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)
Overview
- Phase
- Phase 2
- Intervention
- 177Lu-PSMA-617
- Conditions
- Prostatic Neoplasms
- Sponsor
- Australian and New Zealand Urogenital and Prostate Cancer Trials Group
- Enrollment
- 93
- Locations
- 8
- Primary Endpoint
- PSA progression free survival (PSA-PFS) at 1 year (PCWG3)
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Aged 18 years or older, with histologically confirmed adenocarcinoma of the prostate.
- •Castration-resistant metastatic prostate cancer (defined as disease progressing despite castration by orchidectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist).
- •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
- •Target or non-target lesions according to RECIST 1.1 and PCWG3
- •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.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Adequate bone marrow, hepatic and renal function documented within 28 days of registration, defined as:
Exclusion Criteria
- •Prostate cancer with known significant sarcomatoid, spindle cell or neuroendocrine cell components, or metastasis of other cancers to the prostate.
- •18F-FDG-PET/CT SUVmax ≥10 at a site of measurable disease with no concurrent PSMA expression \> 10mm
- •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.
- •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.
- •Prior treatment with 177Lu-PSMA.
- •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.
- •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.
- •Participants must have recovered from all AE due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.
- •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.
- •Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated.
Arms & Interventions
Combination 177Lu-PSMA-617, Ipilimumab & Nivolumab
177Lu-PSMA (7.5GBq) given every 6 weeks up to 6 cycles in combination with concurrent ipilimumab (3mg/kg Q6W x 4 doses) and nivolumab (1mg/kg Q3W x 8 doses) followed by nivolumab monotherapy (480mg Q4W up to 18 doses) or until disease progression or unacceptable toxicity.
Intervention: 177Lu-PSMA-617
Combination 177Lu-PSMA-617, Ipilimumab & Nivolumab
177Lu-PSMA (7.5GBq) given every 6 weeks up to 6 cycles in combination with concurrent ipilimumab (3mg/kg Q6W x 4 doses) and nivolumab (1mg/kg Q3W x 8 doses) followed by nivolumab monotherapy (480mg Q4W up to 18 doses) or until disease progression or unacceptable toxicity.
Intervention: Ipilimumab
Combination 177Lu-PSMA-617, Ipilimumab & Nivolumab
177Lu-PSMA (7.5GBq) given every 6 weeks up to 6 cycles in combination with concurrent ipilimumab (3mg/kg Q6W x 4 doses) and nivolumab (1mg/kg Q3W x 8 doses) followed by nivolumab monotherapy (480mg Q4W up to 18 doses) or until disease progression or unacceptable toxicity.
Intervention: Nivolumab
177Lu-PSMA-617
177Lu-PSMA (7.5GBq) given every 6 weeks up to 6 cycles or until disease progression or unacceptable toxicity.
Intervention: 177Lu-PSMA-617
Outcomes
Primary Outcomes
PSA progression free survival (PSA-PFS) at 1 year (PCWG3)
Time Frame: Date of randomisation to the date of first evidence of PSA progression at 53 weeks post randomisation.
PSA progression is defined as a rise in PSA by ≥ 25% AND ≥ 2 ng/mL above the nadir (lowest PSA point). This needs to be confirmed by a repeat PSA performed at least 3 weeks later.
Secondary Outcomes
- Time to treatment response(Date of randomisation through to study completion, approximately 3 years from start of recruitment.)
- Overall survival (OS)(Through to study completion, approximately 3 years from start of recruitment.)
- Frequency and severity of adverse events (CTCAE v5.0)(Date of first dose of study treatment until 100 days after cessation of study treatment.)
- PSA progression free survival (PCWG3)(Date of randomisation through to study completion, approximately 3 years from start of recruitment.)
- Objective response rate (ORR)(Date of randomisation through to study completion, approximately 3 years from start of recruitment.)
- Duration of response(Date of randomisation through to first radiological progression or through to study completion, approximately 3 years from start of recruitment.)
- PSA response rate (PSA-RR)(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.)
- Radiological progression free survival (PCWG3/RECIST1.1)(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.)
- Aspects of Health Related Quality of Life (HRQoL) - 2(Within 7 days prior to randomisation, assessed every 12 weeks, through to study completion, approximately 3 years from start of recruitment.)
- Aspects of Health Related Quality of Life (HRQoL) - 1(Within 7 days prior to randomisation, assessed every 12 weeks, through to study completion, approximately 3 years from start of recruitment.)