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JOURNAL ONKOLOGIE – STUDIE
ACTIon

Abiraterone Acetate in Combination With Tildrakizumab

Rekrutierend

NCT-Nummer:
NCT04458311

Studienbeginn:
Dezember 2020

Letztes Update:
28.12.2020

Wirkstoff:
abiraterone acetate, Tildrakizumab

Indikation (Clinical Trials):
Prostatic Neoplasms

Geschlecht:
Männer

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Institute of Cancer Research, United Kingdom

Collaborator:
Sun Pharma Global FZE

Studienleiter

Johann De Bono, MD
Study Director
National Health Service, United Kingdom

Kontakt

Studienlocations
(3 von 7)

Alle anzeigen

Studien-Informationen

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 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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. 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):
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 500 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.

2. Phase II - To determine the antitumour activity of tildrakizumab (at RP2D) in combination with abiraterone in men with mCRPC. (Time Frame - 12 months):
Antitumour activity will be defined by response rate on the basis of the following outcomes. If any of the following occur, patients will be considered to have responded: PSA decline ≥ 50% criteria confirmed 4-weeks or later and/or, Confirmed soft tissue objective response by RECIST (v1.1) in patients with measurable disease and/or, ONLY for patients with detectable circulating tumour cell (CTC) count of ≥ 5/7.5ml blood at baseline, conversion of CTC count to <5/7.5ml blood nadir.

Studien-Arme

  • Experimental: Phase I
    Increasing 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..
  • Experimental: Phase II
    The 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.

Geprüfte Regime

  • Abiraterone Acetate (Yonsa):
    Supplied as 125 mg tablets
  • Tildrakizumab:
    Tildrakizumab will be supplied in single-use 100 mg/mL glass vials intended for IV infusion.

Quelle: ClinicalTrials.gov


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