Cediranib Maleate With or Without Gefitinib in Treating Patients With Recurrent or Progressive Glioblastoma

• Sponsor: University College, London (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01310855
• Collaborator: AstraZeneca (Industry)
• Enrollment: 38
• Locations: 10
• Arms: 2
• Duration (Months): 32.1
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Cediranib Maleate and gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cediranib maleate given together with gefitinib is more effective than cediranib maleate given alone in treating patients with recurrent or progressive glioblastoma.

PURPOSE: This randomized phase II trial is studying the side effects of giving cediranib maleate together with gefitinib and to see how well it works compared with giving cediranib maleate together with a placebo in treating patients with recurrent or progressive glioblastoma.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: cediranib maleate; Drug: gefitinib; Drug: Placebo	Phase 2

Detailed Description

OBJECTIVES:

• To compare progression-free survival, overall survival, radiological response, and safety and tolerability of cediranib maleate in combination with gefitinib versus cediranib maleate in combination with a placebo in patients with recurrent or progressive glioblastoma following standard front-line treatment.

OUTLINE: This is a multicenter study.

Patients receive cediranib maleate and gefitinib or cediranib maleate and a placebo once daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples are collected from some patients for genetic profiling and biomarker analysis.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multi-Center, Randomized, Double-Blind Phase II Study Comparing Cediranib (AZD2171) Plus Gefitinib (Iressa, ZD1839) With Cediranib Plus Placebo in Subjects With Recurrent/Progressive Glioblastoma (DORIC Trial)
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: cediranib maleate; Drug: gefitinib
Placebo Comparator: 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.	Drug: cediranib maleate; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [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)]

   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.

Secondary Outcome Measures

1. Overall Survival [from date of randomization to date of Death due to any cause.]

2. Radiographic Response Rate [from baseline scan to six week and 12 week scans]

3. Progression-free Survival Rate at 6 Months [from the date of randomisation to 6 months]

4. Steroid Use [from randomization to first increase in dexamethasone dose]

5. Time to Deterioration of Neurological Status [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.]

6. Safety and Tolerability [from date of randomisation to death]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University College Hospital	London	England	United Kingdom	NW1 2BU
2	Queen Elizabeth Hospital	Birmingham		United Kingdom
3	Bristol Haematology and Oncology Centre	Bristol		United Kingdom
4	Addenbrooke's Hospital	Cambridge		United Kingdom
5	Royal Surrey County Hospital	Guildford		United Kingdom
6	Castle Hill Hospital	Hull		United Kingdom
7	Charing Cross Hospital	London		United Kingdom
8	The Christie NHS Foundation Trust	Manchester		United Kingdom
9	Southampton General Hospital	Southampton		United Kingdom
10	Royal Marsden Hospital	Sutton		United Kingdom

Sponsors and Collaborators

• University College, London
• AstraZeneca

Investigators

• Principal Investigator: Paul Mulholland, PhD, MRCP, MSC, MBBS, University College London Hospitals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT01310855
• Other Study ID Numbers: CDR0000696313; UCL-10/0035; ZENECA-ISSRECE00002; EUDRACT-2010-021531-13; CRUKE/10/044
• First Posted: Mar 9, 2011
• Last Update Posted: May 31, 2017
• Last Verified: May 1, 2017

• Keywords provided by University College, London: adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma; recurrent adult brain tumor
• Additional relevant MeSH terms: Glioblastoma; Gefitinib; Cediranib

Study Results

Participant Flow

Pre-assignment Detail	Trial closed prematurely because cediranib manufacture was discontinued by AZ. Only 38 patients were recruited

Arm/Group Title	Cediranib & Gefitinib	Cediranbib & Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	19	19
COMPLETED	19	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cediranib & Gefitinib	Cediranbib & Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	19	19	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 78.9%	15 78.9%	30 78.9%
>=65 years	4 21.1%	4 21.1%	8 21.1%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	54.4	56.9	55.7
Sex: Female, Male (Count of Participants)
Female	13 68.4%	14 73.7%	27 71.1%
Male	6 31.6%	5 26.3%	11 28.9%
Region of Enrollment (participants) [Number]
United Kingdom	19 100%	19 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib & Gefitinib	Cediranbib & Placebo
Arm/Group Description	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	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
Measure Participants	19	19
Median (90% Confidence Interval) [months]	3.6	2.8

2. Secondary Outcome

Title	Overall Survival
Time Frame	from date of randomization to date of Death due to any cause.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Radiographic Response Rate
Time Frame	from baseline scan to six week and 12 week scans

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Progression-free Survival Rate at 6 Months
Time Frame	from the date of randomisation to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Steroid Use
Time Frame	from randomization to first increase in dexamethasone dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Time to Deterioration of Neurological Status
Time Frame	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Safety and Tolerability
Time Frame	from date of randomisation to death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Cediranib & Gefitinib		Cediranbib & Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Cediranib & Gefitinib		Cediranbib & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cediranib & Gefitinib		Cediranbib & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/18 (27.8%)		7/19 (36.8%)
Cardiac disorders
Sinus tachycardia	0/18 (0%)		1/19 (5.3%)
Endocrine disorders
cushingoid	0/18 (0%)		1/19 (5.3%)
Infections and infestations
other	0/18 (0%)		1/19 (5.3%)
lung infection	0/18 (0%)		1/19 (5.3%)
sepsis	2/18 (11.1%)		0/19 (0%)
skin infection	1/18 (5.6%)		0/19 (0%)
wound infection	1/18 (5.6%)		0/19 (0%)
Injury, poisoning and procedural complications
Fall	0/18 (0%)		2/19 (10.5%)
Investigations
Alanine aminotransferase increased	0/18 (0%)		1/19 (5.3%)
Nervous system disorders
Ataxia	2/18 (11.1%)		0/19 (0%)
Cognitive disturbance	1/18 (5.6%)		0/19 (0%)
dysphasia	1/18 (5.6%)		0/19 (0%)
headache	1/18 (5.6%)		0/19 (0%)
movement involuntary	1/18 (5.6%)		0/19 (0%)
other, hemispatial neglect of right arm	1/18 (5.6%)		0/19 (0%)
other - right arm numbness	1/18 (5.6%)		0/19 (0%)
other - right homonymous hemiopia	1/18 (5.6%)		0/19 (0%)
other - reduced mobility	1/18 (5.6%)		0/19 (0%)
other - weakness in right arm	1/18 (5.6%)		0/19 (0%)
seizure	2/18 (11.1%)		0/19 (0%)
stroke	1/18 (5.6%)		0/19 (0%)
Psychiatric disorders
confusion	1/18 (5.6%)		0/19 (0%)
Vascular disorders
Pulmonary embolism	1/18 (5.6%)		0/19 (0%)
Thromboembolic event	2/18 (11.1%)		1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Cediranib & Gefitinib		Cediranbib & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/18 (88.9%)		12/19 (63.2%)
Blood and lymphatic system disorders
haemorrage	0/18 (0%)		1/19 (5.3%)
Endocrine disorders
cushingoid	0/18 (0%)		1/19 (5.3%)
Eye disorders
eye disorder	2/18 (11.1%)		0/19 (0%)
blurred vision	1/18 (5.6%)		0/19 (0%)
Gastrointestinal disorders
diarrhoea	1/18 (5.6%)		0/19 (0%)
mucositis oral	1/18 (5.6%)		0/19 (0%)
stomatitis	0/18 (0%)		1/19 (5.3%)
General disorders
fatigue	4/18 (22.2%)		6/19 (31.6%)
Infections and infestations
rash pustular	2/18 (11.1%)		1/19 (5.3%)
sepsis	2/18 (11.1%)		0/19 (0%)
infection	1/18 (5.6%)		0/19 (0%)
Injury, poisoning and procedural complications
fall	0/18 (0%)		2/19 (10.5%)
Investigations
lymphopenia	3/18 (16.7%)		2/19 (10.5%)
alanine aminotransferase increased	0/18 (0%)		2/19 (10.5%)
cholesterol high	0/18 (0%)		1/19 (5.3%)
hypertrigylceridomia	0/18 (0%)		1/19 (5.3%)
GGT increased	0/18 (0%)		1/19 (5.3%)
aspartate aminotransferase increased	0/18 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
anorexia	1/18 (5.6%)		3/19 (15.8%)
hyperglycemia	1/18 (5.6%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
muscle weakness right handed	1/18 (5.6%)		0/19 (0%)
generalised muscle weakness	1/18 (5.6%)		0/19 (0%)
musculoskeletal and connective tissue disorder	1/18 (5.6%)		0/19 (0%)
Nervous system disorders
dysphasia	1/18 (5.6%)		2/19 (10.5%)
headache	2/18 (11.1%)		1/19 (5.3%)
pain	1/18 (5.6%)		1/19 (5.3%)
seizure	1/18 (5.6%)		0/19 (0%)
other	1/18 (5.6%)		0/19 (0%)
movements involuntary	1/18 (5.6%)		0/19 (0%)
paresthesia	1/18 (5.6%)		0/19 (0%)
Psychiatric disorders
cognitive disburbance	2/18 (11.1%)		0/19 (0%)
confusion	1/18 (5.6%)		0/19 (0%)
Skin and subcutaneous tissue disorders
skin ulceration	1/18 (5.6%)		0/19 (0%)
Vascular disorders
hypertension	5/18 (27.8%)		1/19 (5.3%)
thromboembolic event	1/18 (5.6%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The excerpts below are present on all site agreements between site staff (including PI) and the sponsor: The Site shall ensure that only those of its employees or officers directly concerned with the conduct of the Trial at the Site shall have access to the Confidential Information relating to the Trial. The Site agrees it will not publish any information, data or results without the express written permission of the TMG, such permission not to be unreasonably withheld.