Metastatic castration resistant prostate cancer
Conditions
Interventions
Trade Name: YONSA
Product Name: YONSA
Pharmaceutical Form: Tablet
INN or Proposed INN: Abiraterone Acetate
CAS Number: 154229-18-2
Other descriptive name: Yonsa
Concentration unit: mg milligram(s)
Con
Sponsors
The Institute of Cancer Research
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1.Written informed consent and be capable of cooperating with treatment & follow up. 2.Age = 18 years 3.Histologically or cytologically proven adenocarcinoma of the prostate. 4.Metastatic castration resistant prostate cancer. 5.Documented prostate cancer progression as assessed by the investigator with one of the following: a. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or, b. Progression of bone disease by PCWG3 bone scan criteria and/or, c. Progression of PSA by PCWG3 PSA criteria and/or, d. Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases. 6.Patients may have received have progressed after either enzalutamide or abiraterone treatment (having received a minimum of 12 weeks enzalutamide or abiraterone). 7.Ongoing androgen deprivation maintaining serum testosterone of less than 50 ng/dL (less than 2.0 nM) is mandatory. 8.Life expectancy of at least 12-weeks. 9.World Health Organisation (WHO) performance status of 0-2. 10. Able to swallow the study drug 11.Archival tissue must be available for research analysis 12.Patients must have disease that is amenable to biopsy and must be willing to undergo tumour biopsies. 13.Subjects must either have measurable disease as according to RECIST v1.1 or if the patient has bone-only metastases, a CTC count of = 5/7.5 ml blood. 14. Haematological and biochemical indices within the ranges shown in 4.1.1 of the protocol. These measurements must be performed within one week of starting IMP Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1.Patients with predominantly small cell or neuroendocrine differentiated prostate cancer 2.Prior therapy, including major surgery, chemotherapy, radium-223 or other anti-cancer therapy within 4 weeks prior to IMP administration. The use of bisphosphonates or RANK ligand inhibitors in patients with known osteopenia or osteoporosis or bone metastases is permitted. A single fraction of palliative radiation is permitted if at least 14-days before starting trial treatment. 3. Prior hormonal treatment 4.Prior limited field radiotherapy within the previous 2 weeks or wide field radiotherapy within the previous 4 weeks prior to IMP administration 5.Participation in another interventional clinical trial & any concurrent treatment with any investigational drug within 4 weeks prior to IMP 6.Any toxicities due to prior chemotherapy &/or radiotherapy that have not resolved to a NCI-CTCAE v4.02 Gr. =1 with the exception of chemotherapy induced alopecia & Gr.2 peripheral neuropathy 7.Clinical &/or biochemical evidence of hyperaldosteronism or hypopituitarism. 8.Use of drugs that are known strong CYP3A4 inducers and CYP2D6 substrates with a narrow therapeutic index. Seville orange or grapefruit products, and any herbal medications should be avoided 4 weeks prior to trial entry 9.Malabsorption syndrome or other condition that would interfere with enteral absorption 10.Intracerebral metastases 11.Any of the following cardiac criteria: •QT interval > 470 msec •Clinically important abnormalities including rhythm, conduction or ECG changes (left bundle branch block, third degree heart block) •Factors predisposing to QT prolongation including heart failure, hypokalemia, congenital long QT syndrome, family history of prolonged QT syndrome, unexplained sudden death (under 40) & concomitant medications known to prolong QT interval •Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, angina or congestive heart failure (NYHA =gr.2) in the last 6 months 12.Uncontrolled hypotension (systolic blood pressure 180, diastolic blood pressure >100) 14.Patients with known history of adrenal insufficiency or mineralocorticoid excess 15.Patients with a significant history of liver disease (Child-Pugh B or C, viral or other hepatitis, current alcohol abuse or cirrhosis) 16.Serologically positive for hep. B, hep. C or human immunodeficiency virus (HIV). 17.At high medical risk because of non-malignant systemic disease including active infection 18.Known history of tuberculosis 19.Poorly controlled type 2 diabetes with HbA1C >7.5 20.Malignancy other than prostate cancer within 3 years of trial entry with the exception of adequately treated basal cell carcinoma. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy must have no evidence of that disease for at least 3 years & be deemed at negligible risk for recurrence, are deemed eligible 21.Immunocompromised patients including patients who have previously received organ transplants or are on long-term immunosuppression 22.Active or uncontrolled autoimmune disease requiring corticosteroid therapy 23.Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect interpretation of the results or renders the patients at high risk from treatment complicati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I study The main aim of the Phase I study is to describe the safety and tolerability of abiraterone acetate and tildrakizumab when given in combination and to recommend a phase II dose (RP2D) for tildrakizumab, in combination with abiraterone. Phase II study The main aim of the Phase II study is to determine the antitumour activity of tildrakizumab (at RP2D) in combination with abiraterone in patients with mCRPC. ;Secondary Objective: Phase I study: - To investigate the pharmacodynamic (PD) effects of the combination of tildrakizumab and abiraterone in men with mCRPC. - To characterize the pharmacokinetic (PK) profile of tildrakizumab given in combination with abiraterone in men with mCRPC. - To identify molecular determinants of response and antitumour activity, of the tildrakizumab and abiraterone combination in men with mCRPC. - To determine preliminary antitumour activity of tildrakizumab in combination with abiraterone in patients with mcRPC. - To evaluate progression-free survival (PFS) in mCRPC patients receiving the tildrakizumab and abiraterone combination. - To estimate the overall survival (OS) in mCRPC patients receiving the combination of tildrakizumab and abiraterone. Phase II - To evaluate PFS in mCRPC patients receiving tildrakizumab and abiraterone. - To estimate the biochemical anti-tumour activity of tildrakizumab and abiraterone in mCRPC patients. - To determine the pattern of radiologi;Primary end point(s): - In the Phase I study the primary outcome is to identify the DLTs during the DLT period, estimate the MTD, and identify the RP2D of tildrakizumab administered in combination with abiraterone at 1000 mg OD (with prednisolone 5 mg bid). - In the Phase II study the primary objective is to determine the antitumour activity of tildrakizumab (at RP2D) in combination with abiraterone in men with mCRPC. Antitumour activity will be defined by response rate on the basis of the following outcomes. If any of the foll | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: - PD samples (biomarkers) will be analysed from all patients who receive at least one complete cycle of treatment and who provide blood, serum and tumour samples for PD analysis. - PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria - OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause). - Documenting anti-tumour activity is a secondary objective of ACTION P1. Patients must receive 8-weeks of trial treatment to be evaluable for response, unless there is disease progression prior or treatment is stopped because of drug-related toxicity. -AE collection commences from the time of consent until 28 days after last IMP;Secondary end point(s): Phase I - Measuring the impact of the downregulation of IL-23 signaling in tumour, also evaluating the downregulation of androgen receptor (AR), AR splice variants, and AR target genes. -Determine the PK parameters (maximum blood concentration (Cmax), terminal elimination half-life (T1/2) and area under curve (AUC)) of tildrakizumab and abiraterone when dosed together. -Determine biomarkers of response, including but not limited to PTEN loss, MYC amplification, and intra-tumour MDSC counts, in tumour biopsies from responders and non-responders. -Response and progression will be determined using the same measures as that described for the primary objective of the Phase II study. - PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria (RECIST v 1.1, PCWG3 bone scan criteria) or unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy). -OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause). | — |
Countries
Switzerland, United Kingdom
Contacts
Public ContactAlison Turner
The Institute of Cancer Research, Drug Development Unit
Outcome results
None listed