None listed
Conditions
Brief summary
This study is taking a novel approach to using predictive biomarkers to select people for lipid (fat) targeted treatments, to attempt to overcome hormone resistance in people with metastatic hormone resistant prostate cancer. There is increasing evidence that abnormal lipid (fat) metabolism promotes the growth of prostate cancer cells. We have previously shown that abnormal patterns of blood-borne lipids (called ceramides) can identify a group of people with metastatic hormone resistant prostate cancer who are likely to be resistant to the usual hormone treatments: abiraterone and enzalutamide. In the DARO-LIPID study, we will first identify which participants with metastatic hormone resistant prostate cancer have the high ceramide lipid signature through a blood test. Participants who do not have this lipid signature will receive usual care by their oncologist. Participants with this lipid signature who consent to the study will all receive darolutamide as standard of care. Participants will then be randomly split into two groups with one group also receiving the lipid drug called Opaganib to target the abnormal lipid changes and the second group receiving a placebo. The study is designed to see if Opaganib can increase the number of people who respond to darolutamide, and increase the time that they get benefit from the treatment. We will also look at how the Opaganib is affecting lipid/fat metabolism in the body/tumour.
Interventions
Participants with a poor prognostic circulating lipid profile (PCPro positive) who are randomised to Arm A will be instructed to take two tablets of darolutamide, and two capsules of opaganib orally twice daily with food. Each cycle is defined as 4 weeks. On treatment assessments will be performed for all participants within 5 days of day 1 dosing of each cycle and treatment will continue until no longer clinically beneficial, unacceptable toxicity or participant preference. Participants will be
Participants with a poor prognostic circulating lipid profile (PCPro positive) who are randomised to Arm A will be instructed to take two tablets of darolutamide, and two capsules of opaganib orally twice daily with food. Each cycle is defined as 4 weeks. On treatment assessments will be performed for all participants within 5 days of day 1 dosing of each cycle and treatment will continue until no longer clinically beneficial, unacceptable toxicity or participant preference. Participants will be asked to return drug bottes at scheduled clinic visits as per the protocol. Pharmacists will be conducting a count of the remaining tablets to monitor participant's adherence to the intervention. Any discrepancies in the count will be reviewed and discussed with the participant to ensure compliance with the study protocol. Arm A: Darolutamide 600mg twice daily + Opaganib 500mg twice daily
Sponsors
Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Eligibility
Sex/Gender
Male
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1 Metastatic adenocarcinoma of the prostate defined as *Documented histopathology of prostate adenocarcinoma (no features of neuroendocrine carcinoma) OR *Metastatic disease typical of prostate cancer 2 Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinizing hormone-releasing hormone agonist or antagonist) 3 Progressive disease with rising PSA defined by PCWG3 criteria (sequence of 2 rising values at a minimum of 1-week intervals) or progression of disease radiologically 4 Evidence of metastases on bone scan and/or CT scan beyond pelvic lymphadenopathy 5 Participants are allowed to have had previous chemotherapy with docetaxel in the hormone sensitive setting only 6 Acceptable liver function: *Bilirubin less than or equal to 1.5 times upper limit of normal (CTCAE Grade 1 baseline) *AST (SGOT) & ALT (SGPT) less than or equal to 3 x upper limit of normal (ULN) (CTCAE Grade 1 baseline) *Participants with Gilbert's syndrome may be included if the total bilirubin is less than 3x ULN and the direct bilirubin is within normal limits 7 Acceptable kidney function indicated by serum creatinine less than or equal to 1.5 X ULN (CTCAE Grade 1 baseline) 8 Acceptable hematologic status: *Absolute neutrophil count is greater than or equal to 1.0 x 109 /L *Platelet count is equal to or greater than or equal to 75 x 109/L (CTCAE Grade 1 baseline) *Hemoglobin is greater than or equal to 90 g/L 9 ECOG performance status 0-2 10 Life expectancy of at least 3 months 11 Willing to complete all study requirements, including standard of care treatment 12 Willing to complete Health Related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision 13 Signed, written informed consent
Exclusion criteria
1 Prostate cancer with known significant sarcomatoid, spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate 2 Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of darolutamide or opaganib, including difficulty swallowing tablets 3. Any prior use of Androgen Receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide, darolutamide or similar agents) 4. Prior use of chemotherapy in the castration resistant prostate cancer setting 5. People who are receiving opioid-based medications 6. New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG 7. Active, uncontrolled bacterial, viral or fungal infection, requiring systemic therapy 8. Treatment with radiation therapy, surgery, or investigational therapy within 14 days prior to registration 9. Participants who are receiving coumadin, apixaban, argatroban or rivaroxaban. Participants who are receiving other drugs that are sensitive substrates of CYP450 1A2, 3A4, 2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes that cannot be stopped at least 7 days or 5 half-lives (whichever is longer) before starting treatment with opaganib may be treated on this study with careful monitoring for toxic effects or loss of efficacy of the relevant drug. 10. Participants with underlying psychiatric disorders requiring hospitalization within the last 2 years 11. Clinically significant neurological disorders (Parkinson’s disease, dementia, multiple sclerosis) as determined by the enrolling investigator 12. Concurrent participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases 13. People with history of hypersensitivity to the study treatments
Outcome results
None listed