Clinical Trials /

Abiraterone Acetate in Combination With Tildrakizumab

NCT04458311

Description:

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(1000mg 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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Abiraterone Acetate in Combination With Tildrakizumab
  • Official Title: ACTION: Phase I/II Trial of Abiraterone Acetate in Combination With Tildrakizumab (Anti-IL23 Targeting Monoclonal Antibody) in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Clinical Trial IDs

  • ORG STUDY ID: CCR5163
  • NCT ID: NCT04458311

Conditions

  • Metastatic Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
Abiraterone AcetateYonsaPhase I
TildrakizumabPhase I

Purpose

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(1000mg 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.

Detailed Description

      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 1000
      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 1000mg 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase IExperimentalIncreasing doses of tildrakizumab in combination with a fixed dose of abiraterone to establish the recommended phase II dose in patients with metastatic castration resistant prostate cancer..
  • Abiraterone Acetate
  • Tildrakizumab
Phase IIExperimentalThe Phase II part of the study will evaluate the recommended phase II dose identified in Phase I of the study in patients with metastatic castration resistant prostate cancer.
  • Abiraterone Acetate
  • Tildrakizumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Phase I - To describe the safety and tolerability of abiraterone acetate and tildrakizumab when given in combination. To establish a RP2D for tildrakizumab, in combination with abiraterone.
Time Frame:12 months
Safety Issue:
Description:To determine a maximum tolerated dose (MTD) of tildrakizumab by establishing the dose at which the DLT rate is as close to the target DLT rate of 15% as possible, in combination with abiraterone at 1000 mg OD with prednisolone at 5 mg bid, and is deemed to be tolerable by the Safety Review Committee. This will be the RP2D for tildrakizumab.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Institute of Cancer Research, United Kingdom

Last Updated

June 30, 2020