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
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 58
- Locations
- 5
- Primary Endpoint
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) in Part A and Part B
Study Overview
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
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 99 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Part A: Dose Escalation AZD6244 25 mg
Participants will receive a single oral dose of AZD6244 25 mg capsule on Day 1 followed by continuous twice daily (bd) dosing from Day 2 onwards, until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Part A: Dose Escalation AZD6244 50 mg
Participants will receive a single oral dose of AZD6244 50 mg capsule on Day 1 followed by continuous dosing from Day 2 onwards, until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Part A: Dose Escalation AZD6244 75 mg
Participants will receive a single oral dose of AZD6244 75 mg capsule on Day 1 followed by continuous dosing from Day 2 onwards, until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Part A: Dose Escalation AZD6244 100 mg
Participants will receive a single oral dose of AZD6244 100 mg capsule on Day 1 followed by continuous dosing from Day 2 onwards, until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Part B: Relative Bioavailability (Sequence 1) and Safety Assessment Phase
Participants in relative bioavailability phase will receive a single oral dose of AZD6244 100 mg free-base suspension (mix and drink) on Day 1. Following a washout period of 7 days, participants will receive a single oral dose of AZD6244 75 mg capsule on Day 8 (Sequence 1). In the safety assessment phase, participants who will participate in the relative bioavailability phase will receive oral AZD6244 75 mg capsule bd dosing from Day 9 onwards until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Part B: Relative Bioavailability (Sequence 2) and Safety Assessment Phase
Participants in relative bioavailability phase will receive a single oral dose of AZD6244 75 mg capsule on Day 1. Following a washout period of 7 days, participants will receive a single oral dose of AZD6244 100 mg free-base suspension (mix and drink) on Day 8 (Sequence 2). In the safety assessment phase, participants who will participate in the relative bioavailability phase will receive oral AZD6244 75 mg capsule bd dosing from Day 9 onwards until disease progression or another protocol-defined discontinuation criterion will be met, whichever will occur first.
Intervention: AZD6244 (Drug)
Outcomes
Primary Outcomes
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) in Part A and Part B
Time Frame: Day 1 through 11.8 months (maximum observed duration)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs in Part A and Part B
Time Frame: Day 1 through 11.8 months (maximum observed duration)
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of hematology, clinical chemistry, and urinalysis.
Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part A and Part B
Time Frame: Day 1 through 11.8 months (maximum observed duration)
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, oxygen saturation, weight, and pulse rate).
Number of Participants With Abnormal Echocardiogram (ECHO) Parameters Reported as TEAEs in Part A and Part B
Time Frame: Day 1 through 11.8 months (maximum observed duration)
Number of participants with abnormal ECHO parameters reported as TEAEs are reported.
Number of Participants With Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs in Part A and Part B
Time Frame: Day 1 through 11.8 months (maximum observed duration)
Number of participants with abnormal ECG parameters reported as TEAEs are reported.
Secondary Outcomes
- Maximum Plasma Concentration (Cmax) of AZD6244 (Part A)(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)
- Cmax of AZD6244 (Part B Single Dose)(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)
- Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC) of AZD6244 (Part A)(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)
- Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC[0-12]) of AZD6244 (Part A)(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)
- AUC of AZD6244 (Part B Single Dose)(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)
- Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of AZD6244 (Part B Single Dose)(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)
- Time to Reach Maximum Plasma Concentration (Tmax) of AZD6244 (Part A)(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)
- Cmax of AZD6244 Amide (Part B Single Dose)(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)
- AUC(0-12) of AZD6244 Amide (Part A)(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)
- 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)(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)
- AUC(0-24) of AZD6244 Amide (Part B Single Dose)(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)
- Tmax of AZD6244 Amide (Part A)(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)
- Tmax of AZD6244 Amide (Part B Single Dose)(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)
- Tmax of AZD6244 (Part B Single Dose)(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)
- Half-life (t1/2) of AZD6244 (Part A)(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)
- t1/2 of AZD6244 (Part B Single Dose)(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)
- Total Apparent Drug Clearance (CL/F) of AZD6244 (Part A)(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)
- CL/F of AZD6244 (Part B Single Dose)(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)
- Volume of Distribution at Steady State (Vss/F) of AZD6244 (Part A)(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)
- Vss/F of AZD6244 (Part B Single Dose)(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)
- Cmax of N-desmethyl AZD6244 (Part A)(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)
- Cmax of N-desmethyl AZD6244 (Part B Single Dose)(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)
- AUC of N-desmethyl AZD6244 (Part A)(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)
- AUC(0-12) of N-desmethyl AZD6244 (Part A)(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)
- AUC of N-desmethyl AZD6244 (Part B Single Dose)(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)
- AUC(0-24) of N-desmethyl AZD6244 (Part B Single Dose)(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)
- Tmax of N-desmethyl AZD6244 (Part A)(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)
- Tmax of N-desmethyl AZD6244 (Part B Single Dose)(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)
- t1/2 of N-desmethyl AZD6244 (Part A)(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)
- t1/2 of N-desmethyl AZD6244 (Part B Single Dose)(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)
- Cmax of AZD6244 Amide (Part A)(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)
- Cmax of AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Tmax of AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- AUC(0-4) of AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- 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)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Cmax of N-desmethyl AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Tmax of N-desmethyl AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- AUC(0-4) of N-desmethyl AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- AUC(0-t) of N-desmethyl AZD6244 (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Cmax of AZD6244 Amide (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Tmax of AZD6244 Amide (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- AUC(0-4) of AZD6244 Amide (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- AUC(0-t) of AZD6244 Amide (Part B Multiple Doses)(Days 15 and 22: Pre-dose (within 10 minutes of dosing); 1, 2, and 4 hours post-dose)
- Percentage Inhibition of Extracellular Signal-regulated Kinase (ERK) Phosphorylation(1, 4, 8, and 24 hours post-dose on Day 1 (Part A and Part B) and Day 8 (Part B))