3 criteria for bone lesions and RECIST 1.1 for soft tissue lesions) assessed every 12 weeks through to study completion, approximately 3 years from start of recruitment.
measure: PSA progression free survival (PCWG3)
timeFrame: Date of randomisation through to study completion, approximately 3 years from start of recruitment.
measure: Overall survival (OS)
timeFrame: Through to study completion, approximately 3 years from start of recruitment.
measure: Objective response rate (ORR)
timeFrame: Date of randomisation through to study completion, approximately 3 years from start of recruitment.
measure: Duration of response
timeFrame: Date of randomisation through to first radiological progression or through to study completion, approximately 3 years from start of recruitment.
measure: Time to treatment response
timeFrame: Date of randomisation through to study completion, approximately 3 years from start of recruitment.
measure: Aspects of Health Related Quality of Life (HRQoL) - 1
timeFrame: Within 7 days prior to randomisation, assessed every 12 weeks, through to study completion, approximately 3 years from start of recruitment.
measure: Aspects of Health Related Quality of Life (HRQoL) - 2
timeFrame: Within 7 days prior to randomisation, assessed every 12 weeks, through to study completion, approximately 3 years from start of recruitment.
Other outcomes:
measure: Association between Clinical Outcomes and Possible Prognostic/Predictive Biomarkers (tissue and circulating) including PBMCs, ctDNA and CTCs
timeFrame: Date of randomisation through to study completion, approximately 3 years from start of recruitment.
Locations:
city: Darlinghurst
country: Australia
facility: St Vincents Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Womens hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
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: Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner
state: Western Australia
Study officials:
affiliation: Peter MacCallum Cancer Centre, Australia
name: Shahneen Sandhu, MBBS, FRACP
role: STUDY_CHAIR
References: