| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase I part of the study: Solid tumours that are refractory to standard therapies
Phase II part of the study: trastuzumab- or lapatinib-ineligible patients with locally advanced (not amenable to surgery) or metastatic breast cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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. Radiotherapy must be terminated at least 2 weeks prior to enrolment and patients
must have recovered from any toxic effects
4. Suitable for paclitaxel therapy
5. Life expectancy of more than 12 weeks
6. Not previously enrolled/andomised to treatment in this study
7. Females must be of non-childbearing status defined as one of the following criteria at screening:
- negative pregnancy test in women of childbearing potential
- women who are permanently or surgically sterilised (hysterectomy and/or bilateral
oopherectomy and/or bilateral salpingectomy)
- postmenopausal (over 50 years old and amenorrheic for 12 months following cessation of all exogenous hormonal treatments, or over 57 years old)
8. Females must not be breastfeeding
9. Female patients of child-bearing potential must use an acceptable highly
effective method of contraception plus condoms plus spermicide during the study and for 30 days after the last dose of studt drug. 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. Patients must not have received an investigational drug within 30 days or 5 half-lives, whichever is longer, of the first dose of randomised therapy (AZD8931 or matching placebo)
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. No wearing of contact lenses (patients should discontinue wearing any contact lenses 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. Criteria 46 has been deleted
47. Random blood glucose at screening ≤11.1 mmol/L, or 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 locally advanced (not amenable to surgery) or metastatic disease.
Lesions should not be amenable to sugery or radiation of curative intent
50. Patients who have received neo-adjuvant/adjuvant and now present with newly relapsed advanced or metastatic disease are eligible; however, prior neo-adjuvant/adjuvant therapy is not required for study entry
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 plus condoms plus spermicide during the study and for 30 days after last dose of AZD8931/matching placebo.
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. Male patients (including those that have undergone a successful vasectomy) must use condoms plus spermicide during sexual contact with a female of child-bearing potential who is not using a highly effective method of contraception, for the duration of the study and for 3 months after the last dose of AZD8931
7. Male patients will be advised to abstain from sperm donation from first dose until
3 months following receipt of the last dose of AZD8931
8. Refrain from driving for 4 hours following ophthalmic examination if pupillary
dilatation performed
9. 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
10. Patients should refrain from wearing contact lenses in excess of the recommended
daily duration during participation in the study
11. 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) | No |
| 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.8.5 | 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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