EVOLUTION: 177Lu-PSMA Therapy Versus 177Lu-PSMA in Combination With Ipilimumab and Nivolumab for Men With mCRPC (ANZUP2001)

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)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Neoplasms; Prostate Cancer; Prostatic Disease
• Intervention / Treatment: Drug: 177Lu-PSMA-617; Drug: Ipilimumab; Drug: Nivolumab

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.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincents Hospital
    • Newcastle, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Womens Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 177Lu-PSMA-617; Patients will be given 7.5GBq of Lu-PSMA every 6 weeks up to 6 cycles unless there is unacceptable toxicity, commencing following result of 68Ga-PSMA PET within 28 days of registration.; Other Names: 177Lutetium -PSMA 617 also referred to as 177Lu-PSMA; Drug: Ipilimumab; Patients will be given 3mg/kg of Ipilimumab every 6 weeks up to 4 doses unless there is unacceptable toxicity, concurrently with Lu-PSMA and Nivolumab.; Other Names: YERVOY; Drug: Nivolumab; Patients will be given 1mg/kg of Nivolumab every 3 weeks up to 8 doses, concurrently with Lu-PSMA and Ipilimumab unless there is unacceptable toxicity. Followed by 480mg nivolumab monotherapy commencing at week 32. Nivolumab monotherapy will be given to patients every 4 weeks up to 18 doses, or until disease progression or unacceptable toxicity.; Other Names: OPDIVO
Experimental: 177Lu-PSMA-617; 177Lu-PSMA (7.5GBq) given every 6 weeks up to 6 cycles or until disease progression or unacceptable toxicity.	Drug: 177Lu-PSMA-617; Patients will be given 7.5GBq of Lu-PSMA every 6 weeks up to 6 cycles unless there is unacceptable toxicity, commencing following result of 68Ga-PSMA PET within 28 days of registration.; Other Names: 177Lutetium -PSMA 617 also referred to as 177Lu-PSMA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA progression free survival (PSA-PFS) at 1 year (PCWG3)	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.	Date of randomisation to the date of first evidence of PSA progression at 53 weeks post randomisation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA response rate (PSA-RR)	PSA response rate is defined as the proportion of participants in each group with a PSA reduction of ≥ 50% from baseline.	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.
Frequency and severity of adverse events (CTCAE v5.0)	CTCAE v5.0 will be used to measure frequency and severity of AEs during study treatment.	Date of first dose of study treatment until 100 days after cessation of study treatment.
Radiological progression free survival (PCWG3/RECIST1.1)	Radiographic PFS is defined as the interval from the date of randomisation to the date of first evidence of radiographic progression, or the date of last known follow-up without progression.	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.
PSA progression free survival (PCWG3)	PSA progression free survival is defined as the interval from the date of randomisation to the date of first evidence of PSA progression or the date of last known follow-up without PSA progression.	Date of randomisation through to study completion, approximately 3 years from start of recruitment.
Overall survival (OS)	OS is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known follow-up alive.	Through to study completion, approximately 3 years from start of recruitment.
Objective response rate (ORR)	ORR is defined as partial or complete response at any stage of the study (from the date of randomisation to date of subsequent anti-cancer treatment). RECIST 1.1 will be used to assess ORR in participants with measurable disease.	Date of randomisation through to study completion, approximately 3 years from start of recruitment.
Duration of response	Duration of response is defined as the interval from the date of first response (Complete Response / Partial Response as per RECIST 1.1) to the date of first documented radiological progression as per RECIST 1.1 in participants with measurable disease.	Date of randomisation through to first radiological progression or through to study completion, approximately 3 years from start of recruitment.
Time to treatment response	Time to treatment response is defined as the interval from the date of randomisation to the date of first response (Complete Response / Partial Response as per RECIST 1.1) in participants with measurable disease.	Date of randomisation through to study completion, approximately 3 years from start of recruitment.
Aspects of Health Related Quality of Life (HRQoL) - 1	The EORTC QLQ-C30 (European Organisation for Research on Treatment of Cancer - Quality of Life Questionnaire for cancer patients) instrument uses 28 questions about overall quality of life with each question answerable using a scale from 1 (not at all) to 4 (very much). Overall scores can be from a minimum of 28 indicating a better quality of life and higher scores with a maximum of 112 indicating lower overall quality of life. The questionnaire also has two summary questions which asks participants to rank 1) overall health and 2) overall quality of life on scale of from 1 (very poor) to 7 (excellent).	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) - 2	Patient DATA Form (Patient Disease and Treatment Assessment Form - 47 items) 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.	Within 7 days prior to randomisation, assessed every 12 weeks, through to study completion, approximately 3 years from start of recruitment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between Clinical Outcomes and Possible Prognostic/Predictive Biomarkers (tissue and circulating) including PBMCs, ctDNA and CTCs	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. These include but are not limited to analyses of: PBMC samples may be used for immunophenotyping or characterisation of the immune cell subsets in the periphery;; ctDNA, immunological markers, and response data will be used to prospectively investigate the utility of early changes in ctDNA levels;; CTCs may be enumerated and analysed for their potential to predict or correlate with toxicity and efficacy of immune checkpoint inhibitors.	Date of randomisation through to study completion, approximately 3 years from start of recruitment.

Collaborators and Investigators

• Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Collaborators: Bristol-Myers Squibb; University of Sydney; Advanced Accelerator Applications; Prostate Cancer Foundation of Australia
• Investigators: Study Chair: Shahneen Sandhu, MBBS, FRACP, Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2022
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 30, 2021
• First Submitted That Met QC Criteria: November 25, 2021
• First Posted (Actual): December 9, 2021

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Neoplasms; Prostatic Neoplasms; Neoplasms by Site; Urogenital Neoplasms; Prostatic Diseases; Genital Neoplasms, Male; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Radiopharmaceuticals; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab; 177Lu-PSMA-617
• Other Study ID Numbers: ANZUP 2001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Study protocol will be published in a peer-reviewed journal within 24 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No