Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer

• Sponsor: PrECOG, LLC. (Other)
• Overall Status: Completed
• CT.gov ID: NCT00687297
• Collaborator: AstraZeneca (Industry)
• Enrollment: 162
• Locations: 30
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

It has been shown in previous studies that the ability to treat lung cancer could be significantly improved by not only targeting the tumor cells directly with chemotherapy, but also by cutting off the blood supply to the cancer cells. Blood vessels that supply the tumor are formed through a process called angiogenesis. Vandetanib is an investigational drug that acts by producing what is called an anti-angiogenic effect. An Anti-angiogenic effect is able to inhibit the development of new blood vessels required by tumors to survive by blocking the growth factors needed to form new blood vessels.

The purpose of this study is to determine if the addition of vandetanib to a standard chemotherapy regimen will slow or stop the growth of the cancer for a longer period of time compared to the time period generally gained from the use of standard chemotherapy alone

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer; Non Small Cell Lung Cancer	Drug: vandetanib induction; Drug: Docetaxel; Drug: Carboplatin; Drug: Placebo; Drug: Vandetanib maintenance	Phase 2

Detailed Description

Lung cancer is the number one cause of cancer-related mortality in the United States, with an estimated 160,390 deaths in 2007. Over 80% of these patients will have non-small cell lung cancer (NSCLC), and the majority of these patients have advanced disease at the time of diagnosis.

Patients with advanced disease who have an adequate performance status clearly benefit from systemic chemotherapy, and many clinical trials have been carried out to determine the most effective regimen. Comorbidities associated with NSCLC preclude the use of cisplatin in doublet therapies, and, a meta-analysis comparing platinum-based doublet regimens to non-platinum based, third generation regimens revealed that survival outcomes between these regimens were equivalent. Despite poor response and overall survival benefits in this patient population with accepted treatment doublets, the addition of a third cytotoxic agent did not improve survival and demonstrated increased toxicity. Therefore, it appears a threshold maximum response can be gained with cytotoxic chemotherapy alone. However, the poor outcomes still associated with advanced NSCLC clearly demanded the need for continued improvements in treatment. It was postulated that anticancer therapy could be significantly improved by not only targeting the tumor cells directly, but also by targeting neo-angiogenesis. A randomized phase II trial demonstrated a significant improvement in time to progression (TTP) in patients receiving carboplatin, paclitaxel and bevacizumab compared to chemotherapy alone. Due to life-threatening and fatal hemorrhage patients with squamous cell histology, as well as those with a prior history of hemoptysis and brain metastases were excluded from all further clinical trials using bevacizumab. The definitive study of bevacizumab in NSCLC was a randomized phase III clinical trial conducted by ECOG (E4599) in which patients with advanced non-squamous NSCLC received carboplatin + paclitaxel with or without bevacizumab which met the clinical endpoint of improvement in survival and led to the approval of bevacizumab in first line treatment in patients with advanced NSCLC with non-squamous histology.

The epidermal growth factor receptor (EGFR) protein activation leads to TK activation and results in cell proliferation, motility, adhesion, invasion, survival, and angiogenesis. The EGFR is over expressed in many solid tumors, including non-small cell lung cancer (NSCLC), and multiple studies have suggested a shortened survival in NSCLC patients whose tumor over expresses EGFR . Although studies using small-molecule TK inhibitors (TKIs) in NSCLC did not meet efficacy endpoints, a phase III trial demonstrated the benefit of EGFR TKI monotherapy. Patients with advanced NSCLC who have received 2 or 3 prior therapies were randomized to erlotinib or placebo, and those receiving erlotinib demonstrated a survival benefit that led to FDA approval of this drug in 2004.

The studies above clearly demonstrated a benefit to combining anti-angiogenic factors with chemotherapy, and as a monotherapy using anti-EGFR agents, in patients with advanced NSCLC. The potential benefit to simultaneously targeting these 2 pathways has been addressed in the recurrent disease setting.

Vandetanib is a novel oral molecule (anilinoquinazoline) that has dual activity against both the VEGFR and EGFR pathways. Specifically, this compound has potent and reversible inhibitory activity against VEGFR-2 (KDR), VEGFR-3 (Flt-4), EGFR and RET . Vandetanib is a TKI and thus acts through inhibition of ATP binding to the tyrosine kinase domains of these receptors. Recombinant enzyme assays have demonstrated that vandetanib is highly selective for both VEGFR-2 (IC50=40 nm) with only slightly lower affinity for VEGFR-3 (2.7 fold). EGFR tyrosine kinase activity is inhibited with an IC50=500 nm. The results of a second-line setting phase II trial were presented by Heymach et al at the ASCO meeting in 2006. In this trial, patients were randomized to receive either docetaxel alone, or docetaxel with either 100mg or 300mg of vandetanib. Patients with squamous cell histology, controlled brain metastases and prior history of hemoptysis were allowed on study. The primary endpoint of prolongation of progression-free survival (PFS) was met in the 100mg arm (Hazard Ratio(HR) 0.64, p=0.07). There was no increased incidence of hemoptysis in patients receiving vandetanib, and no CNS hemorrhage events were observed, and side effects commonly attributed to EGFR inhibition (rash, diarrhea) were higher on the 300mg arm. Early combination studies suggest that in patients with NSCLC, vandetanib is safe in combination with chemotherapy, may improve the outcomes of chemotherapy when used at the 100 mg dose, and has activity as monotherapy at the 300mg dose. In addition, none of the observed hemorrhagic complications seen with bevacizumab were observed, even in patients at high risk for this complication.

In this study, our main goal is to study the combination of docetaxel + carboplatin and vandetanib, followed by a double-blind randomized assignment to maintenance therapy with vandetanib 300 milligrams (mg) or placebo by mouth daily until disease progression to determine if maintenance therapy can prolong progression-free survival. In addition to clinical efficacy outcomes we will monitor for safety and tolerability, as well as explore any differences in outcome based on age and gender.

Study Design

• Study Type: Interventional
• Actual Enrollment: 162 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study Evaluating Vandetanib (ZD6474) in Combination With Docetaxel and Carboplatin Followed by Placebo or Maintenance Therapy With Vandetanib in Patients With IIIb, IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vandetanib Maintenance Docetaxel day 1, carboplatin day 1 + vandetanib induction days 1 through 21 (daily) of a 28-day cycle for 4 cycles. If free of disease progression after 4 cycles, vandetanib maintenance daily until progression.	Drug: vandetanib induction; 100 mg daily by mouth; Other Names: ZD6474 ; Drug: Docetaxel; (75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression; Other Names: Taxotere ; Drug: Carboplatin; IV (in the vein) to area under the curve (AUC) of 6 on day 1 of a 21 day cycle, for 4 cycles or until disease progression; Drug: Vandetanib maintenance; 300 mg daily by mouth; Other Names: ZD6474
Placebo Comparator: Placebo Maintenance Docetaxel day 1, carboplatin day 1 + vandetanib induction days 1 through 21 (daily) of a 28-day cycle for 4 cycles. If free of disease progression after 4 cycles, placebo maintenance daily until progression.	Drug: vandetanib induction; 100 mg daily by mouth; Other Names: ZD6474 ; Drug: Docetaxel; (75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression; Other Names: Taxotere ; Drug: Carboplatin; IV (in the vein) to area under the curve (AUC) of 6 on day 1 of a 21 day cycle, for 4 cycles or until disease progression; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))]

   Time from randomization (prior to induction) to first evidence of disease progression or death without progression. Participants alive without progression were censored at the date of last disease evaluation.

Secondary Outcome Measures

1. Objective Response Rate [Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))]

   Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0)

2. Progression-free Survival [every 2 cycles (every 6 weeks during induction, every 8 weeks during maintenance)]

   Time from randomization to first evidence of disease progression or death. Patients alive without progression are censored at the date of last disease evaluation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed non-small cell lung cancer

• Advanced disease (stage IIIB disease [malignant pleural or pericardial effusion seen on CT or Chest X-ray, any N, M0] or stage IV disease [Any T, any N, M1: distant metastases]) that is primary or recurrent

• Measurable disease according to the RECIST criteria

• ECOG Performance Status 0 or 1

• Adequate organ function, as evidenced by ALL the following

• Absolute neutrophil count (ANC) ≥ 1500/mm³ and platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 9 gm/dL

• Total bilirubin ≤ 1 X institutional ULN; if patient has Gilbert's disease, then patient must have isolated hyperbilirubinemia (e.g. no other liver function test abnormality), with maximum bilirubin ≤ 2 X institutional ULN.

• AST, ALT and alkaline phosphatase (Alk Phos) must be ≤ 1.5 ULN

• Creatinine ≤ 1.5 X institutional ULN or calculated creatinine clearance ≥ 60 ml/min

• Potassium between 4 mEq/L and institutional ULN (supplementation may be used),

• Calcium (ionized or adjusted for albumin)within institutional normal limits

• Magnesium within institutional normal limits (supplementation may be used)

• No prior cytotoxic chemotherapy or targeted therapy for advanced or metastatic disease (Prior adjuvant therapy for lung cancer allowed if completed > 1 year prior to registration)

• Able to take oral medication

Exclusion Criteria:

• Myocardial infarction, superior vena caval syndrome, NYHA classification of heart disease ≥ 2 within the 3 months prior to entry

• History of an uncontrolled or recurrent ventricular, supraventricular or nodal arrhythmia that requires treatment

• Hypertension not controlled by medication

• Peripheral or sensory neuropathy > grade 1

• Known hypersensitivity to carboplatin or docetaxel

• Active infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boca Raton Community Hospital	Boca Raton	Florida	United States	33486
2	Lakeland Regional Cancer Center	Lakeland	Florida	United States	33805
3	SwedishAmerican Hospital	Rockford	Illinois	United States	61104
4	Cancer Center of Kansas	Wichita	Kansas	United States	67214
5	Ochsner Clinic	New Orleans	Louisiana	United States	70121
6	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
7	St. Joseph Mercy Hospital- Ann Arbor	Ann Arbor	Michigan	United States	48106
8	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
9	Metro-Minnesota CCOP	Saint Louis Park	Minnesota	United States	55416
10	Ocean Medical Center	Brick	New Jersey	United States	08724
11	Morristown Memorial Hospital	Morristown	New Jersey	United States	07960
12	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
13	Riverview Medical Center	Red Bank	New Jersey	United States	07701
14	Montefiore Medical Center	Bronx	New York	United States	10467
15	Aultman Hospital	Canton	Ohio	United States	44710
16	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
17	Hematology & Oncology of NEPA	Dunmore	Pennsylvania	United States	18512
18	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17604
19	Central PA Hematology & Medical Oncology Associaties	Lemoyne	Pennsylvania	United States	17043
20	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
21	Albert Einstein Cancer Center	Philadelphia	Pennsylvania	United States	19141
22	The Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19610
23	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
24	Sanford Clinic	Sioux Falls	South Dakota	United States	57104
25	Meharry Medical College	Nashville	Tennessee	United States	37208
26	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
27	Charleston Area Medical Center	Charleston	West Virginia	United States	25304
28	St. Vincent Hospital	Green Bay	Wisconsin	United States	45301
29	Gundersen Lutheran	La Crosse	Wisconsin	United States	54601
30	Regional Cancer Center	Waukesha	Wisconsin	United States	53188

Sponsors and Collaborators

• PrECOG, LLC.
• AstraZeneca

Investigators

• Study Chair: Joseph Aisner, MD, Rutgers Cancer Institute of New Jersey

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Vandetanib in Advanced Non-Small Cell Lung Cancer

Publications

None provided.

• Responsible Party: PrECOG, LLC.
• ClinicalTrials.gov Identifier: NCT00687297
• Other Study ID Numbers: PrE0501; IRUSZACT0088
• First Posted: May 30, 2008
• Last Update Posted: May 30, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by PrECOG, LLC.: Stage IIIB Non Small Cell Lung Cancer; Stage IV Non Small Cell Lung Cancer; Vandetanib; Docetaxel plus carboplatin
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carboplatin; Docetaxel

Study Results

Participant Flow

Arm/Group Title	Randomized to Vandetanib Maintenance	Randomized to Placebo Maintenance
Arm/Group Description	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: vandetanib (300mg) daily until progression [1 Cycle= 28 days]	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: Placebo 3 tablets daily until progression [1 Cycle= 28 days]
Period Title: Randomization
STARTED	80	82
COMPLETED	77	81
NOT COMPLETED	3	1
Period Title: Randomization
STARTED	77	81
COMPLETED	32	26
NOT COMPLETED	45	55
Period Title: Randomization
STARTED	32	26
COMPLETED	29	25
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Randomized to Vandetanib Maintenance	Randomized to Placebo Maintenance	Total
Arm/Group Description	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: vandetanib (300mg) daily until progression [1 Cycle= 28 days]	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: Placebo 3 tablets daily until progression [1 Cycle= 28 days]	Total of all reporting groups
Overall Participants	80	82	162
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.5	63	63
Sex: Female, Male (Count of Participants)
Female	38 47.5%	40 48.8%	78 48.1%
Male	42 52.5%	42 51.2%	84 51.9%
Region of Enrollment (participants) [Number]
United States	80 100%	82 100%	162 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Time from randomization (prior to induction) to first evidence of disease progression or death without progression. Participants alive without progression were censored at the date of last disease evaluation.
Time Frame	Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))

Outcome Measure Data

Analysis Population Description

All randomized patients were included.

Arm/Group Title	All Randomized Patients
Arm/Group Description	All patients enrolled in the study
Measure Participants	162
Median (95% Confidence Interval) [Months]	4.5

2. Secondary Outcome

Title	Objective Response Rate
Description	Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0)
Time Frame	Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))

Outcome Measure Data

Analysis Population Description

All randomized patients were included.

Arm/Group Title	Randomized to Vandetanib Maintenance	Randomized to Placebo Maintenance
Arm/Group Description	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: vandetanib (300mg) daily until progression [1 Cycle= 28 days]	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: Placebo 3 tablets daily until progression [1 Cycle= 28 days]
Measure Participants	82	80
Number (95% Confidence Interval) [percentage of participants]	18.8 23.5%	18.3 22.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Randomized Patients, Randomized to Placebo Maintenance
	Comments	Fisher's exact test with two-sided Type I error of 5% was used to test the null hypothesis of no difference in response rate between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression-free Survival
Description	Time from randomization to first evidence of disease progression or death. Patients alive without progression are censored at the date of last disease evaluation.
Time Frame	every 2 cycles (every 6 weeks during induction, every 8 weeks during maintenance)

Outcome Measure Data

Analysis Population Description

All randomized patients were included.

Arm/Group Title	Randomized to Vandetanib Maintenance	Randomized to Placebo Maintenance
Arm/Group Description	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: vandetanib (300mg) daily until progression [1 Cycle= 28 days]	Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --> Maintenance treatment: Placebo 3 tablets daily until progression [1 Cycle= 28 days]
Measure Participants	80	82
Median (95% Confidence Interval) [months]	4.5	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Randomized Patients, Randomized to Placebo Maintenance
	Comments	There was 80% power to detect a 50% improvement in median progression-free survival, using a stratified log-rank test with one-sided Type I error of 10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	p-value from Wald test
	Method	Regression, Cox
	Comments	The model was adjusted for gender (male vs. female) and stage (Stage IIIB vs. Stage IV/Recurrent)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 1.07 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were assessed every 3 weeks during induction and every 4 weeks during maintenance.
Adverse Event Reporting Description	Serious adverse events are defined as events of grade 3 or higher that were considered possibly, probably, or definitely treatment-related. Other adverse events include grade 1 or 2 events possibly, probably or definitely treatment-related occurring at a rate of 5% or higher.
Arm/Group Title	Treated on Vandetanib Maintenance		Treated on Placebo Maintenance		All Treated Patients - Induction
Arm/Group Description	Adverse events among patients receiving Vandetanib using the maintenance phase of the study		Adverse events among patients receiving placebo during the maintenance phase of the study		Adverse events occurring during induction among all treated patients
All Cause Mortality
	Treated on Vandetanib Maintenance		Treated on Placebo Maintenance		All Treated Patients - Induction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treated on Vandetanib Maintenance		Treated on Placebo Maintenance		All Treated Patients - Induction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/32 (68.8%)		11/26 (42.3%)		111/157 (70.7%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/32 (0%)		0/26 (0%)		10/157 (6.4%)
Anemia	0/32 (0%)		2/26 (7.7%)		4/157 (2.5%)
Leukocytes increased	0/32 (0%)		0/26 (0%)		25/157 (15.9%)
Cardiac disorders
Atrial fibrillation	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Cardiac - other	1/32 (3.1%)		0/26 (0%)		1/157 (0.6%)
Eye disorders
Photosensitivity	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Gastrointestinal disorders
Anorexia	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
Colitis, infectious	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Diarrhea w/o Prior Colostomy	3/32 (9.4%)		0/26 (0%)		14/157 (8.9%)
Muco/stomatitis by exam, oral cavity	0/32 (0%)		0/26 (0%)		2/157 (1.3%)
Nausea	0/32 (0%)		1/26 (3.8%)		2/157 (1.3%)
Perforation, colon	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Upper GI hemorrhage, NOS	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Vomiting	0/32 (0%)		1/26 (3.8%)		1/157 (0.6%)
Abdomen, pain	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Cholecystitis	1/32 (3.1%)		1/26 (3.8%)		0/157 (0%)
Constipation	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Dental/teeth/periodontal pain	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
GI - other	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
General disorders
Death NOS	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Fatigue	2/32 (6.3%)		1/26 (3.8%)		12/157 (7.6%)
Insomnia	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Death, disease progression NOS	2/32 (6.3%)		0/26 (0%)		0/157 (0%)
Immune system disorders
Allergic Reaction	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
Infections and infestations
Infection w grade 3-4 neutrophils, lung	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
Infection w/unk ANC, abdomen NOS	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Infection w/unk ANC, liver	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Infection w/unk ANC, lung	0/32 (0%)		1/26 (3.8%)		2/157 (1.3%)
Infection - other	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
Infection w/gr 0-2 neutrophils, lung	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Infection w/Unk ANC, stomach	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Investigations
Lymphopenia	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Neutrophil count decreased	1/32 (3.1%)		0/26 (0%)		65/157 (41.4%)
Platelet count decreased	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
QTc Interval prolonged	1/32 (3.1%)		0/26 (0%)		7/157 (4.5%)
Weight loss	1/32 (3.1%)		0/26 (0%)		1/157 (0.6%)
AST, SGOT Increased	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Creatinine increased	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Metabolism and nutrition disorders
Dehydration	1/32 (3.1%)		0/26 (0%)		5/157 (3.2%)
Hyperglycemia	1/32 (3.1%)		0/26 (0%)		1/157 (0.6%)
Hypoalbuminemia	0/32 (0%)		0/26 (0%)		3/157 (1.9%)
Hypocalcemia	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Hypokalemia	1/32 (3.1%)		0/26 (0%)		4/157 (2.5%)
Hypomagnesemia	0/32 (0%)		0/26 (0%)		2/157 (1.3%)
Hyponatremia	1/32 (3.1%)		1/26 (3.8%)		4/157 (2.5%)
Hypophosphatemia	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Metabolic/Laboratory, other	0/32 (0%)		0/26 (0%)		2/157 (1.3%)
Taste disturbance	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/32 (3.1%)		2/26 (7.7%)		1/157 (0.6%)
Extremity - limb, pain	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Joint pain	1/32 (3.1%)		1/26 (3.8%)		1/157 (0.6%)
Muscle pain	0/32 (0%)		1/26 (3.8%)		1/157 (0.6%)
Fracture	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Nervous system disorders
CNS cerebrovascular ischemia	0/32 (0%)		0/26 (0%)		2/157 (1.3%)
Dizziness	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Nonneuropathic generalized weakness	0/32 (0%)		0/26 (0%)		4/157 (2.5%)
Syncope	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Neuropathy, motor	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Seizure	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Psychiatric disorders
Anxiety	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Depression	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Psychosis	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Renal and urinary disorders
Renal failure	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Reproductive system and breast disorders
Chest/thoracic pain NOS	1/32 (3.1%)		2/26 (7.7%)		0/157 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/32 (9.4%)		1/26 (3.8%)		3/157 (1.9%)
Hemorrhage - other	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Hypoxia	1/32 (3.1%)		0/26 (0%)		1/157 (0.6%)
Lung hemorrhage	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Bronchospasm, wheezing	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Cough	0/32 (0%)		1/26 (3.8%)		0/157 (0%)
Skin and subcutaneous tissue disorders
Dry Skin	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Erythema multiforme	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Rash/desquamation	5/32 (15.6%)		2/26 (7.7%)		6/157 (3.8%)
Skin - other	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Sweating	0/32 (0%)		0/26 (0%)		1/157 (0.6%)
Pruritus/itching	3/32 (9.4%)		1/26 (3.8%)		0/157 (0%)
Rash: acne/acneiform	1/32 (3.1%)		0/26 (0%)		0/157 (0%)
Vascular disorders
Hypertension	2/32 (6.3%)		0/26 (0%)		3/157 (1.9%)
Thrombosis/thrombus/embolism	0/32 (0%)		1/26 (3.8%)		9/157 (5.7%)
Other (Not Including Serious) Adverse Events
	Treated on Vandetanib Maintenance		Treated on Placebo Maintenance		All Treated Patients - Induction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/32 (90.6%)		22/26 (84.6%)		145/157 (92.4%)
Blood and lymphatic system disorders
Anemia	3/32 (9.4%)		1/26 (3.8%)		23/157 (14.6%)
Leukopenia	2/32 (6.3%)		0/26 (0%)		9/157 (5.7%)
Gastrointestinal disorders
Abdomen, Pain	3/32 (9.4%)		0/26 (0%)		7/157 (4.5%)
Constipation	1/32 (3.1%)		1/26 (3.8%)		17/157 (10.8%)
Diarrhea w/o prior colostomy	15/32 (46.9%)		3/26 (11.5%)		44/157 (28%)
Dry Mouth	3/32 (9.4%)		0/26 (0%)		0/157 (0%)
Dyspepsia	2/32 (6.3%)		1/26 (3.8%)		11/157 (7%)
Dysphagia	2/32 (6.3%)		1/26 (3.8%)		4/157 (2.5%)
Muco/stomatitis by exam, oral cavity	3/32 (9.4%)		1/26 (3.8%)		27/157 (17.2%)
Nausea	7/32 (21.9%)		4/26 (15.4%)		50/157 (31.8%)
Vomiting	3/32 (9.4%)		0/26 (0%)		22/157 (14%)
General disorders
Edema, head and neck	2/32 (6.3%)		1/26 (3.8%)		1/157 (0.6%)
Edema, limb	2/32 (6.3%)		0/26 (0%)		9/157 (5.7%)
Fatigue	10/32 (31.3%)		10/26 (38.5%)		53/157 (33.8%)
Rigors/chills	2/32 (6.3%)		1/26 (3.8%)		2/157 (1.3%)
Investigations
Creatinine increased	3/32 (9.4%)		0/26 (0%)		6/157 (3.8%)
Platelet count decreased	0/32 (0%)		0/26 (0%)		12/157 (7.6%)
Weight loss	2/32 (6.3%)		0/26 (0%)		9/157 (5.7%)
Metabolism and nutrition disorders
Anorexia	6/32 (18.8%)		3/26 (11.5%)		27/157 (17.2%)
Hyperglycemia	1/32 (3.1%)		3/26 (11.5%)		5/157 (3.2%)
Hypokalemia	2/32 (6.3%)		0/26 (0%)		2/157 (1.3%)
Hypomagnesemia	3/32 (9.4%)		0/26 (0%)		13/157 (8.3%)
Musculoskeletal and connective tissue disorders
Back, pain	0/32 (0%)		2/26 (7.7%)		5/157 (3.2%)
Joint pain	2/32 (6.3%)		0/26 (0%)		6/157 (3.8%)
Nervous system disorders
Dizziness	3/32 (9.4%)		1/26 (3.8%)		5/157 (3.2%)
Neuropathy, sensory	5/32 (15.6%)		3/26 (11.5%)		22/157 (14%)
Taste disturbance	2/32 (6.3%)		0/26 (0%)		14/157 (8.9%)
Respiratory, thoracic and mediastinal disorders
Cough	2/32 (6.3%)		3/26 (11.5%)		6/157 (3.8%)
Dyspnea	3/32 (9.4%)		3/26 (11.5%)		5/157 (3.2%)
Nose, hemorrhage	2/32 (6.3%)		0/26 (0%)		9/157 (5.7%)
Skin and subcutaneous tissue disorders
Alopecia	8/32 (25%)		4/26 (15.4%)		50/157 (31.8%)
Dry Skin	4/32 (12.5%)		4/26 (15.4%)		5/157 (3.2%)
Nail changes	2/32 (6.3%)		4/26 (15.4%)		6/157 (3.8%)
Photosensitivity	3/32 (9.4%)		0/26 (0%)		1/157 (0.6%)
Pruritus/itching	4/32 (12.5%)		2/26 (7.7%)		6/157 (3.8%)
Rash/desquamation	11/32 (34.4%)		5/26 (19.2%)		25/157 (15.9%)
Rash: acne/acneiform	6/32 (18.8%)		1/26 (3.8%)		4/157 (2.5%)
Vascular disorders
Hypertension	2/32 (6.3%)		2/26 (7.7%)		7/157 (4.5%)
Thrombosis/thrombus/embolism	1/32 (3.1%)		0/26 (0%)		8/157 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.