Clinical trial NCT03392428: A Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer
Official title: TheraP: A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer (ANZUP Protocol 1603)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cancer of the Prostate
Metastatic Cancer
Lead sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Sponsor class: OTHER
Collaborators: name: Australian Nuclear Science and Technology Organisation (ANSTO)
name: Endocyte
name: Prostate Cancer Foundation of Australia (PCFA)
name: Australasian Radiopharmaceutical Trials network (ARTnet)
name: Movember Foundation
First posted: 2018-01-08
Enrollment: 201
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label, randomised, stratified, 2-arm, phase 2 trial
Primary purpose: TREATMENT

Brief summary: This open label, randomised, stratified, 2-arm, multicentre, phase 2 trial aims to determine the activity and safety of Lu-PSMA vs cabazitaxel in men with progressive metastatic castration resistant prostate cancer

Detailed description: Despite recent advances in the treatment of prostate cancer, metastatic disease remains incurable.

Prostate specific membrane antigen (PSMA) is present in high quantities on the cell surface of prostate cancers, and is also further increased in metastatic hormone refractory carcinomas. PSMA is an attractive target for both imaging and treatment of prostate cancer. PSMA bound to the radioactive substance Gallium68 (GaPSMA) is rapidly being adopted for imaging prostate cancer using positron emission tomography (PET) scanning.

Radionuclide therapy is an approach for the treatment of cancer that uses tumour targeting agents to deliver high doses of radiation to sites of tumours. The PSMA molecule used for PET imaging can also be labelled with Lutetium177 (Lu177), a radioactive substance.

The aim of this study is to determine the activity and safety of LuPSMA radionuclide therapy.

Patients with metastatic prostate cancer who have progressed despite hormonal therapy and chemotherapy, will be randomised to receive either LuPSMA radionuclide therapy (up to a maximum of 6 cycles of therapy) or cabazitaxel chemotherapy (up to a maximum of 10 cycles of therapy).

200 participants will be recruited from sites across Australia.

The study will determine the effects on PSA response rate (primary endpoint), pain response, progression free survival, quality of life, and frequency and severity of adverse events. Correlative outcomes include associations between PET imaging and clinical outcomes, and biomarkers and clinical outcomes.

Eligibility criteria: Inclusion Criteria:

1. Male aged 18 or older with metastatic adenocarcinoma of the prostate defined by:

   * Documented histopathology of prostate adenocarcinoma OR
   * Metastatic disease typical of prostate cancer (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes)
2. Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing Luteinizing Hormone-Releasing Hormone (LHRH) analog
3. Progressive disease with rising PSA on 3 consecutive measurements, and PSA ≥ 20 ng/mL
4. Target or non-target lesions according to RECIST 1.1
5. Prior treatment with docetaxel
6. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined as a minimum uptake of SUVmax 20 at a site of disease, and SUVmax \> 10 at sites of measurable disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact)
7. ECOG Performance status 0 to 2
8. Assessed by a medical oncologist as suitable for chemotherapy with cabazitaxel
9. Adequate renal function:

   • Cr Cl ≥ 40mL/min (Cockcroft-Gault formula)
10. Adequate bone marrow function:

    * Platelets ≥ 100 x10 billion /L
    * Hb ≥ 90g/L (no red blood cell transfusion in last 4 weeks)
    * Neutrophils \> 1.5 x10 billion/L
11. 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)
12. Estimated life expectancy \> 12 weeks
13. Study treatment both planned and able to start within 21 days of randomisation
14. Willing and able to comply with all study requirements, including all treatments (cabazitaxel or Lu-PSMA); and, the timing and nature of all required assessments
15. Signed, written informed consent

Exclusion Criteria:

1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
2. Site(s) of disease that are FDG positive with minimal PSMA expression defined as FDG intensity \> 68Ga-PSMA activity OR 68Ga-PSMA SUVmax \< 10
3. Sjogren's syndrome
4. Prior treatment with cabazitaxel or Lu-PSMA
5. Contraindications to the use of corticosteroid treatment
6. Active malignancy other than prostate cancer
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. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception

Primary outcomes:
measure: Prostate Specific Antigen response rate (PSA RR)
timeFrame: Through study completion, on average 4 years
Secondary outcomes:
measure: Pain Response (PPI and Analgesic Score)
timeFrame: Through study completion, on average 4 years
measure: Objective Tumour Response Rate
timeFrame: Through study completion, on average 4 years
measure: Progression free survival
timeFrame: Through study completion, on average 4 years
measure: PSA progression free survival
timeFrame: Through study completion, on average 4 years
measure: Pain progression free survival
timeFrame: Through study completion, on average 4 years
measure: Radiographic progression free survival
timeFrame: Through study completion, on average 4 years
measure: Health-related quality of life
timeFrame: Through study completion, on average 4 years
measure: Overall survival
timeFrame: Through study completion, on average 4 years
measure: Frequency and severity of adverse events
timeFrame: From first study dose to 12 weeks after completing study treatment
Other outcomes:
measure: Tertiary Correlative objectives: Associations between Ga-68 PSMA PET/CT, FDG-PET/CT baseline characteristics, and outcomes
timeFrame: Through study completion, on average 4 years
measure: Tertiary Correlative objectives: Associations between clinical outcomes and possible prognostic and/or predictive biomarkers (tissue and circulating) including ctDNA
timeFrame: Through study completion, on average 4 years
Locations:
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Moorabbin
country: Australia
facility: Monash Moorabbin 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, Melbourne, Australia
name: Michael Hofman, A/Prof
role: STUDY_CHAIR
References:
citation: Viljoen B, Hofman MS, Chambers SK, Dunn J, Dhillon HM, Davis ID, Ralph N. Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal study. PLoS One. 2022 Nov 9;17(11):e0276063. doi: 10.1371/journal.pone.0276063. eCollection 2022.
citation: Buteau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, Francis RJ, Zhang AY, Scott AM, Lee ST, Azad AA, McJannett MM, Stockler MR, Williams SG, Davis ID, Hofman MS; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022 Nov;23(11):1389-1397. doi: 10.1016/S1470-2045(22)00605-2. Epub 2022 Oct 16.
citation: Viljoen B, Hofman MS, Chambers SK, Dunn J, Dhillon H, Davis ID, Ralph N. Advanced prostate cancer experimental radioactive treatment-clinical trial decision making: patient experiences. BMJ Support Palliat Care. 2021 Aug 9:bmjspcare-2021-002994. doi: 10.1136/bmjspcare-2021-002994. Online ahead of print.
citation: Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, McJannett MM, Stockler MR, Violet JA, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3. Epub 2021 Feb 11.
citation: Iravani A, Violet J, Azad A, Hofman MS. Lutetium-177 prostate-specific membrane antigen (PSMA) theranostics: practical nuances and intricacies. Prostate Cancer Prostatic Dis. 2020 Mar;23(1):38-52. doi: 10.1038/s41391-019-0174-x. Epub 2019 Oct 8.