Efficacy and Safety of Sunitinib in Metastatic Gastric Cancer

• Sponsor: Johannes Gutenberg University Mainz (Other)
• Overall Status: Completed
• CT.gov ID: NCT00411151
• Collaborator: Pfizer (Industry)
• Enrollment: 52
• Locations: 12
• Duration (Months): 32
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This trial will be conducted to evaluate the efficacy, safety, and tolerability of sunitinib (sunitinib-malate) as a second-line palliative therapy in metastatic gastric cancer. Despite the efforts in front-line therapy, second-line protocols have not yet been established in randomized clinical trials for those patients. Although many patients are still in good performance status and present with low tumor burden after failure of first-line chemotherapy, they may clearly benefit from second-line treatment. Increasingly more metachronic metastatic patients are urging for new platinum-free therapeutic options due to the fast-growing use of (neo-) adjuvant platin-based protocols.

So far, only sparse data on chemotherapy are available after failure of platin-based protocols. Nearly only irinotecan-containing combinations have properly been analyzed, and produced excellent response rates and survival times of up to 30% and 7.6 months, respectively. However, irinotecan has not been approved yet for this indication. In addition, as irinotecan-containing regimens have been submitted for approval for first-line therapy, second-line regimens in irinotecan-refractory patients have not been evaluated in any trial. Thus, there is an urgent need to establish new second-line treatment options for both, cisplatinum- or irinotecan-combination refractory patients with advanced or metastatic gastric cancer.

Sunitinib inhibits the receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, specifically the VEGFR, PDGFR, KIT, FLT-3, and RET. The VEGF pathway has been shown to be a significant factor in metastatic gastric cancer. In gastric carcinoma cells, VEGF ligands and its receptors are definitely involved in the process of tumor progression. KDR and FLT-1 are expressed widely and VEGF stimulated KDR-positive tumor cell growth directly. The ligand VEGF-C has also been shown to be involved in progression of human gastric carcinoma, particularly via lymphangiogenesis. In addition, peritoneal metastases of some cancers such as gastric cancers were largely dependent on VEGF. Therefore, patients with chemo-refractory metastatic gastric cancer might benefit from VEGFR inhibitory therapy with sunitinib.

Condition or Disease	Intervention/Treatment	Phase
Gastric Adenocarcinoma; Barrett Esophagus	Drug: Sunitinib-Malate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter Phase II Trial of Sunitinib for Patients With Chemo-refractory Metastatic Gastric Cancer
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [one year]

   The primary endpoint is the ORR within the first 6 treatment cycles, defined as the percentage of participants with a confirmed reduction in tumor size fulfilling the criteria for complete or partial response (CR or PR) according to RECIST. CR=disappearance of all target lesions, PR=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [one year]

   PFS is defined as the time from first dose of trial medication to first documentation of objective tumor progression or to death due to any cause, whichever occurs first.

2. Overall Survival (OS) [one year]

   OS is defined as the time from the first dose of trial medication to date of death due to any cause.

3. One-Year Survival [one year]

   One-year survival is defined as the percentage of participants surviving for at least one year after first dose of trial medication.

4. Adverse Events [one year]

   The number of participants with at least one adverse event was measured.

5. Safety and Tolerability: Serious Adverse Events [one year]

   The number of participants with at least one Serious Adverse Event was measured.

6. Safety and Tolerability: Adverse Events in ≥10% of Patients [one year]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed and dated informed consent of the patient before the start of specific protocol procedures

• Histologically proven adenocarcinoma of stomach, esophagogastric junction or lower esophagus (Barrett carcinoma)

• Measurable metastatic disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). If locally recurrent disease, it must be associated with at least one measurable lymph node (> 20 mm by computed tomography [CT] scan or > 10 mm with spiral CT).

• Failure of prior palliative chemotherapy/chemotherapies (at least one irinotecan- or cisplatin-based). Failure is defined either by progression of disease or by significant toxicity that precludes further treatment.

• At least 3 weeks from previous chemotherapy at first dose of trial drug

• Resolution of all acute toxic side effects of prior therapy or surgical procedures to grade ≤ 1 National Cancer Institute-Common Toxicity Criteria (NCI-CTC) (except for the laboratory values)

• Adequate organ function as defined by the following criteria:

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy

• Total serum bilirubin ≤ 1.5 x ULN

• Absolute neutrophil count (ANC) ≥1500/microL

• Platelets ≥ 100,000/microL

• Hemoglobin ≥ 8.0 g/dL without support of growth factors (previous administration of erythrocyte concentrate is allowed)

• Serum calcium ≤ 12.0 mg/dL

• Serum creatinine ≤ 2.0 x ULN

• Lipase/amylase ≤ 2.5 x ULN

• All other laboratory values specified in the protocol (white blood cell count, white blood cell differential, alkaline phosphatase, sodium, potassium, creatinine clearance): resolution of all side effects of prior therapy or surgical procedure to grade < 3 NCI-CTC

• At least 4 weeks from any major surgery (at first dose of trial drug)

• Karnofsky Performance Status (KPS) ≥ 70

• Life expectancy > 12 weeks

• Patients must be able to swallow sunitinib capsules

• Patients who understand the nature of the trial and are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures

• Female patients who are capable of bearing children must have a negative pregnancy test result (serum or urine) at trial entry. All women included in the trial must be surgically sterile or postmenopausal or agree to employ adequate birth control measures for the duration of the trial and six months post-dosing. Male patients must be surgically sterile or must agree to use effective contraception during the trial and six months post-dosing.

Exclusion Criteria:

• Tumor type other than adenocarcinoma (e.g., leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion.

• Patients with known brain or leptomeningeal metastasis

• Intake of non-permitted concomitant drugs. (The coordinating investigator should be contacted to discuss the individual case.)

• Concomitant treatment with antiarrhythmics and drugs with dysrhythmic potential (i.e., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide)

• Administration of potent CYP34A inhibitors during or within 7 days before start of sunitinib-treatment (e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir, grapefruit juice)

• Administration of potent CYP3A4 inducers during or within 12 days before start of sunitinib-treatment (e.g. dexamethasone, rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John´s wort, efavirenz, tipranavir)

• Ongoing treatment with therapeutic doses of anticoagulants such as Coumadin or heparins. (However, low dose Coumadin up to 2 mg by mouth [PO] daily for deep vein thrombosis prophylaxis is allowed.)

• Any other medicinal anticancer therapy during treatment phase except treatment with non-conventional therapies (e.g. herbs or acupuncture) and vitamins/mineral supplements, provided that they do not interfere with the trial endpoint, in the opinion of the investigator

• Concurrent systemic immune therapy, chemo- or hormone therapy

• Concomitant or within a 4-week period administration (from first dose of trial drug) of any other experimental drug under investigation (except for irinotecan and cetuximab) and participation in another clinical trial

• Any prior radiotherapy of target lesions

• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (> hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis

• Current history of chronic diarrhoea

• Active disseminated intravascular coagulation, or patients prone to thromboembolism

• Any of the following events (in any grade) prior to starting the trial treatment:

• myocardial infarction

• severe/unstable angina

• coronary/peripheral artery bypass graft

• congestive heart failure

• cerebrovascular accident or transient ischemic attack

• pulmonary embolism

• Known history of QT interval prolongation, ongoing QT prolongation (> 450 msec for males or > 470 msec for females), any cardiac ventricular dysrhythmias, atrial fibrillation of any grade

• Hypertension that cannot be controlled by medications (> 150/100 mmHg despite optimal medical therapy)

• Known human immunodeficiency virus (HIV) infection

• Active uncontrolled infection

• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with trial participation or trial drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into the trial

• Pregnant or lactating women

• Known allergic/hypersensitivity reaction to any of the components of the treatment; or known drug abuse/alcohol abuse

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universität Heidelberg, Nationales Zentrum für Tumorerkrankungen	Heidelberg	Baden-Würtemberg	Germany	69120
2	Universitätsklinikum Tübingen	Tübingen	Baden-Würtemberg	Germany	72076
3	TU München, Klinikum rechts der Isar, II. Med. Klinik und Poliklinik	München	Bayern	Germany	81675
4	Klinikum der Universität Würzburg	Würzburg	Bayern	Germany	97070
5	Universitätsklinikum der GHS Essen, Innere Klinik und Poliklinik, Tumorforschung	Essen	Nordrhein-Westfalen	Germany	45122
6	Universitätsklinik zu Köln, Klinik I für Innere Medizin	Köln	Nordrhein-Westfalen	Germany	50937
7	Klinikum der Johannes Gutenberg-Universität Mainz	Mainz	Rheinland-Pfalz	Germany	55131
8	Universitätsklinikum des Saarlandes	Homburg/Saar	Saarland	Germany	66421
9	Otto-von-Guericke-Universität Magdeburg	Magdeburg	Sachsen-Anhalt	Germany	39120
10	Universitätsklinikum Carl Gustav Carus, Med. Klinik I	Dresden	Sachsen	Germany	01307
11	Charité, Campus Benjamin Franklin	Berlin		Germany	12200
12	KH Nordwest, Abteilung für Hämatologie und Onkologie	Frankfurt		Germany	60488

Sponsors and Collaborators

• Johannes Gutenberg University Mainz
• Pfizer

Investigators

• Principal Investigator: Markus Moehler, MD, Johannes-Gutenberg-University of Mainz, I. Dept. Internal Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00411151
• Other Study ID Numbers: GC-SU-2006; KKS 2005-015
• First Posted: Dec 13, 2006
• Last Update Posted: Jan 20, 2011
• Last Verified: Jan 1, 2011

• Keywords provided by , ,: Adenocarcinoma of esophagogastric junction; Adenocarcinoma of lower esophagus (Barrett carcinoma)
• Additional relevant MeSH terms: Adenocarcinoma; Barrett Esophagus; Sunitinib

Study Results

Participant Flow

Recruitment Details	First patient in (FPI): 15.02.2007 Last patient out (LPO): 20.08.2009

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Period Title: Overall Study
STARTED	52
COMPLETED	5
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Overall Participants	52
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59 (12.07)
Sex: Female, Male (Count of Participants)
Female	12 23.1%
Male	40 76.9%
Karnofsky Performance Status (KPS) (Number) [Number]
100%	17 32.7%
90%	15 28.8%
80%	18 34.6%
70%	2 3.8%
60%	0 0%
50%	0 0%
40%	0 0%
30%	0 0%
20%	0 0%
10%	0 0%
Missing	0 0%
Localisation of adenocarcinoma (Number) [Number]
Stomach	36 69.2%
Gastroesophageal junction	12 23.1%
Lower esophagus	5 9.6%
Missing	0 0%
Grading of adenocarcinoma (Number) [Number]
1	0 0%
2	19 36.5%
3	26 50%
4	2 3.8%
Missing	5 9.6%
Localisation of target lesions (Number) [Number]
Primary tumor	3 5.8%
Lung	8 15.4%
Liver	28 53.8%
Lymph node truncus coeliacus	10 19.2%
Lymph node mediastinum	11 21.2%
Lymph node spleen/pancreas	3 5.8%
Lymph node paraaortal caudal	9 17.3%
Peritoneum	2 3.8%
Soft tissue	5 9.6%
Other	14 26.9%
Missing	0 0%
Total size of target lesions (mm) [Median (Full Range) ]
Median (Full Range) [mm]	62
Localisation of non-target lesions (Number) [Number]
Primary tumor	1 1.9%
Bone	1 1.9%
Lung	4 7.7%
Liver	15 28.8%
Lymph node truncus coeliacus	4 7.7%
Lymph node mediastinum	3 5.8%
Lymph node paraaortal caudal	3 5.8%
Peritoneum	3 5.8%
Other	9 17.3%
No non-target lesions	9 17.3%
Missing	9 17.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	The primary endpoint is the ORR within the first 6 treatment cycles, defined as the percentage of participants with a confirmed reduction in tumor size fulfilling the criteria for complete or partial response (CR or PR) according to RECIST. CR=disappearance of all target lesions, PR=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	51
Number (95% Confidence Interval) [Participants (%)]	3.92 7.5%

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as the time from first dose of trial medication to first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	51
Median (95% Confidence Interval) [Days]	39

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from the first dose of trial medication to date of death due to any cause.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	51
Median (95% Confidence Interval) [Days]	177

4. Secondary Outcome

Title	One-Year Survival
Description	One-year survival is defined as the percentage of participants surviving for at least one year after first dose of trial medication.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	51
Number (95% Confidence Interval) [Participants (%)]	23.7 45.6%

5. Secondary Outcome

Title	Adverse Events
Description	The number of participants with at least one adverse event was measured.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Safety population comprises all patients registered.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	52
Number [Participants]	52 100%

6. Secondary Outcome

Title	Safety and Tolerability: Serious Adverse Events
Description	The number of participants with at least one Serious Adverse Event was measured.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Safety population comprises all patients registered.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	52
Number [Participants]	26 50%

7. Secondary Outcome

Title	Safety and Tolerability: Adverse Events in ≥10% of Patients
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Safety population comprises all patients registered.

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
Measure Participants	52
Fatigue	19 36.5%
Nausea	16 30.8%
Mucosal inflammation	9 17.3%
Anorexia	9 17.3%
Vomiting	8 15.4%
Diarrhoea	8 15.4%
Dysgeusia	6 11.5%
Headache	5 9.6%
Paraesthesia	5 9.6%
Cough	5 9.6%
Abdominal pain	5 9.6%
Palmar-plantar erythrodysaesthesia syndrome	5 9.6%
Blood bilirubin increased	5 9.6%
Leukopenia	11 21.2%
Thrombocytopenia	11 21.2%
Neutropenia	8 15.4%
Anaemia	7 13.5%

Adverse Events

Arm/Group Title	Sunitinib
Arm/Group Description	open-label and uncontrolled treatment cycle "4+2": Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest)
All Cause Mortality
	Sunitinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sunitinib
	Affected / at Risk (%)	# Events
Total	0/52 (0%)
Other (Not Including Serious) Adverse Events
	Sunitinib
	Affected / at Risk (%)	# Events
Total	0/52 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.