Trial Outcomes & Findings for Efficacy Trial Comparing ZD6474 With Erlotinib in NSCLC After Failure of at Least One Prior Chemotherapy (NCT NCT00364351)

Last Updated: 2018-01-25

Results Overview

Median time (in weeks) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable Response Evaluation Criteria In Solid Tumors (RECIST) assessment. Progression was derived according to RECIST 1.0 and is defined as an increase of at least 20% in the total tumour size of measurable lesions over the nadir measurement, unequivocal progression in the non-target lesions or the appearance of one or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1574 participants

Primary outcome timeframe

progressionRECIST tumour assessments carried out every 4 weeks up to week 16 then every 8 weeks thereafter from randomisation until the date of first documented objective disease progression or date of death from any cause, whichever came first, assessed.

Results posted on

2018-01-25

Participant Flow

First patient enrolled 24 August 2006, last patient enrolled 31 October 2007, cut off date 26 September 2008. 1574 patients were enrolled in the study.

1574 patients were enrolled/screened to the study but only 1240 patients were entered treatment/randomized.

Participant milestones

Participant milestones
Measure	Vandetanib Vandetanib 300 mg tablet taken once daily plus a placebo for erlotinib	Erlotinib Erlotinib 150 mg tablet taken once daily plus a placebo for vandetanib
Overall Study STARTED	623	617
Overall Study COMPLETED	31	34
Overall Study NOT COMPLETED	592	583

Reasons for withdrawal

Reasons for withdrawal
Measure	Vandetanib Vandetanib 300 mg tablet taken once daily plus a placebo for erlotinib	Erlotinib Erlotinib 150 mg tablet taken once daily plus a placebo for vandetanib
Overall Study Adverse Event	90	44
Overall Study Condition under investigation worsened	469	497
Overall Study Prohibited concomitant medication	0	2
Overall Study Lost to Follow-up	1	1
Overall Study Withdrawal by Subject	30	29
Overall Study Incorrect enrollment	1	1
Overall Study Sponsor decision	1	0
Overall Study Poor treatment compliance	0	3
Overall Study Investigator error	0	2
Overall Study Patient could not travel to site	0	1
Overall Study Randomised treatment not started	0	3

Baseline Characteristics

Efficacy Trial Comparing ZD6474 With Erlotinib in NSCLC After Failure of at Least One Prior Chemotherapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib	Total n=1240 Participants Total of all reporting groups
Age, Continuous	60 years n=5 Participants	61 years n=7 Participants	60 years n=5 Participants
Sex: Female, Male Female	242 Participants n=5 Participants	224 Participants n=7 Participants	466 Participants n=5 Participants
Sex: Female, Male Male	381 Participants n=5 Participants	393 Participants n=7 Participants	774 Participants n=5 Participants

PRIMARY outcome

Timeframe: progressionRECIST tumour assessments carried out every 4 weeks up to week 16 then every 8 weeks thereafter from randomisation until the date of first documented objective disease progression or date of death from any cause, whichever came first, assessed.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Progression-Free Survival (PFS)	11.3 Weeks Interval 0.14 to 75.43	8.9 Weeks Interval 0.43 to 80.43

SECONDARY outcome

Timeframe: Time to death in months

Overall survival is defined as the time from date of randomization until death. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive (ie their status must be known at the censored date and should not be lost to follow up or unknown).

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Overall Survival (OS)	6.9 Months Interval 0.03 to 18.46	7.8 Months Interval 0.1 to 20.04

SECONDARY outcome

Timeframe: RECIST tumour assessments every 4 weeks up to week 16 then every 8 weeks thereafter from randomisation until the date of first documented objective disease progression or date of death from any cause, whichever came first, assessed up to 21 months

The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) as determined according to RECIST 1.0. CR is defined as the disappearance of all target lesions with no evidence of tumour elsewhere and PR is defined as at least a 30% reduction in the total tumour size of measurable lesions with no new lesions and no progression in the non-target lesions.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Objective Response Rate (ORR)	75 Participants	74 Participants

SECONDARY outcome

Timeframe: RECIST tumour assessments carried out every 4 weeks until week 16 then every 8 weeks thereafter (+/- 3 days) from randomisation until objective progression

Disease control rate is defined as the number of patients who achieved disease control at least 8 weeks following randomisation. Disease control is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) \>= 8 weeks as determined according to RECIST 1.0. CR is defined as the disappearance of all target lesions with no evidence of tumour elsewhere, PR is defined as at least a 30% reduction in the total tumour size of measurable lesions with no new lesions and no progression in the non-target lesions and SD \>= 8 is assigned to patients who have not responded and have no evidence of progression at least 8 weeks after randomisation.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Disease Control Rate (DCR)	254 Participants	242 Participants

SECONDARY outcome

Timeframe: Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication), every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit

Pain was assessed as the average score of two items: Question 9 ("Have you had pain") and 19 ("Did pain interfere with your daily activities") of the QLQ-C30. Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A patient is defined as having a deterioration in symptoms if they have a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 28 days.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Pain	11.1 Weeks Interval 4.4 to 26.0	9.9 Weeks Interval 4.3 to 24.3

SECONDARY outcome

Dyspnea was assessed as the average score of four items: Question 8 of the QLQ-C30 ("Were you short of breath") and Question 3 of the QLQ-C30 ("Were you short of breath when you rested"), Questions 4 ("Were you short of breath when you walked") and 5 ("Were you short of breath when you climbed stairs") of the QLQ-LC13 (or, equivalently, Questions 33, 34 and 35 of the combined QLQ-C30 and QLQ-LC13 questionnaires). Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A patient is defined as having a deterioration in symptoms if they have a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 28 days.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Dyspnoea	12 Weeks Interval 5.7 to 29.7	12.4 Weeks Interval 5.1 to 34.4

SECONDARY outcome

Cough was assessed using Question 1 ("How much did you cough") of the QLQ-LC13 (or, equivalently, Question 31 of the combined QLQ-C30 and QLQ-LC13 questionnaires). Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A patient is defined as having a deterioration in symptoms if they have a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 28 days.

Outcome measures

Outcome measures
Measure	Vandetanib n=623 Participants Vandetanib 300 mg	Erlotinib n=617 Participants Erlotinib
Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Cough	15.6 Weeks Interval 8.1 to 36.1	14.1 Weeks Interval 7.0 to 37.6

Adverse Events

Vandetanib

Serious events: 197 serious events

Other events: 539 other events

Deaths: 0 deaths

Erlotinib

Serious events: 155 serious events

Other events: 542 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Vandetanib n=623 participants at risk Vandetanib 300 mg.	Erlotinib n=614 participants at risk Erlotinib.
Gastrointestinal disorders Constipation	9.3% 58/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	14.2% 87/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Gastrointestinal disorders Diarrhoea	48.2% 300/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	37.8% 232/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Gastrointestinal disorders Dyspepsia	4.7% 29/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	5.0% 31/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Gastrointestinal disorders Nausea	22.2% 138/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	21.3% 131/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Gastrointestinal disorders Stomatitis	5.3% 33/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	5.4% 33/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Gastrointestinal disorders Vomiting	13.6% 85/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	14.8% 91/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
General disorders Asthenia	8.0% 50/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	9.6% 59/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
General disorders Fatigue	19.1% 119/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	17.8% 109/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
General disorders Oedema Peripheral	3.4% 21/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	5.5% 34/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
General disorders Pyrexia	7.1% 44/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	8.1% 50/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Infections and infestations Paronychia	1.9% 12/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	5.0% 31/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Investigations Weight Decreased	5.3% 33/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	4.7% 29/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Metabolism and nutrition disorders Anorexia	18.3% 114/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	20.0% 123/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Musculoskeletal and connective tissue disorders Back Pain	5.9% 37/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	6.5% 40/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	5.3% 33/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	3.9% 24/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Nervous system disorders Dizziness	5.9% 37/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	6.5% 40/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Nervous system disorders Headache	8.8% 55/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	6.5% 40/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Psychiatric disorders Insomnia	9.5% 59/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	6.5% 40/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Renal and urinary disorders Proteinuria	5.3% 33/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	1.3% 8/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Respiratory, thoracic and mediastinal disorders Cough	12.5% 78/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	15.0% 92/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.5% 84/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	11.4% 70/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Respiratory, thoracic and mediastinal disorders Haemoptysis	5.0% 31/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	6.4% 39/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Skin and subcutaneous tissue disorders Acne	7.2% 45/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	8.1% 50/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Skin and subcutaneous tissue disorders Dermatitis Acneiform	12.0% 75/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	16.8% 103/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Skin and subcutaneous tissue disorders Dry Skin	9.6% 60/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	13.7% 84/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Skin and subcutaneous tissue disorders Pruritus	6.1% 38/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	10.9% 67/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Skin and subcutaneous tissue disorders Rash	27.1% 169/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	37.8% 232/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
Vascular disorders Hypertension	15.9% 99/623 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.	2.3% 14/614 The Safety Analysis Set included all randomized participant who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.