Japanese Phase I Study of AZD2014 in Advanced Solid Malignancies

Study Overview
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Brief Summary
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The primary objective of this study is to investigate the safety and tolerability of continuous and/or intermittent dosing of AZD2014 when given orally to patients with advanced solid malignancies.

Detailed Description
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This is an open-label, multi-centre study of AZD2014 administered orally in Japanese patients with advanced solid malignancies. The study design allows an evaluation of each cohort with intensive safety monitoring to ensure the safety of the patients. In this study, a minimum of 3 and a maximum of 6 evaluable patients will be enrolled in each cohort; approximately 24 evaluable patients in total. The total number of patients enrolled will depend upon the number of screen failures, number of cohorts and number of evaluable subjects. Safety, preliminary efficacy and PK (single and multiple dose) are evaluated in this study. Patients will receive a single dose of AZD2014 on Day 1 (to allow assessment of single dose PK), then after a minimum of 48 hours washout period continuous or intermittent twice daily dosing of AZD2014 will be initiated. The washout period of 48 hours may be extended depending on emerging data from previous cohorts.Doses and schedules to be evaluated will be agreed by AstraZeneca and the Safety Review Committee (SRC).

Official Title
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A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered to Japanese Patients With Advanced Solid Malignancies

Conditions
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Advanced Solid Malignancies

Intervention / Treatment
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* Drug: AZD2014


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of a solid, malignant tumour that is refractory to standard therapies or for which no standard therapies exist For Cohort 3-1 and 3-2, followed as, Histological or cytological confirmation of a solid, malignant tumour that is refractory to standard therapies or for which no standard therapies exist or where treatment with paclitaxel is an appropriate treatment option. SqNSCLC patients are excluded from the Cohort 3-2. World Health Organisation (WHO) performance status (PS) 0-1 with no deterioration over the previous 2 weeks prior to informed consent and minimum life expectancy of 12 weeks At least one lesion that can be accurately assessed at baseline by computed tomography (CT) magnetic resonance imaging (MRI) or plain X-ray and is suitable for repeated assessment Exclusion Criteria Prior chemotherapy, biological therapy, radiation therapy, antiandrogens, other anticancer therapies including immunotherapy and any investigational agents within 21 days of starting study treatment (not including palliative radiotherapy at focal sites), or corticosteroids within 14 days of starting study treatment. Major surgery within 4 weeks prior to the study treatment (excluding placement of vascular access), or minor surgery within 2 weeks prior to the study treatment Potent or moderate inhibitors or inducers of cytochrome (CYP) 3A4/5 if taken within the stated washout periods: Potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods: Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters P-gp (MDR1), Breast cancer resistance protein (BCRP), Organic anion transporting polypeptide (OATP)1B1, OATP1B3, Organic cation transporter (OCT)1 and OCT2 within the appropriate wash-out period (at least 5 x reported terminal elimination half-life (t1/2) of each drug) before the study treatment. Any haemopoietic growth factors (eg, granulocyte-colony stimulating factor [G-CSF]) within 2 weeks prior to receiving study drug Previous initiation of treatment with AZD2014 in the present study or prior treatment with AZD8055 With the exception of alopecia, any unresolved toxicities from prior chemotherapy greater than Common toxicity criteria for adverse events (CTCAE) grade 1 at the time of starting study treatment Spinal cord or brain metastases unless asymptomatic and stable off steroids for at least 4 weeks prior to start of study treatment Subjects with interstitial lung disease as a complication or a history

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD2014 50mg, 125mg, 25mg and 50mg intermittent BD<br>50mg BD continuous dosing, 125mg BD intermittent dosing, 25 mg and 50mg intermittent dosing with weekly Paclitaxel | Drug: AZD2014<br>* 50mg continuous dosing, 125mg intermittent dosing, 25 mg and 50mg intermittent dosing with weekly Paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability measured by adverse events | This will be assessed in terms of Adverse Events (AEs), laboratory data, vital signs, ECG and physical exams | 6 months in average | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of AZd2014 | Characterising the pharmacokinetics (PK) of AZD2014 | 21 days | 
| AUC(Area under the plasma concentration-time curve) of AZD2014 | Characterising the pharmacokinetics (PK) of AZD2014 | 21 days | 
| Tmax of AZD2014 | Characterising the pharmacokinetics (PK) of AZD2014 | 21 days | 
| To obtain a preliminary assessment of the anti-tumour activity of AZD2014 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. | Best overall response | 6 months in average | 
| To obtain a preliminary assessment of the anti-tumour activity of AZD2014 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. | Objective response rate | 6 months in average | 
| To obtain a preliminary assessment of the anti-tumour activity of AZD2014 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. | Percentage change in tumour size | 6 months in average |