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

Study Overview
=================
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.

Official Title
-----------------
TheraP: A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer (ANZUP Protocol 1603)

Conditions
-----------------
Cancer of the Prostate, Metastatic Cancer

Intervention / Treatment
-----------------
* Other: 177Lu-PSMA617
* Drug: Cabazitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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) Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing Luteinizing Hormone-Releasing Hormone (LHRH) analog Progressive disease with rising PSA on 3 consecutive measurements, and PSA ≥ 20 ng/mL Target or non-target lesions according to RECIST 1.1 Prior treatment with docetaxel 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) ECOG Performance status 0 to 2 Assessed by a medical oncologist as suitable for chemotherapy with cabazitaxel Adequate renal function: • Cr Cl ≥ 40mL/min (Cockcroft-Gault formula) 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 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) Estimated life expectancy > 12 weeks Study treatment both planned and able to start within 21 days of randomisation 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 Signed, written informed consent Exclusion Criteria: Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components Site(s) of disease that are FDG positive with minimal PSMA expression defined as FDG intensity > 68Ga-PSMA activity OR 68Ga-PSMA SUVmax < 10 Sjogren's syndrome Prior treatment with cabazitaxel or Lu-PSMA Contraindications to the use of corticosteroid treatment Active malignancy other than prostate cancer Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety 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 Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, randomised, stratified, 2-arm, phase 2 trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-PSMA617<br>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: 177Lu-PSMA617<br>* 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.<br>* Other names: Lutetium Prostate-specific membrane antigen;|
| Active Comparator: Cabazitaxel<br>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. | Drug: Cabazitaxel<br>* 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.<br>* Other names: Jevtana;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen response rate (PSA RR) | PSA RR defined as the proportion of participants in each group with a PSA reduction of ≥ 50% from baseline. | Through study completion, on average 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Response (PPI and Analgesic Score) | 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) | Through study completion, on average 4 years | 
| Objective Tumour Response Rate | 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). | Through study completion, on average 4 years | 
| Progression free survival | 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 | Through study completion, on average 4 years | 
| PSA progression free survival | PSA progression free survival, defined as the time from randomisation to PSA progression, assessed using PCWG3 criteria on blood test results. | Through study completion, on average 4 years | 
| Pain progression free survival | 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). | Through study completion, on average 4 years | 
| Radiographic progression free survival | 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). | Through study completion, on average 4 years | 
| Health-related quality of life | 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). | Through study completion, on average 4 years | 
| Overall survival | Overall survival - time from registration to death from any cause or last known follow-up alive. | Through study completion, on average 4 years | 
| Frequency and severity of adverse events | Frequency and severity of adverse events (composite), assessed using CTCAE v4.03. | From first study dose to 12 weeks after completing study treatment |