| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase I part of the study: Advanced solid tumours
Phase II part of the study: Low HER2 expressing locally recurrent and/or metastatic breast cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
|
| 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 |
The primary objective of the Phase I part of this study is:
• To investigate the maximum tolerated dose of AZD8931 in combination with
weekly paclitaxel in patients with advanced solid malignancies, through
assessment of safety and tolerability
The primary objective of the Phase II part of this study is:
• To compare the progression free survival (PFS) in patients treated with
AZD8931 in combination with paclitaxel versus paclitaxel alone |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
1. To investigate whether there is any effect on the pharmacokinetics (PK) of
AZD8931 and/or paclitaxel when co-administered
2. To investigate the safety and tolerability of AZD8931 in combination with
paclitaxel
3. To compare the objective tumour response rate in patients treated with
AZD8931 in combination with paclitaxel versus paclitaxel alone
4. To compare the overall survival (OS) in patients treated with AZD8931 in
combination with paclitaxel versus paclitaxel alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients
1. Provision of signed, written informed consent
2. Age 18 years and older
3. Radiation therapy must be terminated at least 2 weeks prior to enrolment. Patients
must have recovered from the toxic effects of prior therapy
4. Suitable for paclitaxel therapy
5. Life expectancy of more than 12 weeks
6. Not previously randomised to treatment in this study
7. Females of non-childbearing status defined as one of the following criteria at
screening:- negative pregnancy test in women of childbearing potential- or women
who are permanently or surgically sterilised (hysterectomy and/or bilateral
oopherectomy and/or bilateral salpingectomy) - or postmenopausal (over 50 years
old and amenorrheic for 12 months following cessation of all exogenous hormonal
treatments, or over 57 years old)
8. Not pregnant or breastfeeding if female and of child-bearing potential
9. Female patients of child-bearing potential willing to use an acceptable highly
effective method of contraception during the study and for 3 months after the last
dose of IP. It is recommended that women should have been stable on their chosen
method of contraception for at least 3 months before entering the study.
Recommended methods of contraception are listed in Appendix J
10. No receipt of investigational drug within the 14 days or 5 half-lives, whichever is
longer, of the first dose of randomised therapy (AZD8931 or matching placebo) or
participated in a previous clinical study during the last 30 days prior to study entry
Phase I only
40. Male or female with histologically or cytologically confirmed solid, malignant
tumour which is refractory to standard therapies, or for which no standard therapies
exist. Inclusion is irrespective of stage of disease or extent of prior therapy
41. World Health Organisation (WHO) performance status 0 to 2
42. No evidence of ‘dry eye’: persistent symptoms of ocular surface irritation,
Schirmer’s test without anaesthesia of less than 5 mm in 5 minutes and tear breakup
time [TBUT] test of less than 10 seconds (if one of these is satisfactory, the
patient may be included – both of these parameters should be normal if the patient
is receiving anti-cholinergic medication. Eye conditions that are stable and of long
standing, such as scars from trauma, pinguecula, atrophic pterygia etc, should not be
considered as reasons to exclude the patient
43. Not wearing contact lens (patients should discontinue wearing contact lens from at
least 1 week prior to entering the study to 1 week following discontinuation of
AZD8931)
44. No recent acute changes in patient’s vision, or ongoing symptoms of ocular pain,
discomfort or irritation
45. No history of collagen vascular, chronic inflammatory or degenerative disease with eye involvement (eg, rheumatoid, Sjögren syndrome, systemic lupus erythematosus [SLE]) or of ocular surface disease (including Steven-Johnson syndrome, ocular cicatricial pemphigoid or chemical burns, herpes simplex or herpes zoster virus eye disease
46. No history of corneal surgery, including laser refractive surgery, within the past 3
years
47. Random blood glucose at screening ≤11.1 mmol/L, or random blood glucose
between 7 and 11 mmol/L AND fasting blood glucose ≤7 mmol/L
48. No uncontrolled diabetes mellitus (glycosylated haemoglobin [HbA1c] ≤9%)
Phase II only
49. Female patients with histologic or cytologic diagnosis of breast cancer with
evidence of unresectable and/or locally recurrent and/ or metastatic disease.
Lesions should not be amenable to sugery or radiation of curative intent
50. Patient with low HER2 expressing tumours and who are deemed ineligible for
trastuzumab or lapatinib treatment (ie, patients who do not have breast cancer that
can be classified as HER2 IHC 3+ or HER2 IHC 2+ / FISH positive by an approved
diagnostic assay)
− Tumour tissue sample provision for central analysis is a mandatory part of the
screening procedures and must be available. The sample can be taken from
archival diagnostic tissue from the original biopsy or a more recent biopsy.
Both primary lesion and metastatic sites are acceptable. Notification of patient
eligibility will come from the central laboratory informing the site that HER2
expression is within limits for randomisation
51. At least one lesion, not previously irradiated, that can be accurately measured as
≥10 mm in the longest diameter with spiral computed tomography (CT) scan or as
≥ 20 mm with conventional techniques (conventional CT, MRI) and which is suitable for accurate repeated measurements. Patients bone metastases, pleural
effusion or ascites as the only site of disease will be excluded.
For optional pharmacogenetic component only
59. Provision of informed consent for genetic research
60. No previous allogenic bone marrow transplant
61. Any non-leukocyte depleted whole blood transfusion must have been received more than 120 days prior to genetic sample collection |
|
| E.4 | Principal exclusion criteria |
All the points included in this section are restrictions
All patients
1. Female patients of child bearing potential must use an acceptable highly effective
method of contraception during the study, and for 3 months after the last dose of IP.
Recommended methods of contraception are listed in Appendix J
2. Patients should use sunglasses and sun cream with UVA and UVB protection
SPF>15 if exposed to sunlight and avoid use of sun tanning booths during the study
and for 3 months after the last dose of IP
3. Patients who are blood donors should not donate blood during the trial and for 3
months following their last dose of IP
4. All patients must avoid concomitant use of medications, herbal supplements and/or
ingestion of foods that significantly modulate CYP3A4 and/or CYP2D6 activity or
which are significantly metabolised by CYP3A4 and/or CYP2D6. Such drugs must
have been discontinued for an appropriate period before they enter screening and
for a period of 2 weeks after the last dose of AZD8931. Guidance on medications
to avoid and on washout periods is given in Appendix D
5. Refer to the Summary of Product Characteristics (SPC) for restrictions specific to
paclitaxel
Phase I only
6. No food is allowed from 2 hours before to 2 hours after taking IP
7. Male patients will be required to use reliable methods of contraception (condom)
during any sexual contact with a female of childbearing potential for the duration of
the study and until 12 weeks after the last dose of AZD8931 (even if he has
undergone successful vasectomy)
8. Male patients will be advised to abstain from sperm donation from first dose until
12 weeks following receipt of the last dose of AZD8931
9. Refrain from driving for 4 hours following ophthalmic examination if pupillary
dilatation performed
10. Patients should refrain from wearing contact lenses from at least 1week prior to
starting AZD8931 to 1 week after discontinuation of AZD8931
Phase II only
11. Patients should refrain from wearing contact lenses in excess of the recommended
daily duration during participation in the study
12. Patients should not receive any endocrine treatment whilst receiving IP |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary outcome variable – PFS |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 |
| In combination with paclitaxel |
|
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| The end of study is defined as the point at which no patient will be exposed to study related procedures. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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