Cediranib Maleate With or Without Gefitinib in Treating P... | NCT01310855

Status Module

Name	Class
AstraZeneca	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cediranib & Gefitinib	Active Comparator	Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit.	Drug: cediranib maleate Drug: gefitinib
Cediranbib & placebo	Placebo Comparator	Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit.	Drug: cediranib maleate Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
cediranib maleate	Drug		Cediranbib & placebo Cediranib & Gefitinib
gefitinib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Progression-free Survival	Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first. The progression definition will be based on modified RANO criteria (Wen 2010), such that progression will be defined as the earliest time that at least one of the following occurs: Clinical deterioration Failure to return for evaluation as a result of death or deteriorating condition Or, by retrospective radiographic central review: Any new lesion Increase in ≥25% of sum of the products of perpendicular diameters of enhancing lesions compared with baseline scan, on stable or increasing doses of steroids (dexamethasone) compared to baseline (T1 post-contrast scan) Clear progression of non-measureable disease Significant increase in T2/FLAIR non-enhancing lesion - on stable or increasing steroids (dexamethasone) compared with baseline or best response not caused by co-morbid events.	from the date of randomisation to the date of first progression or death due to any cause, until 6 months from the date the last patient finished trial treatment (the day after the date that the last trial drug was taken)

Measure	Description	Time Frame
Overall Survival		from date of randomization to date of Death due to any cause.
Radiographic Response Rate		from baseline scan to six week and 12 week scans

Eligibility Module

Eligibility Criteria

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed glioblastoma
Measurable disease by MRI
Completed standard first-line treatment for glioblastoma including surgery (unless not received due to anatomical location), radiotherapy and temozolomide (last dose given at least 28 days prior to enrollment)
- No other prior treatment for glioblastoma except Gliadel or steroids
Recurrent or progressive disease after standard first-line treatment
- No disease progression within 3 months of completion of radiotherapy
No intra- or peri-tumoral hemorrhage

PATIENT CHARACTERISTICS:

Karnofsky performance status 70-100%
Mini-mental status score ≥ 15
Life expectancy ≥ 12 weeks
Serum bilirubin, ALT/AST, creatinine, and urine protein normal
Adequate bone marrow reserve
Not pregnant or nursing
Normal ECG
No history of familial long QT syndrome
No absorption or swallowing difficulties
No uncontrolled hypertension or cardiac ventricular arrhythmias
No current or history of uncontrolled hypertension or requiring maximal doses of calcium channel blockers
No severe or uncontrolled disease
No history of lung disease
No recent hemorrhage or hemoptysis
No known hypersensitivity to cediranib maleate, gefitinib, or any excipients
No history of other malignancies except adequately treated basal cell or squamous cell carcinoma or carcinoma in situ within the past 5 years, unless disease-free for 2 years with tissue diagnosis
No known HIV positivity
No known hepatitis B or C infection
No unhealed surgical incision
Not involved in planning or conducting this study

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior anticancer therapy, including radiotherapy
At least 3 months since prior cranial radiation
At least 30 days since prior investigational drugs
At least 28 days since prior craniotomy
At least 2 weeks since prior enzyme-inducing antiepileptic drugs
At least 2 weeks since prior and no concurrent dexamethasone (> 8 mg/day) or equivalent
At least 14 days since prior major surgery or brain biopsy
No concurrent steroids OR on stable dose 5 days prior to baseline MRI
No other concurrent anticancer therapy, except for steroids (dexamethasone only)
No previous enrollment on the current study
No prior inhibitors of angiogenesis, EGFR, or downstream targets
No prior radiosurgery or brachytherapy

Name	Affiliation	Role
Paul Mulholland, PhD, MRCP, MSC, MBBS	University College London Hospitals	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University College Hospital		London	England	NW1 2BU	United Kingdom
Queen Elizabeth Hospital

PubMed Identifier	Type	Citation	Retractions
27232884	Derived	Brown N, McBain C, Nash S, Hopkins K, Sanghera P, Saran F, Phillips M, Dungey F, Clifton-Hadley L, Wanek K, Krell D, Jeffries S, Khan I, Smith P, Mulholland P. Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. PLoS One. 2016 May 27;11(5):e0156369. doi: 10.1371/journal.pone.0156369. eCollection 2016.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Cediranib & Gefitinib	Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. cediranib maleate gefitinib

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Cediranib & Gefitinib	Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. cediranib maleate gefitinib
BG001	Cediranbib & Placebo	Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. cediranib maleate Placebo
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00019 BG00119 BG00238

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

Progression-free Survival

Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first.

The progression definition will be based on modified RANO criteria (Wen 2010), such that progression will be defined as the earliest time that at least one of the following occurs:

Clinical deterioration
Failure to return for evaluation as a result of death or deteriorating condition

Or, by retrospective radiographic central review:
Any new lesion
Increase in ≥25% of sum of the products of perpendicular diameters of enhancing lesions compared with baseline scan, on stable or increasing doses of steroids (dexamethasone) compared to baseline (T1 post-contrast scan)
Clear progression of non-measureable disease
Significant increase in T2/FLAIR non-enhancing lesion - on stable or increasing steroids (dexamethasone) compared with baseline or best response not caused by co-morbid events.

Posted

Median

90% Confidence Interval

months

from the date of randomisation to the date of first progression or death due to any cause, until 6 months from the date the last patient finished trial treatment (the day after the date that the last trial drug was taken)

ID	Title	Description
OG000	Cediranib & Gefitinib	Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. cediranib maleate gefitinib
OG001	Cediranbib & Placebo	Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. cediranib maleate Placebo

Units	Counts
Participants	OG00019 OG00119

Title

Denominators

Categories

Title	Measurements
	OG0003.6(2.8 to 4.1) OG0012.8(2.1 to 3.4)

Secondary

Overall Survival

Not Posted

from date of randomization to date of Death due to any cause.

Participants

Secondary

Radiographic Response Rate

Not Posted

from baseline scan to six week and 12 week scans

Participants

Secondary

Progression-free Survival Rate at 6 Months

Not Posted

from the date of randomisation to 6 months

Participants

Secondary

Steroid Use

Not Posted

from randomization to first increase in dexamethasone dose

Participants

Secondary

Time to Deterioration of Neurological Status

Not Posted

from date of randomization to the date of first neurological status worsening in comparison to baseline (first of 2 confirmatory reports at 2 consecutive visits, 6 weeks apart) as assessed by the clinician, or until date of death, whichever is first.

Participants

Secondary

Safety and Tolerability

Not Posted

from date of randomisation to death

Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cediranib & Gefitinib	Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. Due to the early discontinuation of Cediranib by AZ, the trial was discontinued early so that only 38 patients (19 per arm) were recruited. One patient in the Cediranib arm did not complete their patient diary, and it was not known how much of the trial treatment they had. Therefore the adverse events reported by the patient could not be attributed to the trial treatment and they were excluded from all analyses.			5	18	16	18
EG001	Cediranbib & Placebo	Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. Due to the early discontinuation of Cediranib by AZ, the trial was discontinued early so that only 38 patients (19 per arm) were recruited.			7	19	12	19

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Pulmonary embolism	Vascular disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
Thromboembolic event	Vascular disorders	Systematic Assessment	EG0002 affected18 at risk EG0011 affected19 at risk
Fall	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 affected18 at risk EG0012 affected19 at risk
Alanine aminotransferase increased	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
Sinus tachycardia	Cardiac disorders	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
Ataxia	Nervous system disorders	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
Cognitive disturbance	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
dysphasia	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
headache	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
movement involuntary	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other, hemispatial neglect of right arm	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other - right arm numbness	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other - right homonymous hemiopia	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other - reduced mobility	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other - weakness in right arm	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
seizure	Nervous system disorders	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
stroke	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
confusion	Psychiatric disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other	Infections and infestations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
lung infection	Infections and infestations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
sepsis	Infections and infestations	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
skin infection	Infections and infestations	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
wound infection	Infections and infestations	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
cushingoid	Endocrine disorders	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
hypertension	Vascular disorders	Systematic Assessment	EG0005 affected18 at risk EG0011 affected19 at risk
thromboembolic event	Vascular disorders	Systematic Assessment	EG0001 affected18 at risk EG0011 affected19 at risk
fatigue	General disorders	Systematic Assessment	EG0004 affected18 at risk EG0016 affected19 at risk
cognitive disburbance	Psychiatric disorders	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
confusion	Psychiatric disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
fall	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 affected18 at risk EG0012 affected19 at risk
lymphopenia	Investigations	Systematic Assessment	EG0003 affected18 at risk EG0012 affected19 at risk
alanine aminotransferase increased	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0012 affected19 at risk
cholesterol high	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
hypertrigylceridomia	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
GGT increased	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
haemorrage	Blood and lymphatic system disorders	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
dysphasia	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0012 affected19 at risk
headache	Nervous system disorders	Systematic Assessment	EG0002 affected18 at risk EG0011 affected19 at risk
pain	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0011 affected19 at risk
seizure	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
other	Nervous system disorders		EG0001 affected18 at risk EG0010 affected19 at risk
movements involuntary	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
paresthesia	Nervous system disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
eye disorder	Eye disorders	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
blurred vision	Eye disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
diarrhoea	Gastrointestinal disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
mucositis oral	Gastrointestinal disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
stomatitis	Gastrointestinal disorders	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
skin ulceration	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
muscle weakness right handed	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
generalised muscle weakness	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
musculoskeletal and connective tissue disorder	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
cushingoid	Endocrine disorders	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk
anorexia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected18 at risk EG0013 affected19 at risk
hyperglycemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected18 at risk EG0011 affected19 at risk
rash pustular	Infections and infestations	Systematic Assessment	EG0002 affected18 at risk EG0011 affected19 at risk
sepsis	Infections and infestations	Systematic Assessment	EG0002 affected18 at risk EG0010 affected19 at risk
infection	Infections and infestations	Systematic Assessment	EG0001 affected18 at risk EG0010 affected19 at risk
aspartate aminotransferase increased	Investigations	Systematic Assessment	EG0000 affected18 at risk EG0011 affected19 at risk

ID	Type	Description	Link
UCL-10/0035
ZENECA-ISSRECE00002
EUDRACT-2010-021531-13
CRUKE/10/044

ID	Term
D005909	Glioblastoma
D018316	Gliosarcoma
D001932	Brain Neoplasms

ID	Term
D001254	Astrocytoma
D005910	Glioma
D018302	Neoplasms, Neuroepithelial
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D009375	Neoplasms, Glandular and Epithelial
D009380	Neoplasms, Nerve Tissue
D016543	Central Nervous System Neoplasms
D009423	Nervous System Neoplasms
D009371	Neoplasms by Site
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

ID	Term
D011799	Quinazolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds