Phase I/II AZD8931/Paclitaxel in Treatment of Advanced Solid Tumours (Phase I) and Advanced Breast Cancer (Phase II)

Study Overview
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Brief Summary
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The main purpose of this study is to determine if AZD8931 can improve the efficacy of standard chemotherapy for the treatment of advanced breast cancer. This study will be conducted in 2 parts: the first part (phase I) will determine a dose of AZD8931 that can be safely administered with paclitaxel chemotherapy. The second part (phase II) will determine the efficacy and safety of AZD8931 in combination with paclitaxel chemotherapy in breast cancer.

Official Title
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A Phase I/II Multi-centre Study of AZD8931 in Combination With Weekly Paclitaxel to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy in Patients With Advanced Solid Tumours and in a Selected Population With Low HER2-expressing Locally Recurrent and/or Metastatic Breast Cancer

Conditions
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Neoplasms, Breast Neoplasms, Breast Cancer

Intervention / Treatment
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* Drug: AZD8931
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male/ female with solid, malignant tumour which is unresponsive to standard therapies (Phase I). Female patients with advanced breast cancer with low HER2 expression (Phase II) Suitable for paclitaxel chemotherapy Life expectancy more than 12 weeks Exclusion Criteria: Inadequate kidney, liver, heart, gastric, lung or eye function Hypersensitive to paclitaxel No symptomatic uncontrolled brain metastases Previous taxane chemotherapy within 12 months (Phase II)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 150 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>AZD8931 plus Paclitaxel | Drug: AZD8931<br>* Tablet Oral bid<br>Drug: Paclitaxel<br>* IV once weekly for 3 weeks followed by a week off (repeated cycles)<br>* Other names: Taxol;|
| Placebo Comparator: 2<br>Placebo plus Paclitaxel | Drug: Paclitaxel<br>* IV once weekly for 3 weeks followed by a week off (repeated cycles)<br>* Other names: Taxol;Drug: Placebo<br>* Oral bid (twice daily)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: The Number of Dose Limiting Toxicities in AZD8931 in Combination With Weekly Paclitaxel | DLT is an AE or laboratory abnormality related to AZD8931, starting during the DLT evaluation period and meeting any of the following criteria (further detail in protocol): Symptomatic ocular surface lesion; CTCAE grade 4 haematological AE; CTCAE grade ≥3 of febrile neutropenia / neutropenia / thrombocytopenia / hyperkalaemia / hyperglycaemia / hypotension / urological toxicity / ILD / pneumonitis; QTcF interval > 500 msec, two ECGs ≥ 30 minutes apart; Symptomatic congestive cardiac failure and a drop in LVEF; Decrease in LVEF of ≥20% to below the LLN; CS rash remaining CTCAE grade ≥3 for ≥5 days despite optimal treatment; CTCAE grade ≥3 nausea, vomiting or diarrhoea, despite optimal therapy; Other CTCAE grade ≥3 toxicity which, in the opinion of the investigator, is CS and related to AZD8931; Delay to the administration of paclitaxel on D1 of Cycle 2 by ≥7 days. Patients could have more than one DLT. | Weekly visits for routine safety monitoring from Day 1 to Day 28 for each participant | 
| Phase II: Progression-free-survival (PFS) Were Analyzed in Patients Treated With AZD8931 in Combination With Weekly Paclitaxel Versus Weekly Paclitaxel Alone | Time from the date of randomization until the date of objective disease progression (as per RECIST 1.1) or the date of death (by any cause in the absence of progression) | Baseline and every 8 weeks, accessed up to data cut off on 11th April 2012 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Objective Tumour Response Rate (ORR) Was Compared in Patients Treated With AZD8931 in Combination With Weekly Paclitaxel Versus Weekly Paclitaxel Alone | The number of subjects with at least one visit response of CR or PR (Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Not Evaluable (NE), All target lesion measurements are missing or >1/3 target lesion measurements are missing and sum of diameters of non-missing target lesions does not qualify for PD; Not applicable (NA), No target lesions are recorded at baseline)) | Baseline and every 8 weeks, accessed up to data cut off on 11th April 2012 | 
| Phase II: The Overall Survival (OS) Was Compared in Patients Treated With AZD8931 in Combination With Weekly Paclitaxel Versus Weekly Paclitaxel Alone | The time from the date of randomization until the date of death due to any cause. | Weekly visits for routine safety monitoring, accessed up to data cut off on 11th April 2012 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Tumour, Breast cancer, Metastatic, Secondary