A Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer (TheraP)

• ClinicalTrials.gov Identifier: NCT03392428
• Recruitment Status: Completed
• First Posted: January 8, 2018
• Last Update Posted: June 13, 2022
• Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Collaborators: Australian Nuclear Science and Technology Organisation (ANSTO); Endocyte; Prostate Cancer Foundation of Australia (PCFA); Australasian Radiopharmaceutical Trials network (ARTnet); Movember Foundation
• Information provided by (Responsible Party): Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Tracking Information

• First Submitted Date: December 11, 2017
• First Posted Date: January 8, 2018
• Last Update Posted Date: June 13, 2022
• Actual Study Start Date: January 29, 2018
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2018)

Prostate Specific Antigen response rate (PSA RR) [ Time Frame: Through study completion, on average 4 years ]

PSA RR defined as the proportion of participants in each group with a PSA reduction of ≥ 50% from baseline.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 2, 2018)

• Pain Response (PPI and Analgesic Score) [ Time Frame: Through study completion, on average 4 years ]
  Pain response rate, defined as:

  • >=2 point reduction in PPI score from baseline with no increase in analgesic score; and/or
  • >=50% decrease in analgesic score with no increase in PPI PPI: McGill-Melzack Present Pain Intensity Scale (PPI) Analgesic score: Using Morphine Equivalent Daily Dose (MEDD)
• Objective Tumour Response Rate [ Time Frame: Through study completion, on average 4 years ]
  Objective Tumour Response Rate - defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) divided by the total number of participants (using RECIST 1.1).
• Progression free survival [ Time Frame: Through study completion, on average 4 years ]
  Progression free survival - the time from randomisation to date of PSA progression (blood samples), pain progression (on PPI) or radiographic progression (PCWG3 for bone and RECIST 1.1 for soft tissue), whichever occurs first
• PSA progression free survival [ Time Frame: Through study completion, on average 4 years ]
  PSA progression free survival, defined as the time from randomisation to PSA progression, assessed using PCWG3 criteria on blood test results.
• Pain progression free survival [ Time Frame: Through study completion, on average 4 years ]
  Pain progression free survival - defined as the time from randomisation to pain progression (>=1 point increase on PPI from nadir and >=25% increase in analgesic score (MEDD) from nadir, OR need for palliative radiotherapy).
• Radiographic progression free survival [ Time Frame: Through study completion, on average 4 years ]
  Radiographic progression free survival - defined as the time from randomisation to radiographic progression (assessed using PCWG3 criteria for bone lesions and RECIST 1.1 for soft tissue lesions).
• Health-related quality of life [ Time Frame: Through study completion, on average 4 years ]
  Health-related quality of life, assessed using a composite of the EORTC core quality of life questionnaire (QLQ C-30) and the Patient Disease and Treatment Assessment Form (PDF).
• Overall survival [ Time Frame: Through study completion, on average 4 years ]
  Overall survival - time from registration to death from any cause or last known follow-up alive.
• Frequency and severity of adverse events [ Time Frame: From first study dose to 12 weeks after completing study treatment ]
  Frequency and severity of adverse events (composite), assessed using CTCAE v4.03.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 2, 2018)

• Tertiary Correlative objectives: Associations between Ga-68 PSMA PET/CT, FDG-PET/CT baseline characteristics, and outcomes [ Time Frame: Through study completion, on average 4 years ]
  Identification of Ga-68 PSMA PET/CT, FDG-PET/CT markers to predict outcomes.
• Tertiary Correlative objectives: Associations between clinical outcomes and possible prognostic and/or predictive biomarkers (tissue and circulating) including ctDNA [ Time Frame: Through study completion, on average 4 years ]
  Identification of biomarkers to predict outcomes.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Open label, randomised, stratified, 2-arm, phase 2 trial

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Cancer of the Prostate
• Metastatic Cancer

Intervention

• Other: 177Lu-PSMA617

  Patients randomised to the 177Lu-PSMA617 arm will receive 6-8.5GBq of 177Lu-PSMA617 by intravenous injection once every 6 weeks until progressive disease, prohibitive toxicity or a maximum of 6 cycles.

  The first dose will be administered at 8.5GBq, reducing by 0.5GBq with every cycle given (i.e. to 6.0GBq on the sixth cycle, if reached). In some patients who have an exceptional response, treatment will be paused but can be re-commenced up to the maximum of 6 cycles upon progression.

  Other Name: Lutetium Prostate-specific membrane antigen
• Drug: Cabazitaxel

  Patients randomised to the Cabazitaxel arm will receive 20mg/m2 Cabazitaxel by intravenous infusion once every 3 weeks until progressive disease, prohibitive toxicity or a maximum of 10 cycles.

  Patients in this arm will also receive prednisolone 10mg orally per day for the duration of their cabazitaxel treatment.

  Other Name: Jevtana

Study Arms

• Experimental: 177Lu-PSMA617

  Patients randomised to the 177Lu-PSMA617 arm will receive 6-8.5GBq of 177Lu-PSMA617 by intravenous injection once every 6 weeks until progressive disease, prohibitive toxicity or a maximum of 6 cycles.

  The first dose will be administered at 8.5GBq, reducing by 0.5GBq with every cycle given (i.e. to 6.0GBq on the sixth cycle, if reached). In some patients who have an exceptional response, treatment will be paused but can be re-commenced up to the maximum of 6 cycles upon progression.

  Intervention: Other: 177Lu-PSMA617
• Active Comparator: Cabazitaxel

  Patients randomised to the Cabazitaxel arm will receive 20mg/m2 Cabazitaxel by intravenous infusion once every 3 weeks until progressive disease, prohibitive toxicity or a maximum of 10 cycles.

  Patients in this arm will also receive prednisolone 10mg orally per day for the duration of their cabazitaxel treatment.

  Intervention: Drug: Cabazitaxel

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 25, 2019): 201
• Original Estimated Enrollment (submitted: January 2, 2018): 200
• Actual Study Completion Date: December 31, 2021
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: This study is looking at prostate cancer which only affects males. The prostate gland is a male reproductive organ

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT03392428
• Other Study ID Numbers: ANZUP 1603
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Original Study Sponsor: Same as current

Collaborators

• Australian Nuclear Science and Technology Organisation (ANSTO)
• Endocyte
• Prostate Cancer Foundation of Australia (PCFA)
• Australasian Radiopharmaceutical Trials network (ARTnet)
• Movember Foundation

Investigators

• Study Chair: Michael Hofman, A/Prof; Peter MacCallum Cancer Centre, Melbourne, Australia

• PRS Account: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Verification Date: June 2022