Five Year Adjuvant Imatinib Mesylate (Gleevec®) in Gastrointestinal Stromal Tumor (GIST)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00867113
• Collaborator: (none)
• Enrollment: 91
• Locations: 21
• Arm: 1
• Actual Duration (Months): 89
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase II, non-randomized, open-label, multi-center study conducted in the USA. The purpose of this trial is to evaluate the use of long term adjuvant imatinib mesylate in patients at significant risk for recurrence following complete resection of primary GIST.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumor (GIST)	Drug: imatinib mesylate	Phase 2

Detailed Description

This is a Phase II, non-randomized, open-label, multi-center study conducted in the USA. The primary endpoint is to evaluate the use of long term adjuvant imatinib mesylate in patients at significant risk for recurrence following complete resection of primary GIST. A total of 85 adult patients, 18 years of age and older will be enrolled.Participants will take 400 mg of imatinib mesylate daily by mouth for a total of 5 years. At the conclusion of the treatment period, patients will be followed for 2 years for survival, status of response and antineoplastic treatments and quality of life.

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Non-Randomized, Open-Label Multicenter Study of 5 Year Adjuvant Imatinib Mesylate (Gleevec®) in Patients at Significant Risk for Recurrence Following Complete Resection of Primary Gastrointestinal Stromal Tumor (GIST)
• Actual Study Start Date: Jul 22, 2009
• Actual Primary Completion Date: Dec 20, 2016
• Actual Study Completion Date: Dec 20, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Imatinib All subjects received in tablet form imatinib (STI571) 400 mg once daily.	Drug: imatinib mesylate; imatinib mesylate was supplied in 100 and 400 mg tablets

Outcome Measures

Primary Outcome Measures

1. Recurrence-free Survival up to 60 Months [Baseline up to 60 months]

   Recurrence-free survival assessment is based on the radiologic evidence and is defined as the time from the date of first dose of imatinib to the date of the first documented disease recurrence or death due to any cause (event).

2. Kaplan-Meier Estimates for Recurrence-free Survival up to 60 Months [Baseline up to 60 months]

   Recurrence-free survival (RFS) assessment is based on the radiologic evidence and is defined as the time from the date of first dose of imatinib to the date of the first documented disease recurrence or death due to any cause (event). RFS estimates were summarized using the Kaplan-Meier product-limit method (Kaplan 1958). Censoring rules for RFS with the earliest occurring rule used in the analysis: subjects without objective recurrence of disease who were alive at the time of their discontinuation from study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment and subjects recording antineoplastic therapy during the study were censored on the date of the therapy initiated

Secondary Outcome Measures

1. Overall Survival (OS) at 60 Months [Baseline up to approximately 60 months]

   Overall survival was defined as the time from the date of the first dose of study drug to the date of death. Subjects who were alive at the time of discontinuation/completion of the study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment. Full analysis set.

2. Kaplan-Meier Estimates for Overall Survival (OS) up to 60 Months [Baseline up to appoximately 60 months]

   Overall survival was defined as the time from the date of the first dose of study drug to the date of death. Subjects who were alive at the time of discontinuation/completion of the study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment. Full analysis set.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients 18 years of age or older.

2. Patient must have had a histological diagnosis of primary GIST.

3. The tumor must expressed KIT (CD117) protein by immunohistochemistry performed by central pathology.

4. Patient must have been at significant risk of tumor recurrence as defined by either:

• Primary GIST (any site): ≥ 2 cm and a mitotic rate of ≥ 5/50 HPF's

• Non-gastric primary GIST: ≥ 5cm

1. Patient must have undergone complete gross resection of a primary GIST within 12 weeks prior to first dose of imatinib study drug. The inclusion of R1 resections will be reviewed on a case by case basis by the Study Management Committee.

2. Patient must had no evidence of metastatic GIST on either 1) a post-operative CT of the abdomen and pelvis with intravenous and oral contrast or 2) MRI of the abdomen and pelvis with intravenous contrast. CT or MRI must have been performed within 8 weeks prior to first dose of imatinib study drug.

3. Performance status 0 or 1 (ECOG)

4. Patient must had the following post-operative laboratory values confirmed within 14 days prior to first dose of imatinib study drug:

• total bilirubin < 1.5 x ULN NOTE: Patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study.

• ALT and AST < 2.5 x ULN

• creatinine < 1.5 x ULN

• ANC > 1.5 x 109/L

• platelets > 100 x 109/L

1. If patient is a cancer survivor, ALL of the following criteria apply:

• Patient had undergone potentially curative therapy for all prior malignancies.

• No evidence of any prior malignancies for at least 3 years with no evidence of recurrence (except for effectively treated basal cell or squamous carcinoma of the skin, carcinoma in-situ of the cervix that has been effectively treated by surgery alone, or lobular carcinoma in-situ of the ipsilateral or contralateral breast treated by surgery alone).

• Patient is deemed by their treating physician to be at low risk for recurrence from prior malignancies.

1. Female patients of childbearing potential must have had negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Female patients of reproductive potential must have jagreed to employ an effective barrier method of birth control throughout the study and for up to 7 days following discontinuation of study drug.

2. Written, voluntary informed consent.

Exclusion Criteria:

1. Patient has metastatic GIST to the peritoneum, liver, lymph node, or other sites or recurrent GIST.

2. Prior treatment for GIST with the exception of prior treatment with imatinib adjuvant lasting ≤ 8 weeks following gross surgical resection.

3. Patient has received any other investigational agents within 28 days of first day of study drug dosing.

4. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)

5. Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risk or compromise compliance with the protocol (i.e., uncontrolled diabetes, chronic renal disease, chronic liver disease, or active uncontrolled infection).

6. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.

7. Patient receiving concurrent treatment with warfarin (acceptable alternative: low-molecular weight heparin).

8. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego - Moores Cancer Center Moores UCSD Cancer Center (31)	La Jolla	California	United States	92093-0658
2	University of Colorado University of Colorado	Aurora	Colorado	United States	80045
3	Washington Hospital Center Department of Medical Oncology	Washington	District of Columbia	United States	20010
4	University Cancer & Blood Center, LLC	Athens	Georgia	United States	30607
5	Longstreet Cancer Center	Gainesville	Georgia	United States	30501
6	Kootenai Medical Center Kootenai Cancer Cancer	Coeur d'Alene	Idaho	United States	83814
7	North Shore University Health System	Evanston	Illinois	United States	60201
8	Dana Farber Cancer Institute Dana-Farber	Boston	Massachusetts	United States	02215
9	Karmanos Cancer Institute Karmonos Cancer Instit. (40)	Detroit	Michigan	United States	48201
10	Washington University School of Medicine Center for Advanced Medicine	Saint Louis	Missouri	United States	63110
11	Southern Nevada Cancer Research Foundation S. Nevada Cancer Res (2)	Las Vegas	Nevada	United States	89106
12	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
13	Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering (7)	New York	New York	United States	10021
14	Duke University Medical Center Duke University Med Ctr (8)	Durham	North Carolina	United States	27710
15	Oregon Health & Science University OHS University	Portland	Oregon	United States	97239
16	Penn State University / Milton S. Hershey Medical Center Penn Stat University	Hershey	Pennsylvania	United States	17033-0850
17	Roger Williams Medical Center Medical Center	Providence	Rhode Island	United States	02908
18	Kingport Hematology Oncology	Kingsport	Tennessee	United States	37660
19	MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (4)	Houston	Texas	United States	77030
20	South Texas Oncology and Hematology, PA South Texas Onc/Hem	San Antonio	Texas	United States	78259
21	Virginia Oncology Associates Viriginia Oncology Assoc.	Norfolk	Virginia	United States	23502

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00867113
• Other Study ID Numbers: CSTI571BUS282
• First Posted: Mar 23, 2009
• Last Update Posted: Mar 14, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Novartis Pharmaceuticals: Imatinib; Protein Kinase Inhibitors; Gastrointestinal Stromal Tumors; Digestive System Diseases; Digestive System Neoplasms; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Adjuvant; PERSIST; PERSIS-5
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Imatinib Mesylate

Study Results

Participant Flow

Pre-assignment Detail	Total of 113 subjects were screened and 91 were enrolled..

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Period Title: Treatment Period
STARTED	91
Safety Set	91
Full Analysis Set (FAS)	91
COMPLETED	46
NOT COMPLETED	45
Period Title: Treatment Period
STARTED	68
COMPLETED	57
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Overall Participants	91
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.9 (12.64)
Sex: Female, Male (Count of Participants)
Female	43 47.3%
Male	48 52.7%
ECOG Status (Count of Participants)
ECOG = 0	59 64.8%
ECOG = 1	32 35.2%
Primary lesion location (participant) [Number]
Gastric	50
Duodenum	4
Jejunum ileum	21
Rectum	1
Other	15
Abdomen	1
Abdominal; Proximal Jejunal	1
Exact Location In Small Bowel Not Identified	1
Gastric Serosa-Min Invasion Outer Musc Prop	1
Ileum And Cecum	1
Pelvis - Organ Of Origin Unknown	1
Recto Vaginal	1
Retroperitoneal Mass	1
Sigmoid Colon	1
Small Bowel	6

Outcome Measures

1. Primary Outcome

Title	Recurrence-free Survival up to 60 Months
Description	Recurrence-free survival assessment is based on the radiologic evidence and is defined as the time from the date of first dose of imatinib to the date of the first documented disease recurrence or death due to any cause (event).
Time Frame	Baseline up to 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Measure Participants	91
Subject with an event	9 9.9%
Event = disease recurrence	7 7.7%
Event=death	2 2.2%
Subjects censored	82 90.1%

2. Primary Outcome

Title	Kaplan-Meier Estimates for Recurrence-free Survival up to 60 Months
Description	Recurrence-free survival (RFS) assessment is based on the radiologic evidence and is defined as the time from the date of first dose of imatinib to the date of the first documented disease recurrence or death due to any cause (event). RFS estimates were summarized using the Kaplan-Meier product-limit method (Kaplan 1958). Censoring rules for RFS with the earliest occurring rule used in the analysis: subjects without objective recurrence of disease who were alive at the time of their discontinuation from study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment and subjects recording antineoplastic therapy during the study were censored on the date of the therapy initiated
Time Frame	Baseline up to 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Measure Participants	91
12 months	97.7
18 months	97.7
24 months	96.5
36 months	95.1
48 months	95.1
60 months	90.1

3. Secondary Outcome

Title	Overall Survival (OS) at 60 Months
Description	Overall survival was defined as the time from the date of the first dose of study drug to the date of death. Subjects who were alive at the time of discontinuation/completion of the study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment. Full analysis set.
Time Frame	Baseline up to approximately 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Measure Participants	91
subjects who died	3 3.3%
subjects censored	88 96.7%

4. Secondary Outcome

Title	Kaplan-Meier Estimates for Overall Survival (OS) up to 60 Months
Description	Overall survival was defined as the time from the date of the first dose of study drug to the date of death. Subjects who were alive at the time of discontinuation/completion of the study were censored at the end of study date or end of treatment visit date if the subject refused to be followed post treatment. Full analysis set.
Time Frame	Baseline up to appoximately 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib
Arm/Group Description	All subjects received in tablet form imatinib (STI571) 400 mg once daily.
Measure Participants	91
12 months	100.00 109.9%
18 months	100.00 109.9%
24 months	98.0 107.7%
36 months	98.0 107.7%
48 months	98.0 107.7%
60 months	93.8 103.1%

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 7 years
Arm/Group Title	Imatinib
Arm/Group Description	Imatinib
All Cause Mortality
	Imatinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Imatinib
	Affected / at Risk (%)	# Events
Total	28/91 (30.8%)
Blood and lymphatic system disorders
ANAEMIA	4/91 (4.4%)
LEUKOCYTOSIS	1/91 (1.1%)
Cardiac disorders
CARDIAC FAILURE	1/91 (1.1%)
CARDIAC FAILURE CHRONIC	1/91 (1.1%)
CORONARY ARTERY DISEASE	1/91 (1.1%)
MITRAL VALVE INCOMPETENCE	1/91 (1.1%)
Gastrointestinal disorders
ABDOMINAL ADHESIONS	1/91 (1.1%)
ABDOMINAL PAIN	2/91 (2.2%)
COLITIS	1/91 (1.1%)
DIARRHOEA	1/91 (1.1%)
GASTRIC ULCER	1/91 (1.1%)
GASTROINTESTINAL HAEMORRHAGE	1/91 (1.1%)
HAEMORRHOIDAL HAEMORRHAGE	1/91 (1.1%)
HAEMORRHOIDS	1/91 (1.1%)
NAUSEA	2/91 (2.2%)
PANCREATITIS	1/91 (1.1%)
RECTAL HAEMORRHAGE	1/91 (1.1%)
RETCHING	1/91 (1.1%)
SMALL INTESTINAL OBSTRUCTION	3/91 (3.3%)
SMALL INTESTINAL PERFORATION	1/91 (1.1%)
VOMITING	2/91 (2.2%)
General disorders
CHEST PAIN	1/91 (1.1%)
MALAISE	2/91 (2.2%)
PAIN	1/91 (1.1%)
Hepatobiliary disorders
CHOLELITHIASIS	1/91 (1.1%)
Immune system disorders
HYPERSENSITIVITY	1/91 (1.1%)
Infections and infestations
ABDOMINAL INFECTION	1/91 (1.1%)
APPENDICITIS	1/91 (1.1%)
APPENDICITIS PERFORATED	1/91 (1.1%)
CELLULITIS	1/91 (1.1%)
GASTROENTERITIS	1/91 (1.1%)
PERITONITIS	2/91 (2.2%)
PNEUMONIA	4/91 (4.4%)
SIALOADENITIS	1/91 (1.1%)
Injury, poisoning and procedural complications
FALL	1/91 (1.1%)
HIP FRACTURE	2/91 (2.2%)
HUMERUS FRACTURE	1/91 (1.1%)
OVERDOSE	1/91 (1.1%)
Investigations
HEPATIC ENZYME INCREASED	1/91 (1.1%)
LIPASE INCREASED	1/91 (1.1%)
WEIGHT DECREASED	1/91 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
DESMOID TUMOUR	1/91 (1.1%)
HAIR FOLLICLE TUMOUR BENIGN	1/91 (1.1%)
NEOPLASM MALIGNANT	1/91 (1.1%)
PROSTATE CANCER	3/91 (3.3%)
UTERINE LEIOMYOMA	1/91 (1.1%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	2/91 (2.2%)
RADICULOPATHY	1/91 (1.1%)
TRANSIENT ISCHAEMIC ATTACK	1/91 (1.1%)
Psychiatric disorders
CONFUSIONAL STATE	1/91 (1.1%)
DELIRIUM	1/91 (1.1%)
DEPRESSION	1/91 (1.1%)
Renal and urinary disorders
ACUTE KIDNEY INJURY	1/91 (1.1%)
RENAL MASS	1/91 (1.1%)
URETERIC STENOSIS	1/91 (1.1%)
Respiratory, thoracic and mediastinal disorders
ALVEOLITIS	1/91 (1.1%)
PLEURAL EFFUSION	1/91 (1.1%)
Vascular disorders
HYPERTENSION	2/91 (2.2%)
Other (Not Including Serious) Adverse Events
	Imatinib
	Affected / at Risk (%)	# Events
Total	91/91 (100%)
Blood and lymphatic system disorders
ANAEMIA	15/91 (16.5%)
LEUKOPENIA	6/91 (6.6%)
NEUTROPENIA	8/91 (8.8%)
Ear and labyrinth disorders
VERTIGO	7/91 (7.7%)
Eye disorders
CONJUNCTIVAL HAEMORRHAGE	6/91 (6.6%)
LACRIMATION INCREASED	5/91 (5.5%)
PERIORBITAL OEDEMA	31/91 (34.1%)
Gastrointestinal disorders
ABDOMINAL DISCOMFORT	5/91 (5.5%)
ABDOMINAL DISTENSION	5/91 (5.5%)
ABDOMINAL PAIN	22/91 (24.2%)
ABDOMINAL PAIN UPPER	6/91 (6.6%)
CONSTIPATION	7/91 (7.7%)
DIARRHOEA	57/91 (62.6%)
DYSPEPSIA	14/91 (15.4%)
FLATULENCE	12/91 (13.2%)
GASTROOESOPHAGEAL REFLUX DISEASE	5/91 (5.5%)
NAUSEA	65/91 (71.4%)
VOMITING	34/91 (37.4%)
General disorders
CHILLS	7/91 (7.7%)
FATIGUE	45/91 (49.5%)
OEDEMA	7/91 (7.7%)
OEDEMA PERIPHERAL	18/91 (19.8%)
PAIN	7/91 (7.7%)
PYREXIA	9/91 (9.9%)
TEMPERATURE INTOLERANCE	6/91 (6.6%)
Infections and infestations
SINUSITIS	8/91 (8.8%)
UPPER RESPIRATORY TRACT INFECTION	10/91 (11%)
URINARY TRACT INFECTION	8/91 (8.8%)
Injury, poisoning and procedural complications
CONTUSION	5/91 (5.5%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/91 (7.7%)
ASPARTATE AMINOTRANSFERASE INCREASED	10/91 (11%)
BLOOD BILIRUBIN INCREASED	5/91 (5.5%)
BLOOD CREATININE INCREASED	6/91 (6.6%)
NEUTROPHIL COUNT DECREASED	6/91 (6.6%)
WEIGHT INCREASED	9/91 (9.9%)
WHITE BLOOD CELL COUNT DECREASED	5/91 (5.5%)
Metabolism and nutrition disorders
DECREASED APPETITE	12/91 (13.2%)
HYPERGLYCAEMIA	5/91 (5.5%)
HYPOKALAEMIA	10/91 (11%)
HYPOMAGNESAEMIA	6/91 (6.6%)
HYPOPHOSPHATAEMIA	14/91 (15.4%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	16/91 (17.6%)
BACK PAIN	11/91 (12.1%)
JOINT SWELLING	5/91 (5.5%)
MUSCLE SPASMS	37/91 (40.7%)
MUSCULOSKELETAL CHEST PAIN	5/91 (5.5%)
MUSCULOSKELETAL PAIN	11/91 (12.1%)
MYALGIA	8/91 (8.8%)
PAIN IN EXTREMITY	13/91 (14.3%)
Nervous system disorders
DIZZINESS	17/91 (18.7%)
DYSGEUSIA	6/91 (6.6%)
HEADACHE	20/91 (22%)
NEUROPATHY PERIPHERAL	8/91 (8.8%)
PARAESTHESIA	6/91 (6.6%)
SCIATICA	5/91 (5.5%)
Psychiatric disorders
DEPRESSION	8/91 (8.8%)
INSOMNIA	8/91 (8.8%)
Respiratory, thoracic and mediastinal disorders
COUGH	11/91 (12.1%)
DYSPNOEA	11/91 (12.1%)
OROPHARYNGEAL PAIN	6/91 (6.6%)
Skin and subcutaneous tissue disorders
ALOPECIA	9/91 (9.9%)
DRY SKIN	6/91 (6.6%)
NIGHT SWEATS	7/91 (7.7%)
RASH	24/91 (26.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial