The purpose of this study is to find out the side effects and safety of a combination of the
anti-IL23 targeting monoclonal antibody tildrakizumab in combination with abiraterone acetate
in men with metastatic castration resistant prostate cancer and to determine the most
appropriate dose of this combination. In the Phase I part of this study small groups of
patients will be treated with increasing doses of tildrakizumab in combination with a fixed
dose of abiraterone acetate (500mg once daily). Once Phase I has been completed the
combination with the optimum safety and pharmacokinetic/pharmacodynamic profile will be taken
forward to the Phase II part of the study. The Phase II part of the study will evaluate the
optimized dose/schedule identified in Phase I of the study in patients with metastatic
castration resistant prostate cancer.
The trial will be divided into 2 parts: Phase I and Phase II. The Phase I study will adopt a
Bayesian Continual Reassessment Method. Patients will receive single-agent abiraterone 500 mg
orally, once daily (continuous dosing) along with prednisolone at 5 mg BD for up to 4 weeks.
Upon confirmation of PSA progression, tildrakizumab IV will be started and given once every
4-weeks in combination with the fixed dose abiraterone (and prednisolone). The starting dose
of tildrakizumab will be 100mg with single dose escalations to 300mg and 600mg to determine
the RP2D to take forward to the Phase II study. Depending on the number of responses
observed, dose levels that are deemed tolerable may be expanded to up to a total of 10
patients who are evaluable for response
The Phase II study will employ a two-stage Minimax design, recruiting up to 25 patients.
During the first stage 15 evaluable patients will be enrolled and followed for a minimum of 2
cycles each. If there are one or more responses confirmed at least 4-weeks later an
additional 10 evaluable patients will be recruited. If 4 or more responses are seen in the 25
patients evaluable for response, the combination will be deemed successful, warranting
further evaluation in subsequent phases of testing. In the phase II study patients will start
taking 500mg abiraterone as an oral tablet once daily along with 5mg of prednisolone twice
daily on Day -28 for the first 4 weeks. Upon confirmation of PSA progression, the
tildrakizumab will be given as an intravenous infusion at the dose established in the Phase I
safety run in part of the study in combination with the abiraterone (and prednisolone)from
Cycle 1 Day 1 onwards.
Inclusion Criteria:
1. Written (signed and dated) informed consent and be capable of co-operating with
treatment and follow-up.
2. Age 18 or above.
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 RECIST
(v1.1) and PCWG3 criteria with at least one of the following criteria:
1. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,
2. Progression of bone disease by PCWG3 bone scan criteria and/or,
3. Progression of PSA by PCWG3 PSA criteria and/or,
4. Clinical progression with worsening pain and need for palliative radiotherapy for
bone metastases.
6. Patients that have progressed after either enzalutamide or abiraterone treatment
(having received a minimum of 12-weeks of 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. Participants must either have measurable disease according to RECIST v1.1 or if the
patient has bone-only metastases, the CTC count at baseline must be ≥ 5/7.5 ml blood.
14. Haematological and biochemical indices within the required ranges in protocol. These
measurements must be performed within one week prior to the patient's first dose of
any investigational medicinal products (IMP).
Exclusion Criteria:
1. Patients with predominantly small cell or neuroendocrine differentiated prostate
cancer are not eligible.
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 exclusions as follows:
- prior flutamide treatment during previous four-weeks N.B. Patients whose PSA did
not decline in response to antiandrogens given as a second line or later
intervention will only require a 14-day washout;
- prior bicalutamide (Casodex) and nilutimide (Nilandron) treatment during previous
six-weeks;
- prior progesterone, medroxyprogesterone, progestins, cyproterone acetate,
tamoxifen, and 5-alpha reductase inhibitors during previous two-weeks (14-days).
4. Prior limited field radiotherapy within the previous two weeks (14-days), or wide
field radiotherapy within the previous four weeks of trial entry.
5. Participation in another interventional clinical trial and any concurrent treatment
with any investigational drug within four weeks prior to IMP administration.
6. Any toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to
NCI-CTCAE v5.0 Grade ≤1 with the exception of chemotherapy induced alopecia and Grade
2 peripheral neuropathy.
7. Clinical evidence of hyperaldosteronism or hypopituitarism.
8. Use of drugs that are known strong CYP3A4 inducers and CYP2D6 substrates with a narrow
therapeutic index (please refer to
http://medicine.iupui.edu/clinpharm/ddis/table.aspx). Seville orange or grapefruit
products, and any herbal medications should be avoided for four weeks prior to
starting trial treatment.
9. Malabsorption syndrome or other condition that would interfere with enteral absorption
of the study drugs.
10. Known intracerebral metastases
11. Any of the following cardiac criteria:
1. QT interval > 470 msec.
2. Clinically important abnormalities including rhythm, conduction or ECG changes
(left bundle branch block, third degree heart block).
3. Factors predisposing to QT prolongation including congenital long QT syndrome;
family history of prolonged QT syndrome, unexplained sudden death (under 40);
concomitant medications known to prolong QT interval.
4. Coronary artery bypass, angioplasty, vascular stent, myocardial infarction,
angina or congestive heart failure (NYHA ≥ grade 2) in the last 6 months (see
appendix 5 for NYHA scale).
12. Uncontrolled hypotension (systolic blood pressure < 90mmHg and or diastolic blood
pressure < 50 mmHg).
13. Uncontrolled hypertension on optimal medication (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. Known history of hepatitis B, hepatitis 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 diabetes with HbA1C > 7.5%.
20. Malignancy other than prostate cancer within three-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-three years and 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 (e.g. corticosteroids of > 10 mg
daily equivalent of prednisolone).
22. Active or uncontrolled autoimmune disease requiring corticosteroid therapy or other
forms of systemic immunosuppression.
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 complications e.g.
patients with a hypersensitivity to tildrakizumab, abiraterone or prednisolone.
24. Patients with female partners of child-bearing potential (unless they agree to take
measures not to father children by using a barrier method of contraception [condom
plus spermicide] or to sexual abstinence effective from the first administration of
any of the study drugs throughout the trial and for six months afterwards. Men with
partners of child-bearing potential must also be willing to ensure that their partner
uses an effective method of contraception for the same duration for example, hormonal
contraception, intrauterine device, diaphragm with spermicidal gel or sexual
abstinence). Men with pregnant or lactating partners must be advised to use barrier
method contraception (for example, condom plus spermicidal gel) to prevent exposure of
the foetus or neonate.
NB. Abstinence is only considered to be an acceptable method of contraception when
this is in line with the preferred and usual lifestyle of the participants. Periodic
abstinence (e.g., calendar, ovulation, sympathothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception
25. Prior bone marrow transplant.
26. Extensive radiotherapy to greater than 25% of bone marrow within 8 weeks.
27. Any other condition, which in the Investigator's opinion would not make the patient a
good candidate for the clinical trial.
28. Symptoms of COVID-19 and/or documented COVID-19 infection
