A Phase I, Open-Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD6244 (ARRY-142886)

Study Overview
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Brief Summary
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This study is being conducted to determine if a combination of AZD6244 given orally twice a day with standard doses of selected chemotherapies will be safe and tolerable for cancer patients with advanced solid tumors. The highest tolerated dose of AZD6244 in combination with selected chemotherapies will be evaluated. The study will also investigate how AZD6244 in combination with standard chemotherapies are absorbed, distributed and excreted by the body as well as the length of time that the drugs remain in the body. Initial and periodic assessments will establish patient response to the combination therapies

Official Title
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A Phase I, Open-Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD6244 (ARRY-142886) When Given in Combination With Standard Doses of Selected Chemotherapies to Patients With Advanced Solid Tumors

Conditions
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Breast Cancer, Breast Neoplasms, Colon Cancer, Colonic Cancer, Colon Neoplasms, Lung Cancer, Melanoma, Kidney Cancer

Intervention / Treatment
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* Drug: AZD6244
* Drug: Dacarbazine
* Drug: Erlotinib
* Drug: Docetaxel
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will have measurable and/or non-measurable disease, lacking curative options for whom the selected chemotherapy agents represent the standard of care WHO performance status 0-1 Patients must be able to swallow AZD6244 capsules Exclusion Criteria: Prior treatment with a MEK inhibitor Participation in a clinical study during the last 30 days or have not recovered from side effects of an investigational study drug Brain metastases or spinal cord compression unless treated and stable (for at least 1 month) off steroids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>AZD6244 + docetaxel | Drug: AZD6244<br>* twice daily oral dose<br>* Other names: ARRY-142886;Drug: Docetaxel<br>* intravenous infusion<br>* Other names: Taxotere®;|
| Experimental: 2<br>AZD6244 + Dacarbazine | Drug: AZD6244<br>* twice daily oral dose<br>* Other names: ARRY-142886;Drug: Dacarbazine<br>* intravenous infusion<br>|
| Experimental: 3<br>AZD6244 + Erlotinib | Drug: AZD6244<br>* twice daily oral dose<br>* Other names: ARRY-142886;Drug: Erlotinib<br>* daily oral dose<br>|
| Experimental: 4<br>AZD6244 + Temsirolimus | Drug: AZD6244<br>* twice daily oral dose<br>* Other names: ARRY-142886;Drug: Temsirolimus<br>* intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of twice daily oral doses of AZD6244 when administered in combination with standard doses of selected chemotherapies. | Incidence and intensity of adverse events as graded by CTCAE (version 3.0), physical examinations, vital signs (including weight, blood pressure and pulse rate), ECG parameters, MUGA scan and echocardiography, clinical chemistry (including liver function tests), Brain Natriuretic Peptide (BNP), Troponin I, hematology, urinalysis, and ophthalmologic examinations. | 28 days + | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK of AZD6244 and selected chemotherapies. | The PK parameters will be derived using noncompartmental analysis. The maximum plasma concentrations (Cmax) and the time to reach the maximum plasma concentrations (tmax) will be determined by visual inspection of the plasma concentration-time profiles. The area under the plasma concentration-time curve from zero to 12 hours post dose, AUC(0-12), will be calculated by the linear trapezoidal rule. Where more than one maxima occurs, the reported value will be assigned to the first occurrence. | Cycle 1 Day 3 and Cycle 2 day 1 | 
| Define highest tolerated dose of AZD6244 when in combination with selected chemotherapies. | The starting dose of AZD6244 in each arm will be 50mg. Continuous dosing (commencing Cycle 1/Day 3 for docetaxel and dacarbazine and Cycle 1/Day 8 for erlotinib and temsirolimus) will be BD. The AZD6244 dose may be maintained or reduced. | 28 days + | 
| Tumor response. | To make a preliminary assessment of tumor response as measured by Objective Response Rate (ORR) per investigator's assessment using Response Evaluation Criteria in Solid Tumors (RECIST) when AZD6244 Hyd-Sulfate is given in combination with standard doses of selected chemotherapies. | 28 days + | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARRY-142886, AZD6244, Cancer, Colon Cancer, Breast Cancer, Lung Cancer, Melanoma, Kidney Cancer