Combination Study of AZD5069 and Enzalutamide.

NCT03177187 | Terminated Phase 1

• 1 other identifier: CCR4500
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 4

Brief Summary

ACE is a multi-centre 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). The investigators will be investigating the safety and toxicity of the combination.

Conditions

Metastatic Castration Resistant Prostate Cancer

Outcome Measures

Primary Outcomes (3)

• Establish the maximum tolerated dose (MTD) in Phase I of AZD5069 administered in combination with enzalutamide at 160mg OD.

  The maximum dose at which no more than 1 of 6 patients at same dose level experience a drug related toxicity (DLT), as defined in the protocol.

  12 months

• Antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase II

  * Prostate specific antigen (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.

  12 months

• Antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase II

  For disease progression (see section 3.6) 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.

  12 months

Secondary Outcomes (12)

• PSA decline

  24 months

• Overall survival of patients in Phase II

  24 months

• To estimate the radiologic progression free survival (rPFS) on the combination in Phase II

  24 months

• To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells in Phase II

  24 months

• To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide in Phase II

  24 months

Study Arms (2)

Phase I

EXPERIMENTAL

Increasing doses of AZD5069 in combination with a fixed dose of enzalutamide to establish the recommended phase II dose.

Drug: AZD5069; Drug: Enzalutamide 40 MG

Phase II

EXPERIMENTAL

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. RECRUITING

Drug: AZD5069; Drug: Enzalutamide 40 MG

Interventions

AZD5069 DRUG

10mg and 40mg plain, beige, film-coated tablets packaged in bottles

Phase I; Phase II

Enzalutamide 40 MG DRUG

Enzalutamide is presented in 40mg white to off white capsules or tablets. The capsules/tablets are provided in a cardboard wallet incorporating a PVC/PCTFE/aluminium blister which holds 28 soft capsules/tablets. Each carton contains 4 wallets (112 soft capsules/tablets). Or tablets in bottles (120 per bottle).

Also known as: Xtandi

Phase I; Phase II

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent and be capable of cooperating with treatment.
• Age ≥ 18 years
• 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.
• Metastatic castration resistant prostate cancer.
• Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG2 criteria (section 3.6) with at least one of the following criteria:
• a. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or, b. Progression of bone disease by PCWG2 bone scan criteria and/or, c. Progression of PSA by PCWG2 PSA criteria and/or, d. Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases.
• PSA ≥ 10ng/ml.
• Received prior castration by orchiectomy and/or ongoing luteinizing hormone releasing hormone agonist treatment.
• Ongoing androgen deprivation with serum testosterone \< 50 ng/dL (\<2.0 nM).
• Willing to have pre- and post-treatment biopsies to obtain proof of mechanism from translational studies. Archival tissue must be available for research analysis
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Documented willingness to use an effective means of contraception while participating in the study and for 6 months post last treatment dose as defined in section 9.6.
• Able to swallow the study drug.
• All efforts should be made to discontinue steroid usage but up-to 5mg BD prednisolone (or equivalent) will be allowed.
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.

You may not qualify if:

• \. 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.
• \. 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.
• \. Prior limited field radiotherapy within 2 weeks and wide field radiotherapy within 4 weeks prior to trial entry.
• \. Clinical and/or biochemical evidence of hyperaldosteronism or hypopituitarism.
• \. 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.
• \. 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. Malabsorbtion syndrome or other condition that would interfere with enteral absorption.
• \. 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).

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Astellas Pharma Inc: collaborator
• AstraZeneca: collaborator
• Prostate Cancer UK: collaborator

Study Sites (4)

Bellinzona Hospital

Bellinzona, Switzerland

Location

Belfast City Hospital

Belfast, UK, BT9 7AB, United Kingdom

Location

The Royal Marsden Hospital Foundation Trust

Sutton, UK, SM2 5PT, United Kingdom

Location

University Hospital Southampton

Southampton, United Kingdom

Location

Related Publications (1)

• Guo C, Sharp A, Gurel B, Crespo M, Figueiredo I, Jain S, Vogl U, Rekowski J, Rouhifard M, Gallagher L, Yuan W, Carreira S, Chandran K, Paschalis A, Colombo I, Stathis A, Bertan C, Seed G, Goodall J, Raynaud F, Ruddle R, Swales KE, Malia J, Bogdan D, Tiu C, Caldwell R, Aversa C, Ferreira A, Neeb A, Tunariu N, Westaby D, Carmichael J, Fenor de la Maza MD, Yap C, Matthews R, Badham H, Prout T, Turner A, Parmar M, Tovey H, Riisnaes R, Flohr P, Gil J, Waugh D, Decordova S, Schlag A, Cali B, Alimonti A, de Bono JS. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Nature. 2023 Nov;623(7989):1053-1061. doi: 10.1038/s41586-023-06696-z. Epub 2023 Oct 16.

  PMID: 37844613 BACKGROUND

MeSH Terms

Interventions

N-(2-(2,3-difluoro-6-benzylthio)-6-(3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide; enzalutamide

Study Officials

• Johann De Bono, MD

  National Health Service, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2017
• First Posted: June 6, 2017
• Study Start: November 13, 2017
• Primary Completion: September 15, 2022
• Study Completion: November 16, 2022
• Last Updated: September 26, 2024

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1); GB (3)