| 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 |
| Cancer of the prostate that is advanced |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062904 |
| E.1.2 | Term | Hormone-refractory prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 safety run in
To find out how safe and how well tolerated the combination treatment of enzalutamide and AZD5363 is.
To estimate the maximum dose of AZD5363 that is tolerated in combination with enzalutamide.
To identify the dose of AZD5363 to use in the combination treatment in the randomised phase II trial.
Randomised phase II
To measure the response to AZD5363 + enzalutamide and placebo + enzalutamide.
To compare the responses to AZD5363 + enzalutamide and placebo + enzalutamide.
Single stage phase II expansion cohort
To measure the response to AZD5363 + enzalutamide
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| E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES
Phase I safety run in
To find out the what the body does to the drugs (pharmacokinetics) when AZD5363 and enzalutamide are given in combination.
To measure the response of the combination treatment by using images to assess the cancer and looking at the changes in the blood (CTC evaluation and PSA).
Randomised phase II and single stage phase II expansion cohort
To assess progression free survival using images to assess the spread of the cancer; overall survival; number of bone fractures; looking at the changes in the blood (CTC evaluation and PSA) and to changes in the amount of pain reported (using BPI-SF). Also to find out how safe and well tolerated the combination treatment is compared to placebo + enzalutamide.
EXPLORATORY OBJECTIVES
Phase I safety run in and Single Stage Phase II Expansion
To find out what the combination treatment does to the body (pharmacodynamics)
Randomised phase II and Single Stage Phase II Expansion
To look at ho |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Written informed consent.
2)Histological diagnosis of adenocarcinoma of the prostate and with archival tumour tissue
3)Metastatic Castration-Resistant Prostate Cancer (mCRPC).
4)Progressed after 1 or 2 lines of taxane based chemotherapy.
5)Progressed after at least 12 weeks of abiraterone
6)Age 18 years or above.
7)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
8)PSA greater than or equal to 10ng/ml.
9)Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment
10)Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).
11)Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment.
12)Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria;
a.disease progression as defined by at least 2 new lesions on bone scan.
b.Soft tissue disease progression defined by modified RECIST 1.1.
c.Clinical progression (worsening pain & the need for palliative radiotherapy).
PHASE I SAFETY RUN IN and EXPANSION COHORT - inclusion criteria:
13)Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment.
SINGLE STAGE PHASE II EXPANSION COHORT ONLY - inclusion criteria:
14)Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression
15)Archival tumour tissue available for the analysis of PTEN loss by the central laboratory
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| E.4 | Principal exclusion criteria |
1)Prior treatment with enzalutamide (not applicable for the phase I safety run in or for the single stage phase II expansion cohort).
2)Prior treatment with PI3K, AKT, TOR kinase or mTOR inhibitors
3)Surgery, chemotherapy, or other anti-cancer therapy within 4 weeks prior to trial entry / randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5-alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug.
4)Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation.
5)Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry / randomisation.
6)History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.
7)History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry / randomisation.
8)Known brain or leptomeningeal involvement.
9)Use of potent inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 2 weeks before trial entry / randomisation (3 weeks for St John¡¯s Wort) must be avoided.
10)Clinically significant abnormalities of glucose metabolism as defined by any of the following:
a.Diagnosis of diabetes mellitus type I or II
b.Glycosylated haemoglobin (HbA1C) ≥8.0% at screening
c.Fasting Plasma Glucose ≥8.9mmol/L at screening.
11)Inadequate organ and bone marrow function as evidenced by:
a.Haemoglobin <8.5 g/dL
b.Absolute neutrophil count <1.0 x 109/L
c.Platelet count < 75 x 109/L
d.Albumin ≤25 g/dL.
e.AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥5 x ULN if liver metastases)
f.Total bilirubin ≥ 1.5 x ULN (except for patient with Gilbert's disease)
g.Serum Creatinine > 1.5 x ULN
12)Inability or unwillingness to swallow oral medication.
13)Malabsorption syndrome or other condition that would interfere with enteral absorption.
14)Any of the following cardiac criteria;
a.Mean resting corrected QT interval (QTcF) >470msec obtained triplicate ECGs
b.Clinically important abnormalities(rhythm/conduction/morphology)resting ECG
c.Factors that increase risk of QTc prolongation or risk of arrhythmic events
d.Experience of any of the following in the preceding six months:
- coronary artery bypass graft
- angioplasty
- vascular stent
- myocardial infarction
- angina pectoris
- congestive heart failure NYHA ≥ Grade2
e.Uncontrolled hypotension
15)Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
16)Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.
17)Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti inflammatory corticosteroid.
18)Malignancies other than prostate cancer within 5 years prior to trial entry / randomisation, except for adequately treated basal or squamous cell skin cancer.
19)Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy.
20)Inability to comply with study and follow up procedures.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE I - SAFETY RUN IN:
- Type according to MedDRA (Medical Dictionary for Regulatory Activities), frequency and severity according to NCICTCAE V4, seriousness, and relatedness of study treatment-emergent adverse events will be assessed.
- Laboratory abnormalities will be assessed according to the NCI CTCAE v.4.
RANDOMISED PHASE II:
- The primary endpoint of best overall tumour response will be defined on the basis of the following outcomes; if any of these occur without contrary evidence from any other of the other criteria patients will be considered to have responded:
- PSA decline of ≥ 50% (according to the PCWG2)
- Confirmed objective response (complete &/or partial response) by RECIST v1.1
- ONLY for patients with detectable CTC of ≥5/7.5ml blood at baseline, conversion of CTC to <5/7.5ml blood nadir.
Failure of treatment will be defined as progression by RECIST (v1.1) and/or progression by bone scan. The PCWG2 and RECIST (v1.1) criteria will be used to determine PSA response and soft tissue response respectively.
SINGLE STAGE PHASE II EXPANSION COHORT:
Best overall response after the addition of AZD5363 in patients who progress after 12 weeks of enzalutamide alone will be defined on the basis of the following outcomes. If any of these occur without contrary evidence from any other of the other criteria patients will be considered to have responded:
- PSA decline of ≥ 50% after at least 12 weeks (according to the PCWG2 criteria) - - Confirmed objective response (complete and/or partial response) by RECIST v1.1
- ONLY for patients with detectable circulating tumour cell count (CTC) of ≥5/7.5ml blood at baseline, conversion of CTC to <5/7.5ml blood nadir.
Failure of treatment will be defined as progression by RECIST and/or progression by bone scan. PSA response and PSA progression (for the addition of AZD5363 on the single stage expansion cohort) will be defined according to the consensus guidelines of the PCWG2. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I – safety run in: when all 18 (approximately) patients have received 12 weeks of trial treatment or they have progressed prior to that or have withdrawn before this due to unacceptable toxicity.
Randomised Phase II : Once all patients have been evaluated 12 weeks post randomisation or have progressed prior to that, and after the data have been through quality control checks. This strategy will be reviewed by the IDMC in light of PFS events and the likely duration of response. If the target of accrued events (n=70) has not been reached by the time of the primary analysis an additional analysis will take place once these have been observed.
Single Stage Expansion cohort: Once 13 patients have completed 12 weeks of combination treatment.
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| E.5.2 | Secondary end point(s) |
Phase I – safety run in:
Pharmacokinetic assay analyses.
Antitumour activity of the combination.
Pharmacodynamic assay analyses (tertiary/ exploratory endpoint)
Randomised Phase II:
Radiographic progression-free survival (rPFS- according to PCWG2 criteria & RECIST v1.1) measured from date of randomisation until:
• Bone scan progression- a patient is considered to have progressed by bone scan if:
i.The first bone scan with ≥2 new lesions compared to baseline is observed at 12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline).
ii. A bone scan obtained later than the 12 week assessment shows ≥2 new lesions.
• Progression of soft tissue lesions measured by CT or MRI
• Death from any cause
If a patient is 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.
Overall survival measured from the date of randomisation to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow up.
Number of skeletal-related events defined as either the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention.
Maximum PSA decline at any time during the trial and PSA decline at 12 weeks (as per PCWG2 criteria) presented as a waterfall plot.
Circulating Tumour Cell (CTC) fall by >30%: This will be expressed as the proportion of patients that have demonstrated a CTC fall of >30%. Also the maximum CTC decline at any time during the trial and CTC decline at 12 weeks will be presented as a waterfall plot.
Pain palliation will be assessed using the BPI-SF worst pain intensity score. Standard scoring algorithms will be used with a focus on worst pain intensity score and analgesic score. A composite of the four pain items (worse, least, average, right now) will be presented as supplemental information.
Safety: Using the safety population the extent of exposure of study drug will be summarised. Adverse events will be graded according to NCI-CTCAEv4.
Single Stage Expansion cohort:
Maximum PSA decline at any time during the trial and PSA decline after 12 weeks (as per PCWG2 criteria) of combination treatment will be presented as a waterfall plot.
Overall survival: It will be measured from the date of AZD5363 addition to enzalutamide to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow up.
Radiographic progression-free survival (rPFS) measured from the date of AZD5363 addition to enzalutamide until:
• Bone scan progression: A patient is considered to have progressed by bone scan if:
i.The first bone scan with ≥2 new lesions compared to baseline is observed at 12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline).
ii.A bone scan obtained later than the 12 week assessment shows ≥2 new lesions.
• Progression of soft tissue lesions measured by CT or MRI as defined by RECIST v1.1.
• Death from any cause.
If a patient is 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.
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.
Safety: Using the safety population the extent of exposure of study drug will be summarised. Adverse events will be graded according to NCI-CTCAEv4.
Pharmacodynamic assay analyses (tertiary/ exploratory endpoint)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I – safety run in: when all 18 (approximately) patients have received 12 weeks of trial treatment or they have progressed prior to that or have withdrawn before this due to unacceptable toxicity.
Randomised Phase II : Once all patients have been evaluated 12 weeks post randomisation or have progressed prior to that, and after the data have been through quality control checks. This strategy will be reviewed by the IDMC in light of PFS events and the likely duration of response. If the target of accrued events (n=70) has not been reached by the time of the primary analysis an additional analysis will take place once these have been observed.
Single Stage Expansion cohort: Once 13 patients have completed 12 weeks of combination treatment.
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration of enzalutamide and AZD5363 in combination. |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 trial is the defined as the last date of data capture. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 1 |
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