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SNCTP000002267 | EUCTR2016-003141-28 | BASEC2017-01002

Studio di Fase I/II con l’antagonista di- CXCR2 AZD 5069 somministrato in combinazione con enzalutamide in pazienti con carcinoma prostatico metastatico resistente alla terapia ormonale

Base di dati: BASEC (Importata da 29.11.2021), WHO (Importata da 18.04.2021)
Cambiato: 19.10.2021
Categoria di malattie: Cancro della prostata

Descrizione riassuntiva della sperimentazione (Fonte di dati: BASEC)

Studio di fase I
Si tratta di uno studio in cui viene somministrata per la prima volta nell’uomo la combinazione di una terapia standard con l’agente ormonale enzalutamide, somministrato a dose fissa, e un nuovo farmaco AZD5069, somministrato a dosi crescenti, che agisce bloccando il recettore all’interleukina 8 responsabile dei processi infiammatori nel tumore e che blocca la risposta alla terapia ormonale. Questo studio vuole identificare le tossicità principali e la dose raccomandata della combinazione che verrà poi utilizzata in uno studio successivo di Fase II.
Fase II
Lo studio precedente di Fase I è stato eseguito per determinare la dose adatta di AZD5069 quando dato in combinazione con enzalutamide. In questo studio di Fase II entrambi AZD5069 e enzalutamide vengono dati a dosaggio fisso e lo scopo è verificare l’efficacia di AZD5069 in combinazione con enzalutamide nel ridurre il tumore della prostata e del PSA (antigene specifico della prostata). Inoltre si vuole conoscere meglio la sicurezza e i potenziali effetti collaterali della combinazione dei due farmaci. Lo studio prevede due gruppi di pazienti, un gruppo coinvolge pazienti che hanno ricevuto enzalutamide per almeno 12 settimane entro i sei mesi prima di iniziare questo studio e che non hanno tratto beneficio dal trattamento (pazienti con confermata resistenza a enzalutamide) mentre l’altro gruppo coinvolge pazienti che hanno ricevuto enzalutamide per almeno 12 settimane più di sei mesi prima di iniziare questo studio (pazienti con dubbia resistenza a enzalutamide). Quest’ultimo gruppo può accedere ad uno studio preliminare per confermare la resistenza a enzalutamide, cioè per verificare se enzalutamide non è efficace nel trattamento e successivamente accedere allo studio di fase II con la combinazione. Il primo gruppo invece accede direttamente allo studi di fase II.

Malattie studiate (Fonte di dati: BASEC)

carcinoma prostatico metastatico resistente alla terapia ormonale

Health conditions (Fonte di dati: WHO)

Metastatic castration resistant prostate cancer;Therapeutic area: Diseases [C] - Cancer [C04]

Malattia rara (Fonte di dati: BASEC)

No

Interventi esaminati (p. es. medicamento, terapia, campagna) (Fonte di dati: BASEC)

Studio di fase I
Il trattamento consiste nell'assunzione di AZD5069 per bocca due volte al giorno assieme all'enzalutamide, da assumere una volta al giorno per 4 settimane. Il trattamento con la combinazione per 4 settimane costituisce un ciclo di terapia. AZD5069 verrà dato a dosi crescenti in gruppi di 3-6 pazienti.
Questo studio include anche dei sottostudi di farmacocinetica, farmacodinamica e sui biomarcatori tramite delle biopsie fresche (due obbligatore e una opzionale) e dei prelievi di sangue aggiuntivi.

Studio di fase II per dubbia resistenza a enzalutamide (studio preliminare)
I pazienti che hanno dubbia resistenza a enzalutamide effettueranno la parte preliminare dello studio che consiste nell’assunzione di enzalutamide per bocca una volta al giorno fino a progressione della malattia. Il trattamento è suddiviso in cicli, ogni ciclo è di 28 giorni. In caso di progressione di malattia i pazienti potranno accedere allo studio di fase II.

Lo studio di fase II
Questo studio consiste nell’assunzione di AZD5069 per bocca due volte al giorno e enzalutamide una volta al giorno a dosi fisse. Il trattamento è suddiviso in cicli, ogni ciclo è di 28 giorni. Questo studio include anche dei sottostudi di farmacodinamica e sui biomarcatori tramite delle biopsie fresche obbligatorie e dei prelievi di sangue aggiuntivi.

Interventions (Fonte di dati: WHO)


Trade Name: Xtandi
Product Name: Xtandi
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Enzalutamide
CAS Number: 915087-33-1
Current Sponsor code: MDV3100
Other descriptive name: Xtandi
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Product Name: AZD5069
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZD5069
CAS Number: 878385-84-3
Current Sponsor code: D5660C00004
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
INN or Proposed INN: AZD5069
CAS Number: 878385-84-3
Current Sponsor code: D5660C00004
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Trade Name: Xtandi
Product Name: Xtandi
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Enzalutamide
CAS Number: 915087-33-1
Current Sponsor code: MDV3100
Other descriptive name: Xtandi
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Criteri per la partecipazione alla sperimentazione (Fonte di dati: BASEC)

- Età ≥ 18 anni
- Adenocarcinoma della prostata confermato istologicamente cui pazienti acconsentono a effettuare delle biopsie per confermare la diagnosi
- Carcinoma prostatico metastatico resistente alla terapia ormonale
- Precedente orchiectomia e / o trattamento in corso con un antagonista dell'ormone di rilascio dell'ormone luteinizzante
- Deprivazione androgena in corso con testosterone < 50 ng/dL

SOLO per fase I
- Progressione dopo almeno 1 linea di chemioterapia con taxani e enzalutamide o abiraterone

SOLO per fase II
- Progressione dopo almeno 1 linea di chemioterapia con taxani e progressione dopo trattamento con enzalutamide ricevuto per almeno 12 settimane

Criteri di esclusione (Fonte di dati: BASEC)

- Evidenza clinica o biochimica di operaldosteronismo o ipopituitarismo
- Storia clinica di convulsioni o fattori di predisposizione a lesioni cerebrali sottostanti, ictus, tumori cerebrali primari, metastasi cerebrali e malattia leptomeningale o alcolismo
- Utilizzo di potenti inibitori/induttori di CYP3A4, CYP2C9 e CYP2C19 durante lo studio e da almeno quattro settimane prima di iniziare lo studio
- Sindrome da malassorbimento o altre condizioni che potrebbero interferire con l'assorbimento dei farmaci in studio
- Anomalie cardiache
- Storia clinica di malattie epatiche
- Tumori, oltre al tumore della prostata, negli ultimi 5 anni
- Prevalentemente tumore della prostata a piccole cellule o neuroendocrine differenziate
- Pazienti immunocompromessi
- Storia clinica di malattia tromboembolica negli ultimi 12 mesi
- Intolleranza a enzalutamide

Inclusion/Exclusion Criteria (Fonte di dati: WHO)

Inclusion criteria:
1.Written informed consent and be capable of cooperating with treatment.
2.Age = 18 years
3.Histologically confirmed adenocarcinoma of the prostate and with tumour tissue accessible for research analysis for this trial. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.
4.Metastatic castration resistant prostate cancer.
5.Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG2 criteria.
6.PSA = 10ng/ml.
7.Received prior castration by orchiectomy and/or ongoing luteinizing hormone releasing hormone agonist treatment.
8.Ongoing androgen deprivation with serum testosterone < 50 ng/dL (<2.0 nM).
9.Willing to have pre- and post-treatment biopsies to obtain proof of mechanism from translational studies. Archival tissue must be available for research analysis
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
11. Documented willingness to use an effective means of contraception while participating in the study and for 6 months post last treatment dose.
12. Able to swallow the study drug.
13. All efforts should be made to discontinue steroid usage but up-to 5mg BD prednisolone (or equivalent) will be allowed.
14. Haematological and biochemical indices within the required ranges. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
15. Phase I safety run in cohort ONLY: Patients that have progressed after either enzalutamide, apalutamide, darolutamide or abiraterone treatment (having received a minimum of 12 weeks of one of these treatments).
16. Phase II enzalutamide resistance run in cohort ONLY: Patients with histologically confirmed adenocarcinoma of the prostate that have progressed after either enzalutamide, apalutamide or darolutamide (having received a minimum of 12 weeks of one of these treatments) more than 6 months prior to entry (day of starting IMP). Prior treatment with abiraterone is not an exclusion criteria.
17. Phase II reversal of enzalutamide resistance cohort ONLY: Patients with histologically confirmed adenocarcinoma of the prostate that have progressed after either enzalutamide, apalutamide or darolutamide treatment (having received a minimum of 12 weeks of one of these treatments) within 6 months prior to entry (day of starting IMP). Prior treatment with abiraterone is not an exclusion criteria.

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:
1.Surgery, chemotherapy or other anti-cancer therapy within 4 weeks prior to trial entry/randomization into the study (with the exception of enzalutamide, apalutamide or darolutamide).Any other therapy for prostate cancer, other than gonadotropin releasing hormone analogue therapy, such as progesterone, medroxyprogesterone, progestins or 5-alpha reductase inhibitors, must be discontinued at least 2 weeks before the first dose of the study drug.
2.Participation in another interventional clinical trial of an IMP within 4 weeks prior to trial entry. Participation in trials of licenced medications is allowed provided the medication is not a prohibited concomitant medication.
3.Prior limited field radiotherapy within 2 weeks and wide field radiotherapy within 4 weeks prior to trial entry.
4.Clinical and/or biochemical evidence of hyperaldosteronism or hypopituitarism.
5.History of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases and leptomeningeal disease, or alcoholism.
6.Use of potent inhibitors/inducers of CYP3A4, CYP2C9 and CYP2C19 should be avoided during the trial and 4 weeks prior to trial entry.
Co-administration of drugs that are known potent or moderate CYP3A4 inhibitors, potent or moderate CYP3A4 inducers (with the exception of enzalutamide), P-gp substrates with narrow therapeutic index, sensitive CYP2B6 substrates, warfarin or any other coumarin derivative, BCRP-substrates that reduce blood neutrophils, Seville orange or grapefruit products.
Use of herbal medications during the trial and 4 weeks afterwards.
7.Malabsorption syndrome or other condition that would interfere with enteral absorption.
8.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) and concomitant medications known to prolong QT interval.
•Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, angina or congestive heart failure (NYHA = grade 2) in the last 6 months (see appendix 4 for NYHA scale).
•Uncontrolled hypotension (systolic blood pressure < 90mmHg and or diastolic blood pressure < 50 mmHg).
•Uncontrolled hypertension on optimal medical management
9.Clinically significant history of liver disease (Chlid-Pugh B or C, viral or other hepatitis, current alcohol abuse or cirrhosis).
10.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 the active substance or any of the excipients.
11.Malignancy other than prostate cancer within 5 years of trial entry with the exception of adequately treated basal cell carcinoma.
12.Unresolved significant toxicity from prior therapy (except alopecia and grade 1 peripheral neuropathy).
13.Inability to comply with study and follow-up procedures.
14.Patients with predominantly small cell or neuroendocrine differentiated prostate cancer are not eligible.
15.Immunocompromised patients.
16.Active or uncontrolled autoimmune disease requiring corticosteroid thera

Altri dati sulla sperimentazione nel registro primario dell’OMS

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003141-28

Altri dati sulla sperimentazione dalla banca dati dell’OMS (ICTRP)

https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-003141-28-GB

Altre informazioni sulla sperimentazione

Data di registrazione della sperimentazione

30.01.2017

Inserimento del primo partecipante

04.04.2017

Stato di reclutamento

Authorised-recruitment may be ongoing or finished

Titolo scientifico (Fonte di dati: WHO)

ACE: Proof of concept Phase I/II trial of the CXCR2 antagonist AZD5069, administered in combination with enzalutamide, in patients with metastatic castration resistant prostate cancer(mCRPC) - ACE: A PhaseI/II trial of AZD5069 in combination with enzalutamide

Tipo di sperimentazione (Fonte di dati: WHO)

Interventional clinical trial of medicinal product

Disegno della sperimentazione (Fonte di dati: WHO)

Controlled: no
Randomised: no
Open: no
Single blind: no
Double blind: no
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: no
Other: no

Fase (Fonte di dati: WHO)

Human pharmacology (Phase I): yesTherapeutic exploratory (Phase II): yesTherapeutic confirmatory - (Phase III): noTherapeutic use (Phase IV): no

Punti finali primari (Fonte di dati: WHO)

Main Objective: Phase I study
The main aim of the Phase I study is to establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of AZD5069 and enzalutamide in patients with metastatic castration resistant prostate cancer. To then determine the maximum tolerated dose of the best combination to take forward to the Phase II study. To also assess the safety and toxicity profile of the combination of AZD5069 and enzalutamide.

Phase II study
The main aim of the Phase II study is to establish how effective AZD5069 in combination with enzalutamide is at reducing prostate cancer. ;Secondary Objective: Phase I study:
- To characterize the pharmacokinetic profile of AZD5069 in combination with enzalutamide
- To characterize the pharmacodynamic behaviour of AZD5069 in combination with enzalutamide
- To establish how effective AZD5069 in combination with enzalutamide is at reducing prostate cancer

Phase II study:
- To determine the maximum PSA (prostate specific antigens) decline during the study for patients on AZD5069 and enzalutamide
- To estimate overall survival (OS) in these patients.
- To estimate the radiologic progression free survival (rPFS) on the combination of AZD5069 and enzalutamide in these patients.
- To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells.
- To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide.
- To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination.
;Primary end point(s): - In the Phase I study the primary objective is to identify the safety and tolerability of enzalutamide and AZD5069 when given in combination continuously. This will be determined by identifying the dose-limiting toxicities (DLTs), estimate the maximum tolerated dose (MTD) and identify the recommended phase II dose (RP2D) of AZD5069 administered in combination with enzalutamide at 160mg OD.

- In the Phase II study the primary objective is to estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate. Antitumour activity will be defined by response rate on the basis of the following outcomes; if any of these 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 count (CTC) of = 5/7.5ml blood at baseline, conversion of CTC <5/7.5ml blood nadir.

For disease progression the Prostate Cancer Working Group 2 (PCWG2) criteria and RECIST (v1.1) criteria will be used. Treatment failure will be defined as:
•Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,
•Progression of bone disease by PCWG2 bone scan criteria and/or
•Progression of PSA by PCWG2 PSA criteria.




;Timepoint(s) of evaluation of this end point: Evaluation of the safety and tolerability of the combination of enzalutamide and AZD5069 over one cycle of treatment. A safety review meeting will be carried out after recruitment of each dosing cohort throughout the study. In addition, there will be fortnightly safety meetings throughout the study.

Response assessment will be carried out for patients that have received at least 1 cycle (4 weeks) of treatment and have a baseline disease assessment. A status of complete response (CR) or partial response (PR) will be confirmed by repeat measurements performed no less than four weeks after the response criteria are met.

Punti finali secondari (Fonte di dati: WHO)

Secondary end point(s): PhaseI
- To characterise the PK and PD of enzalutamide and AZD5069 when administered in combination and assess drug interaction.
-To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate.
- To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate.

Phase II
-To establish the maximum PSA decline at any point on trial and at 12 weeks for patients on AZD5069 and enzalutamide.
-To estimate overall survival (OS) in these patients.
-To estimate the radiologic progression free survival (rPFS) on the combination of AZD5069 and enzalutamide in these patients.
-To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells (CTCs).
-To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide.
-To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination.
;Timepoint(s) of evaluation of this end point: Phase I and II
-Safety and tolerability of combination treatment will be assessed by the Safety Review Committee and PK/PD data will be reviewed as part of that.
-Response assessment will be carried out for patients that have received at least 1 cycle of treatment and have a baseline disease assessment. A status of complete response (CR) or partial response (PR) will be confirmed by repeat measuraments performed no less than four weeks after the response criteria are met.
-Maximal PSA decline at any time during the trial and PSA decline after 12 weeks (as per PCWG2 criteria) of combination treatment.
-Overall survival will be measured from the date of combination treatment to the date of death (whatever cause).
- CTC fall will be defined as >30% after 12 weeks of combination treatme

Risultati della sperimentazione (Fonte di dati: WHO)

Sintesi dei risultati

ACE: Proof of concept Phase I/II trial of the CXCR2 antagonist AZD5069, administered in combination with enzalutamide, in patients with metastatic castration resistant prostate cancer(mCRPC)

Collegamento ai risultati nel registro primario

ancora nessuna informazione disponibile

Informazioni sulla disponibilità dei dati dei singoli partecipanti

ancora nessuna informazione disponibile

Siti di esecuzione della sperimentazione

Siti di esecuzione in Svizzera (Fonte di dati: BASEC)

Bellinzona

Paesi di esecuzione (Fonte di dati: WHO)

Switzerland, United Kingdom

Contatto per maggiori informazioni sulla sperimentazione

Dati della persona di contatto in Svizzera (Fonte di dati: BASEC)

Prof. Dr. Andrea Alimonti
+41 (0)91 8210071
andrea.alimonti@ior.iosi.ch

Contatto per informazioni generali (Fonte di dati: WHO)

Alison Turner
Sycamore House, Down's Road
The Institute of Cancer Research, Drug Development Unit
02087224303
alison.turner@icr.ac.uk

Contatto per informazioni scientifiche (Fonte di dati: WHO)

Alison Turner
Sycamore House, Down's Road
The Institute of Cancer Research, Drug Development Unit
02087224303
alison.turner@icr.ac.uk

Responsabile della sperimentazione

Sponsor principale (Fonte di dati: WHO)

The Institute of Cancer Research

Autorizzazione da parte della commissione d’etica (Fonte di dati: BASEC)

Nome della commissione d’etica che rilascia l’autorizzazione (nel caso di studi multicentrici solo la commissione direttiva)

Comitato etico cantonale Ticino

Data di autorizzazione da parte della commissione d’etica

18.08.2017

Altri numeri di identificazione delle sperimentazioni

Numero di identificazione della sperimentazione della commissione d’etica (BASEC-ID) (Fonte di dati: BASEC)

2017-01002

Secondary ID (Fonte di dati: WHO)

CCR4500