Clinical trial NCT00463814: AZD6244 (ARRY-142886) Solid Oral Dosage Formulation in Participants With Advanced Solid Malignancies
Official title: A Phase I, Open-Label, Multi-centre Study to Assess the Safety, Tolerability and Pharmacokinetics of a Solid Oral Dosage Formulation (Capsule) of AZD6244 in Patients With Advanced Solid Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Tumor
Cancer
Keywords: Advanced Malignancy
Cancer Eligibility
Malignancy
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2007-04-20
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the study is to assess the safety, tolerability and pharmacokinetics of a capsule of AZD6244 in participants with advanced solid malignancies.


Eligibility criteria: Inclusion Criteria:

* cancer which is refractory to standard therapies
* World Health Organization (WHO) performance status 0 to 2
* evidence of post-menopausal status or negative pregnancy test

Exclusion Criteria:

* Radiotherapy/chemotherapy within 21 days prior to entry
* brain metastases/spinal cord compression unless stable off steroids/anticonvulsants
* evidence of severe/uncontrolled systemic disease
* participated in an investigational drug study within 30 days

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) in Part A and Part B
timeFrame: Day 1 through 11.8 months (maximum observed duration)
measure: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs in Part A and Part B
timeFrame: Day 1 through 11.8 months (maximum observed duration)
measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part A and Part B
timeFrame: Day 1 through 11.8 months (maximum observed duration)
measure: Number of Participants With Abnormal Echocardiogram (ECHO) Parameters Reported as TEAEs in Part A and Part B
timeFrame: Day 1 through 11.8 months (maximum observed duration)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs in Part A and Part B
timeFrame: Day 1 through 11.8 months (maximum observed duration)
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Cmax of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC[0-12]) of AZD6244 (Part A)
timeFrame: Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: AUC of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Time to Reach Maximum Plasma Concentration (Tmax) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Tmax of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Half-life (t1/2) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: t1/2 of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Total Apparent Drug Clearance (CL/F) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: CL/F of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Volume of Distribution at Steady State (Vss/F) of AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Vss/F of AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Cmax of N-desmethyl AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Cmax of N-desmethyl AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: AUC of N-desmethyl AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: AUC(0-12) of N-desmethyl AZD6244 (Part A)
timeFrame: Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: AUC of N-desmethyl AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: AUC(0-24) of N-desmethyl AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Tmax of N-desmethyl AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Tmax of N-desmethyl AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: t1/2 of N-desmethyl AZD6244 (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: t1/2 of N-desmethyl AZD6244 (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Cmax of AZD6244 Amide (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Cmax of AZD6244 Amide (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: AUC(0-12) of AZD6244 Amide (Part A)
timeFrame: Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours Post Dose (AUC[0-4]) of AZD6244 Amide (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: AUC(0-24) of AZD6244 Amide (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Tmax of AZD6244 Amide (Part A)
timeFrame: Day 1: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose; Day 8: Pre-dose (within 10 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, and 12 hours post-dose
measure: Tmax of AZD6244 Amide (Part B Single Dose)
timeFrame: Days 1 and 8: Pre-dose (within 30 minutes of dosing); 5, 15, and 30 minutes, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose
measure: Cmax of AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Tmax of AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: AUC(0-4) of AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC[0-t]) of AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Cmax of N-desmethyl AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Tmax of N-desmethyl AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: AUC(0-4) of N-desmethyl AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: AUC(0-t) of N-desmethyl AZD6244 (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Cmax of AZD6244 Amide (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Tmax of AZD6244 Amide (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: AUC(0-4) of AZD6244 Amide (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: AUC(0-t) of AZD6244 Amide (Part B Multiple Doses)
timeFrame: Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose
measure: Percentage Inhibition of Extracellular Signal-regulated Kinase (ERK) Phosphorylation
timeFrame: 1, 4, 8, and 24 hours post-dose on Day 1 (Part A and Part B) and Day 8 (Part B)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Nijmegen
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Emerging Oncology Medical Science Director, MD
role: STUDY_DIRECTOR
References:
citation: Boers-Sonderen MJ, Desar IM, Blokx W, Timmer-Bonte JN, van Herpen CM. A prolonged complete response in a patient with BRAF-mutated melanoma stage IV treated with the MEK1/2 inhibitor selumetinib (AZD6244). Anticancer Drugs. 2012 Aug;23(7):761-4. doi: 10.1097/CAD.0b013e328350737d.