Clinical Trials /

Combination Study of AZD5069 and Enzalutamide.

NCT03177187

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Study of AZD5069 and Enzalutamide.
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: CCR4500
  • NCT ID: NCT03177187

Conditions

  • Metastatic Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
AZD5069Phase I
Enzalutamide 40 MGXtandiPhase I

Purpose

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.

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).
    

Trial Arms

NameTypeDescriptionInterventions
Phase IExperimentalIncreasing doses of AZD5069 in combination with a fixed dose of enzalutamide to establish the recommended phase II dose.
  • AZD5069
  • Enzalutamide 40 MG
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.
  • AZD5069
  • Enzalutamide 40 MG

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Establish the maximum tolerated dose (MTD) in Phase I of AZD5069 administered in combination with enzalutamide at 160mg OD.
Time Frame:12 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:PSA decline
Time Frame:24 months
Safety Issue:
Description:Maximal PSA decline at any time during the trial and PSA decline after 12 weeks (as per PCWG2 criteria) of combination treatment.
Measure:Overall survival of patients in Phase II
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To estimate the radiologic progression free survival (rPFS) on the combination in Phase II
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells in Phase II
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide in Phase II
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination in Phase II
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To characterise the pharmacokinetic (PK) profile of enzalutamide and AZD5069 when administered in combination in Phase I
Time Frame:24 months
Safety Issue:
Description:Plasma concentration of enzalutamide and AZD5069 in whole blood
Measure:To characterise the pharmacodynamic (PD) profile of AZD5069 and enzalutamide when administered in combination in Phase I
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase I.
Time Frame:24 months
Safety Issue:
Description: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.
Measure:To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination in Phase II
Time Frame:24 months
Safety Issue:
Description:Number of patients patients whose circulating myeloid derived suppressor cells (MDSCs) and intratumoral MDSCs reduce by 50% with AZD5069 and enzalutamide in combination.
Measure:To characterise the pharmacodynamic (PD) profile of AZD5069 and enzalutamide when administered in combination in Phase I
Time Frame:24 months
Safety Issue:
Description:Number of patients whose circulating myeloid derived suppressor cells (MDSCs) and intratumoral MDSCs reduce by 50% with AZD5069 and enzalutamide in combination.
Measure:To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate in Phase I.
Time Frame:24 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institute of Cancer Research, United Kingdom

Last Updated

June 2, 2020