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Combination Study of AZD5069 and Enzalutamide. (ACE)

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ClinicalTrials.gov Identifier: NCT03177187
Recruitment Status : Recruiting
First Posted : June 6, 2017
Last Update Posted : October 2, 2019
Sponsor:
Collaborators:
Astellas Pharma Inc
AstraZeneca
Prostate Cancer UK
Information provided by (Responsible Party):
Institute of Cancer Research, United Kingdom

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.

Condition or disease Intervention/treatment Phase
Metastatic Castration Resistant Prostate Cancer Drug: AZD5069 Drug: Enzalutamide 40 MG Phase 1 Phase 2

Detailed Description:

The purpose of this study is to find out the side effects and safety of a combination of the CXCR2 antagonist, AZD5069 in combination with the androgen receptor antagonist, enzalutamide in patients with metastatic castration resistant prostate cancer and to determine the most appropriate dose of this combination. In the Phase I part of this study groups of 3 to 6 patients will be treated with increasing doses of AZD5069 in combination with a fixed dose of enzalutamide (160mg 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.

In the Phase I part of the study, the AZD5069 is started first and will be taken twice daily as an oral tablet at Cycle 1, Day -14 for 14 days. Two weeks later on Cycle 1 Day 1, patients will start taking 160mg enzalutamide once a day in addition to the AZD5069. The starting dose of AZD5069 will be 40mg taken orally twice daily with single dose escalations to 80mg, 120mg and 160mg taken orally twice daily to determine the MTD to take forward to a Phase II reversal of resistance cohort. The Phase II reversal of enzalutamide resistance study will explore whether the addition of AZD5069 to enzalutamide reverses resistance to enzalutamide alone. In the phase II reversal of enzalutamide resistance study patients will start taking the AZD5069 at the dose established in the Phase I safety run in part of the study in combination with 160mg of enzalutamide once a day and at the same time from Cycle 1 Day 1 onwards. Potential patients who previously progressed on enzalutamide (having received at least 12 weeks treatment) within 6 months of trial entry (first dose of IMP) will enter the Phase II reversal of enzalutamide resistance study immediately. However, those patients who progressed on enzalutamide (having received at least 12 weeks treatment) greater than 6 months before trial entry will first enter the Phase II enzalutamide resistance cohort to confirm resistance. Study patients will receive 160mg enzalutamide once a day until disease progression. Once enzalutamide resistance is confirmed in these patients, they will be eligible to enter the Phase II reversal of enzalutamide resistance cohort.

Approximately 26 to 49 patients will be entered into this trial, approximately 12 to 24 patients in the phase I safety run in cohort depending on number of patients required to determine RP2D and schedule and between 14 and 25 patients in the phase II reversal of enzalutamide resistance cohort (the investigators predict around 50% of these patients will enter the phase II enzalutamide resistance run in cohort first).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Health Services Research
Official Title: 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)
Actual Study Start Date : November 13, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Phase I
Increasing doses of AZD5069 in combination with a fixed dose of enzalutamide to establish the recommended phase II dose.
Drug: AZD5069
10mg and 40mg plain, beige, film-coated tablets packaged in bottles

Drug: Enzalutamide 40 MG
Enzalutamide is presented in 40mg white to off white capsules. The capsules are provided in a cardboard wallet incorporating a PVC/PCTFE/aluminium blister which holds 28 soft capsules. Each carton contains 4 wallets (112 soft capsules).
Other Name: Xtandi

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.
Drug: AZD5069
10mg and 40mg plain, beige, film-coated tablets packaged in bottles

Drug: Enzalutamide 40 MG
Enzalutamide is presented in 40mg white to off white capsules. The capsules are provided in a cardboard wallet incorporating a PVC/PCTFE/aluminium blister which holds 28 soft capsules. Each carton contains 4 wallets (112 soft capsules).
Other Name: Xtandi




Primary Outcome Measures :
  1. Establish the maximum tolerated dose (MTD) in Phase I of AZD5069 administered in combination with enzalutamide at 160mg OD. [ Time Frame: 12 months ]
    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.

  2. Antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase II [ Time Frame: 12 months ]
    • 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.

  3. Antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase II [ Time Frame: 12 months ]

    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.


Secondary Outcome Measures :
  1. PSA decline [ Time Frame: 24 months ]
    Maximal PSA decline at any time during the trial and PSA decline after 12 weeks (as per PCWG2 criteria) of combination treatment.

  2. Overall survival of patients in Phase II [ Time Frame: 24 months ]
    Overall survival will be measured from the date of AZD5069 addition to enzalutamide to the date of death (whatever cause). Survival time of living patients will be censored on the last date of patient is known to be alive or lost to follow up.

  3. To estimate the radiologic progression free survival (rPFS) on the combination in Phase II [ Time Frame: 24 months ]

    rPFS will be measured from the date of AZD5069 addition to enzalutamide until:

    • Progression of soft tissue/visceral disease by RESIST and/or,
    • Progression of bone disease by PCWG2 bone scan criteria and/or,
    • Death of any cause

    Patients withdrawn for any reason prior to radiological progression then the patient should be assessed until radiological progression has occurred. If however they have started another treatment then they will be censored at the start of the new treatment.


  4. To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells in Phase II [ Time Frame: 24 months ]
    CTC fall by >30% will be expressed as the proportion of patients that have demonstrated a CTC fall of >30% after 12 weeks of combination treatment.

  5. To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide in Phase II [ Time Frame: 24 months ]
    Recording the population exposure to the AZD5069 and enzalutamide combination will summarise safety. Adverse events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

  6. To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination in Phase II [ Time Frame: 24 months ]
    Number of patients with a neutrophil to lymphocyte ratio (NLR) ≥ 3 (at baseline) that convert to an NLR < 3 (blood nadir) with AZD5069 and enzalutamide in combination.

  7. To characterise the pharmacokinetic (PK) profile of enzalutamide and AZD5069 when administered in combination in Phase I [ Time Frame: 24 months ]
    Plasma concentration of enzalutamide and AZD5069 in whole blood

  8. To characterise the pharmacodynamic (PD) profile of AZD5069 and enzalutamide when administered in combination in Phase I [ Time Frame: 24 months ]
    Number of patients with a neutrophil to lymphocyte ratio (NLR) ≥ 3 (at baseline) that convert to an NLR < 3 (blood nadir) with AZD5069 and enzalutamide in combination.

  9. To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase I. [ Time Frame: 24 months ]

    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.

  10. To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination in Phase II [ Time Frame: 24 months ]
    Number of patients patients whose circulating myeloid derived suppressor cells (MDSCs) and intratumoral MDSCs reduce by 50% with AZD5069 and enzalutamide in combination.

  11. To characterise the pharmacodynamic (PD) profile of AZD5069 and enzalutamide when administered in combination in Phase I [ Time Frame: 24 months ]
    Number of patients whose circulating myeloid derived suppressor cells (MDSCs) and intratumoral MDSCs reduce by 50% with AZD5069 and enzalutamide in combination.

  12. To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase I. [ Time Frame: 24 months ]

    For disease progression (see section 3.6) the 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Male
Accepts Healthy Volunteers:   No
Criteria

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 (section 3.6) 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 PCWG2 bone scan criteria and/or,
    3. Progression of PSA by PCWG2 PSA criteria and/or,
    4. Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases.
  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 as defined in section 9.6.
  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 ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.

    Laboratory Test Value required Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L WBC ≥ 3.0 x 109/L Calculated creatinine clearance ≥ 50 mL/min (uncorrected value) Serum bilirubin

    ≤ 1.5 x upper limit of normal (ULN) unless documented Gilbert's disease. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

    ≤ 2.5 x (ULN) unless raised due to known metastatic liver disease in which case ≤ 5 x ULN is permissible

  15. Phase I safety run in cohort ONLY Patients that have progressed after at least 1 line of taxane based chemotherapy and either enzalutamide or abiraterone treatment (having received a minimum of 12 weeks enzalutamide or abiraterone).
  16. 1.1.1.1.1.1 Phase II enzalutamide resistance run in cohort ONLY Patients with histologically confirmed adenocarcinoma of the prostate that have progressed after at least 1 line of taxane based therapy and progressed on enzalutamide treatment (having received a minimum of 12 weeks enzalutamide) 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 at least 1 line of taxane based therapy and progressed on enzalutamide treatment (having received a minimum of 12 weeks enzalutamide) within 6 months prior to entry (day of starting IMP). Prior treatment with abiraterone is not an exclusion criteria.

Exclusion Criteria:

  • 1. Surgery, chemotherapy or other anti-cancer therapy within 4 weeks prior to trial entry/randomization into the study. 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 clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry.

    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. Malabsorbtion 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 therapy.

    17. History of thromboembolic disease within 12 months of commencement of trial.

    18. At high-risk because of non-malignant systemic disease including active infection and any serious concurrent illness.

    19. Any known intolerance to enzalutamide, AZD5069 or to any constituents


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03177187


Contacts
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Contact: Ruth Matthews, PhD +44 (0)20 8915 6713 ruth.toward@icr.ac.uk
Contact: Alison Turner, PhD +44 (0)20 8722 4303 alison.turner@icr.ac.uk

Locations
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Switzerland
Bellinzona Hospital Recruiting
Bellinzona, Switzerland
Contact: Andrea Alimonti, MD         
United Kingdom
Belfast City Hospital Recruiting
Belfast, UK, United Kingdom
Contact: Suneil Jain, MD         
The Royal Marsden Hospital Foundation Trust Recruiting
Sutton, UK, United Kingdom
Contact: Johann S De Bono, MD         
Sponsors and Collaborators
Institute of Cancer Research, United Kingdom
Astellas Pharma Inc
AstraZeneca
Prostate Cancer UK
Investigators
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Principal Investigator: Johann De Bono, MD National Health Service, United Kingdom

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Responsible Party: Institute of Cancer Research, United Kingdom
ClinicalTrials.gov Identifier: NCT03177187     History of Changes
Other Study ID Numbers: CCR4500
First Posted: June 6, 2017    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases