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 |
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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 |
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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 |
The primary objective of the Phase I part of this study is: • To investigate the MTD 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 |
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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 its metabolites 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 (ORR) in patients treated with AZD8931 in combination with weekly paclitaxel versus weekly paclitaxel alone 4. To compare the overall survival (OS) in patients treated with AZD8931 in combination with paclitaxel versus paclitaxel alone
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All patients 1. Provision of signed, written informed consent prior to any study specific procedures 2. Age 18 years and older 3. Suitable for paclitaxel therapy 4. Estimated life expectancy of more than 12 weeks 5. Not previously randomised to treatment in this study 6. 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 oophorectomy 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) 7. Females must not be breastfeeding 8. Female patients of child bearing potential must use an acceptable highly effective method of contraception. Recommended methods of contraception are listed in Appendix J 9. 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) 10. A haemoglobin ≥9 g/dL (5.59 mmol/L). [Note: any blood transfusion must be >14 days prior to the determination of a haemoglobin ≥9 g/dL (5.59 mmol/L)] Phase II only 37. 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 surgery or radiation of curative intent 38. Patients must not have received previous taxane therapy in an adjuvant or neo-adjuvant setting, within 12 months prior to the start of AZD8931/matching placebo 39. Patients must not have received taxane therapy for treatment of locally advanced (not amenable to surgery) or metastatic breast cancer 40. Patients must not have received more than one cytotoxic chemotherapy regimen for the treatment of locally advanced (not amenable to surgery) or metastatic breast cancer. (Previous endocrine therapy for the treatment of the locally advanced, or metastatic breast cancer with endocrine therapy is permitted) NOTE: If during recruitment, it is determined that a high proportion of randomised patients have received prior chemotherapy for their locally advanced/metastatic disease, enrolment of new patients may be restricted to those with no previous cytotoxic chemotherapy for their locally advanced and/or metastatic disease. 41. Patients must be deemed ineligible for trastuzumab or lapatinib treatment (by local assessment. This should include IHC analysis to determine HER2 status with further testing by FISH/CISH when considered part of local practice.-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 NOTE: Patients whose tumours are classified as having no HER2 expression by local testing methods i.e. are IHC 0 may be eligible for the study. In such cases central analysis will confirm eligibility of these patients 42. At least one lesion, (measurable and/or non-measurable) , that can be accurately assessed at baseline by with computed tomography (CT) magnetic resonance imaging (MRI) or plain x-ray and is suitable for repeated assessment 43. WHO performance status 0 to 1 44. Patients must not have received previous therapy with an agent that targets ErbB1 and/or ErbB2 (including trastuzumab or lapatinib) 45. Patients receiving or expected to require biphosphonate therapy for skeletal related events at any time during the study, must have been on their current dose or must commence therapy, at least 5 days prior to randomisation 46. Patients receiving ongoing treatment with angiotensin converting enzyme (ACE) inhibitors, potassium sparing diuretics or potassium supplements must have been on therapy for at least 2 weeks prior to first dose of study treatment with no changes in dose in that time. Similarly, patients receiving a stable or decreasing dose regime of steroids or systemic (oral) anti cholinergic (anti muscarinic) medication are allowed 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
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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>30 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. 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 who wear contact lenses should discontinue wearing their lenses if they have any mild to moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with AZD8931/matching placebo until at least one week after symptoms have resolved. If a patient has a recurrence of eye symptoms or experiences any severe (CTCAE grade ≥3) ocular events they should discontinue wearing their contact lenses until at least one week after treatment with AZD8931/matching placebo is permanently discontinued 11. Patients should not use any eye drops or ointment for treatment of eye symptoms, unless agreed by a study doctor, at any time during the study until 1 week after AZD8931/matching placebo has been permanently discontinued 12. Patients should not receive endocrine therapy prior to progression of their disease
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome variable – PFS |
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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 | 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 |
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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.8.3 |
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 |
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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 study is defined as the point at which no patient will be exposed to study related procedures. |
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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 | 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 |