AZD6244 in Combination With Docetaxel Versus Docetaxel Al... | NCT00890825

Description Module

Detailed Description

The primary objective of this study was to assess the efficacy in terms of overall survival (OS) of AZD6244 in combination with docetaxel, compared with docetaxel alone, in second-line patients with KRAS mutation-positive locally advanced or metastatic NSCLC. Amendment 4 of the CSP altered the primary objective and outcome variable from progression-free survival (PFS) to OS, and the secondary outcome variable changed from OS to PFS.

The secondary objectives of the study were:

To further assess the efficacy of AZD6244 in combination with docetaxel, compared with docetaxel alone, in second-line patients with KRAS mutation-positive locally advanced or metastatic NSCLC
To assess the safety and tolerability profile of AZD6244 in combination with docetaxel
To investigate the use of plasma and serum as a potential source of circulating free tumour DNA (cfDNA) for the analysis of KRAS mutation status
To investigate the PK of AZD6244 and N-desmethyl AZD6244 and any other known metabolites when AZD6244 is administered in combination with docetaxel.

The exploratory objectives of the study were:

To assess the prevalence, severity and change over time of advanced NSCLC cancer specific symptoms in patients receiving AZD6244 in combination with docetaxel and docetaxel alone
To explore potential biomarkers in residual tumour, plasma and/or serum taken for KRAS mutational analysis which may influence development of NSCLC (and associated clinical characteristics) and/or response (optional)
To investigate the relationship between AZD6244 and/or N-desmethyl AZD6244 and any other known metabolite plasma concentrations or exposure and clinical outcomes, efficacy, AEs, and/or safety parameters if deemed appropriate
To collect and store deoxyribonucleic acid (DNA), derived from a blood sample, for future exploratory research into genes that may influence response, eg, distribution, safety, tolerability, and efficacy of AZD6244 and/or agents used in combination and/or as comparators (optional).

Label	Type	Description	Intervention Names
AZD6244 + Docetaxel	Active Comparator	AZD6244 75 mg bd + Docetaxel 75 mg/m^2	Drug: AZD6244 Drug: docetaxel
Placebo + Docetaxel	Placebo Comparator	Placebo + Docetaxel 75 mg/m^2	Drug: docetaxel Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
AZD6244	Drug	oral capsules, 75mg twice daily	AZD6244 + Docetaxel	Selumetinib

Measure	Description	Time Frame
Overall Survival	OS was calculated as the interval from the date of randomisation to the date of patient death (any cause). Patients who had not died at the time of the final analysis, or who withdrew consent, were censored at the last date the patient was known to be alive.	At least 12 months since start of treatment.

Measure	Description	Time Frame
Progression Free Survival	PFS was defined as the interval between the date of randomisation and the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression. Patients who did not progress or die at the time of analysis were censored at the time of their latest evaluable objective tumour assessment. This also included patients who withdrew consent.

Eligibility Module

Name	Affiliation	Role
Dr. Pasi Janne	Dana-Farber Cancer Institute, Boston, USA	Principal Investigator
Dr. Gabriella Mariani	AstraZeneca, Hertfordshire, UK	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Los Angeles	California	90095	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
26125448	Derived	Janne PA, Smith I, McWalter G, Mann H, Dougherty B, Walker J, Orr MC, Hodgson DR, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios CH, Franke FA, Crino L, Smith P. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J Cancer. 2015 Jul 14;113(2):199-203. doi: 10.1038/bjc.2015.215. Epub 2015 Jun 30.
23200175

Label	URL
Cancer Study Locator (For US and Canada sites only)	View source

ID	Title	Description
FG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
FG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Overall Survival

OS was calculated as the interval from the date of randomisation to the date of patient death (any cause). Patients who had not died at the time of the final analysis, or who withdrew consent, were censored at the last date the patient was known to be alive.

MITT

Posted

Count of Participants

Participants

At least 12 months since start of treatment.

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG00043 OG00140

Title

Denominators

Categories

Title	Measurements
Died	OG00029 OG00127
Alive at DCO	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Regression, Cox	Analysis adjusted for the following covariates; WHO PS, gender, histology and smoking status	0.2069	One-sided p-value. The p-value is associated with the point estimate (e.g. HR comparing AZD6244 + Docetaxel vs Placebo + Docetaxel) on the outcome measure - Overall survival.	Hazard Ratio (HR)	0.80			2-Sided	80	0.56	1.14			A Hazard Ratio less than 1 favoured AZD6244 + Docetaxel		Superiority or Other

Secondary

Progression Free Survival

PFS was defined as the interval between the date of randomisation and the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression. Patients who did not progress or die at the time of analysis were censored at the time of their latest evaluable objective tumour assessment. This also included patients who withdrew consent.

MITT

Posted

Count of Participants

Participants

At least 12 months after start of treatment

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Secondary

Objective Response Rate

ORR is defined as the ratio of proportions, patients with at least one visit response of CR or PR in AZD6244 + Docetaxel vs Placebo + Docetaxel.

MITT

Posted

Count of Participants

Participants

At least 12 months after start of treatment

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Secondary

Duration of Response

Duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.

MITT

Posted

Mean

Standard Error

Days

At least 12 months after start of treatment

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Tumour Size at 6 Week.

Percentage change from baseline in tumour size at 6 week. Values calculated as tumour sizes at 6 weeks minus value at baseline.

MITT

Posted

Least Squares Mean

80% Confidence Interval

Percentage change from baseline

6 weeks after first dose of treatment

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Tumour Size at Week 12

Percentage change from baseline in tumour size at Week 12. Values calculated as tumour sizes at 12 weeks minus value at baseline.

MITT

Posted

Least Squares Mean

80% Confidence Interval

Percent change from baseline

12 weeks

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Secondary

Alive and Progression-Free at 6 Months

Percentage of patients alive and progression-free at 6 months

MITT

Posted

Number

percentage

6 months after first dose of treatment

ID	Title	Description
OG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
OG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Febrile neutropena	Blood and lymphatic system disorders	MedDRA version 14	Systematic Assessment	EG0006 events6 affected44 at risk EG0010 events0 affected42 at risk
Neutropena	Blood and lymphatic system disorders	MedDRA version 14	Systematic Assessment	EG0003 events3 affected44 at risk EG0013 events3 affected42 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0003 events3 affected44 at risk EG0012 events2 affected42 at risk
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0002 events2 affected44 at risk EG0010 events0 affected42 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0002 events2 affected44 at risk EG0010 events0 affected42 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Pulmonary haemorrhage	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Pneumonia	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0004 events4 affected44 at risk EG0010 events0 affected42 at risk
Lower respiratory tract infection bacterial	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0011 events1 affected42 at risk
Cystitis	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Empyema	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Influenza	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Neutropenic infection	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Respiratory tract infection viral	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Sepsis	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Urinary tract infection	Infections and infestations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Acute coronary syndrome	Cardiac disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Atrial flutter	Cardiac disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Cardiac arrest	Cardiac disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Pericardial effusion	Cardiac disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Sinus bradycardia	Cardiac disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Vomiting	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0011 events1 affected42 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Colitis	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Gastric ulcer haemorrhage	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Retroperitoneal haematoma	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Face oedema	General disorders	MedDRA version 14	Systematic Assessment	EG0002 events2 affected44 at risk EG0010 events0 affected42 at risk
Pyrexia	General disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Creatinine renal clearance decreased	Investigations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Electrocardiogram t wave inversion	Investigations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Neutrophil count decreased	Investigations	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0012 events2 affected42 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Tumour necrosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Psoriasis	Skin and subcutaneous tissue disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Drug hypersensitivity	Immune system disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA version 14	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected42 at risk
Syncope	Nervous system disorders	MedDRA version 14	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected42 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG00032 events32 affected44 at risk EG0017 events7 affected42 at risk
Nausea	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG00019 events19 affected44 at risk EG00112 events12 affected42 at risk
Vomiting	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG00019 events19 affected44 at risk EG0019 events9 affected42 at risk
Stomatitis	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG00016 events16 affected44 at risk EG0018 events8 affected42 at risk
Constipation	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG00014 events14 affected44 at risk EG0018 events8 affected42 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0008 events8 affected44 at risk EG0014 events4 affected42 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0008 events8 affected44 at risk EG0014 events4 affected42 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA version 14	Systematic Assessment	EG0008 events8 affected44 at risk EG0011 events1 affected42 at risk
Fatigue	General disorders	MedDRA version 14	Systematic Assessment	EG00012 events12 affected44 at risk EG00114 events14 affected42 at risk
Asthenia	General disorders	MedDRA version 14	Systematic Assessment	EG00031 events31 affected44 at risk EG00128 events28 affected42 at risk
Oedema peripheral	General disorders	MedDRA version 14	Systematic Assessment	EG00018 events18 affected44 at risk EG0017 events7 affected42 at risk
Pyrexia	General disorders	MedDRA version 14	Systematic Assessment	EG00012 events12 affected44 at risk EG0015 events5 affected42 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG00010 events10 affected44 at risk EG0018 events8 affected42 at risk
Dysonoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0008 events8 affected44 at risk EG00110 events10 affected42 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0005 events5 affected44 at risk EG00110 events10 affected42 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA version 14	Systematic Assessment	EG0007 events7 affected44 at risk EG0012 events2 affected42 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA version 14	Systematic Assessment	EG00013 events13 affected44 at risk EG0019 events9 affected42 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA version 14	Systematic Assessment	EG00017 events17 affected44 at risk EG0012 events2 affected42 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA version 14	Systematic Assessment	EG00010 events10 affected44 at risk EG0014 events4 affected42 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA version 14	Systematic Assessment	EG00017 events17 affected44 at risk EG00115 events15 affected42 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA version 14	Systematic Assessment	EG0007 events7 affected44 at risk EG0015 events5 affected42 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA version 14	Systematic Assessment	EG0007 events7 affected44 at risk EG0010 events0 affected42 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA version 14	Systematic Assessment	EG00015 events15 affected44 at risk EG00111 events11 affected42 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0006 events6 affected44 at risk EG0017 events7 affected42 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0003 events3 affected44 at risk EG0018 events8 affected42 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0002 events2 affected44 at risk EG0018 events8 affected42 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 14	Systematic Assessment	EG0002 events2 affected44 at risk EG0016 events6 affected42 at risk
Headache	Nervous system disorders	MedDRA version 14	Systematic Assessment	EG0006 events6 affected44 at risk EG0015 events5 affected42 at risk
Dysgeusia	Nervous system disorders	MedDRA version 14	Systematic Assessment	EG0005 events5 affected44 at risk EG0012 events2 affected42 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA version 14	Systematic Assessment	EG0005 events5 affected44 at risk EG0011 events1 affected42 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA version 14	Systematic Assessment	EG0005 events5 affected44 at risk EG0011 events1 affected42 at risk
Vision blurred	Eye disorders	MedDRA version 14	Systematic Assessment	EG0006 events6 affected44 at risk EG0011 events1 affected42 at risk

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D043823	Taxoids
D043822	Cyclodecanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D004224	Diterpenes
D013729	Terpenes

ID	Title	Description
BG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2
BG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	AZD6244 + Docetaxel	AZD6244 75 mg bd + Docetaxel 75 mg/m^2			26	44	43	44
EG001	Placebo + Docetaxel	Placebo + Docetaxel 75 mg/m^2			13	42	42	42