A Phase I/II Multi-centre Study of AZD8931 in Combination with WeeklyPaclitaxel to Assess the Safety, Tolerability, Pharmacokinetics and Efficacyin Patients with Advanced Solid Tumours and in a Selected Population withLow HER2-expressing Locally Recurrent and/or Metastatic Breast Cancer(THYME) - THYME

Conditions: 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 version: 9.1Level: LLTClassification code 10049280Term: Solid tumour

Registration Number: EUCTR2009-010551-26-SE

Lead Sponsor: AstraZeneca AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 192

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 plus condoms plus spermicide during the study and for 30 days after the last dose of study 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 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 neoadjuvant 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 IHCO may be eligible for the study. In such ca

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