| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration resistant prostate cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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| E.4 | Principal 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 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
20.Symptoms of COVID-19 and/or documented COVID-19 infection |
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| E.5 End points |
| E.5.1 | 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.
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| E.5.1.1 | 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. |
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| E.5.2 | 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.
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| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the last visit of the last patient participating in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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