Neoadjuvant and Adjuvant Imatinib Mesylate in Treating Patients With Primary or Recurrent Malignant Gastrointestinal Stromal Tumor

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00028002
• Collaborator: American College of Radiology Imaging Network (Other), Eastern Cooperative Oncology Group (Other), Radiation Therapy Oncology Group (Other)
• Enrollment: 63
• Location: 1
• Arm: 1
• Actual Duration (Months): 82
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Phase II trial to study the effectiveness of neoadjuvant and adjuvant imatinib mesylate in treating patients who are undergoing surgery for primary or recurrent malignant gastrointestinal stromal tumor. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Giving imatinib mesylate before and after surgery may shrink the tumor so it can be removed and may kill any tumor cells remaining after surgery.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumor	Procedure: Conventional Surgery; Drug: Imatinib Mesylate	Phase 2

Detailed Description

OBJECTIVES:

1. Determine the progression-free survival of patients with primary or recurrent potentially resectable malignant gastrointestinal stromal tumor treated with neoadjuvant and adjuvant imatinib mesylate.

2. Determine the objective response rate of patients treated with this drug. III. Determine the safety of this drug in these patients.

OUTLINE:

Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Neoadjuvant/Adjuvant STI-571 (Gleevec NSC #716051) for Primary and Recurrent Operable Malignant GIST Expressing the KIT Receptor Tyrosine Kinase (CD117)
• Actual Study Start Date: Mar 31, 2002
• Actual Primary Completion Date: Jan 28, 2009
• Actual Study Completion Date: Jan 28, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.

Procedure: Conventional Surgery; Undergo surgical resection; Drug: Imatinib Mesylate; Given orally; Other Names: CGP 57148 CGP57148B Gleevec Glivec STI 571 STI-571 STI571

Outcome Measures

Primary Outcome Measures

1. Rate of Disease Progression at 2 Years [From registration to two years]

   Kaplan-Meier estimate of disease progression rate. Disease progression is determined by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf

Secondary Outcome Measures

1. Rates of Objective Response (Complete, Partial, and Stable) [Pretreatment and prior to surgery (at 4-10 weeks, based on surgery timing)]

   The percentage of patients who achieved a complete, partial or stable response prior to surgery as assessed by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf.

2. Percentage of Patients With Major Toxicity (Toxicity Grade ≥ 3) [Analysis occurs after all patients have been on study for at least 2 years. Measured from start of treatment to end of follow-up, to a maximum of 4.95 years.]

   Highest grade toxicity per subject was counted. Toxicities were graded using Common Toxicity Criteria (CTC) v 2.0. Grade refers to the severity of the toxicity, using Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity.

3. FDG-PET as Biological Marker of Metabolic Response(MR) During Imatinib Mesylate (IM) Treatment, in Patients With GIST Who Are naı¨ve to Tyrosine Kinase Inhibitor Therapy [change from baseline to 1 week post therapy]

   evaluate FDG-PET as a non-invasive functional imaging tool to assess in situ tumor metabolism (as measured by the Standardized Uptake Values of FDG in the tumor) prior to and during the administration of IM. %change in SUVmax <1 indicate decreased tumor metabolism while values >1 indicated an increase in tumor metabolism. Metabolic response by 18F-FDG PET was determined in accordance with the criteria of the European Organization for Research and Treatment of Cancer EORTC), with increases or decreases of more than 25% in SUVmax defining progressive metabolic disease (PMD) and partial metabolic response (PMR), respectively, and new lesions defining PMD.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed malignant gastrointestinal stromal tumor

• Potentially resectable primary disease

• Potentially resectable recurrent disease

• Local or intra-abdominal/pelvic metastatic disease

• Documented c-kit (CD117) expression by immunohistochemical analysis of either initial core specimen or, if recurrent disease, from original tumor block

• Primary disease must be visceral, intra-abdominal, or pelvic in origin

• At least 1 unidimensionally measurable lesion

• At least 5 cm for primary disease

• At least 2 cm for recurrent disease

• At least 1 viable core biopsy tumor specimen obtained within 8 weeks before registration

• Performance status - Zubrod 0-2

• WBC at least 3,000/mm^3

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• ALT/AST no greater than 2.5 times ULN

• No uncontrolled chronic liver disease

• Creatinine no greater than 1.5 times ULN

• No uncontrolled chronic renal disease

• No New York Heart Association class III or IV cardiac disease

• Must be able to lie still in the PET scanner for approximately 1-2 hours

• No uncontrollable hyperglycemia

• No medical or psychological condition that would preclude study participation

• No severe or uncontrolled medical disease

• No active uncontrolled infection

• No known or suspected hypersensitivity to any component of the study drug

• Any prior malignancy is allowed provided patient remains disease free from that malignancy

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for 3 months after study participation

• At least 28 days since prior biologic therapy

• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)

• At least 28 days since prior chemotherapy

• At least 28 days since prior radiotherapy

• See Disease Characteristics

• At least 28 days since prior investigational drugs

• At least 28 days since prior imatinib mesylate

• No concurrent therapeutic doses of warfarin

• Concurrent low-molecular weight heparin or mini-dose warfarin (1 mg per day) prophylaxis is allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania	United States	19103

Sponsors and Collaborators

• National Cancer Institute (NCI)
• American College of Radiology Imaging Network
• Eastern Cooperative Oncology Group
• Radiation Therapy Oncology Group

Investigators

• Principal Investigator: Burton Eisenberg, Radiation Therapy Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00028002
• Other Study ID Numbers: NCI-2012-02437; NCI-2012-02437; ECOG-RTOG-R0132; RTOG S-0132; ACRIN-6665; CDR0000069111; RTOG-S-0132; RTOG-0132; RTOG-0132; U10CA021661
• First Posted: Jan 27, 2003
• Last Update Posted: Oct 26, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
Period Title: Overall Study
STARTED	63
COMPLETED	52
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
Overall Participants	52
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58.5
Sex: Female, Male (Count of Participants)
Female	24 46.2%
Male	28 53.8%

Outcome Measures

1. Primary Outcome

Title	Rate of Disease Progression at 2 Years
Description	Kaplan-Meier estimate of disease progression rate. Disease progression is determined by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf
Time Frame	From registration to two years

Outcome Measure Data

Analysis Population Description

All eligible patients.

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
Measure Participants	52
Number (95% Confidence Interval) [percentage of participants]	13.8 26.5%

2. Secondary Outcome

Title	Rates of Objective Response (Complete, Partial, and Stable)
Description	The percentage of patients who achieved a complete, partial or stable response prior to surgery as assessed by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf.
Time Frame	Pretreatment and prior to surgery (at 4-10 weeks, based on surgery timing)

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
Measure Participants	52
Complete Response	0 0%
Partial Response	5.8 11.2%
Stable Disease	86.5 166.3%

3. Secondary Outcome

Title	Percentage of Patients With Major Toxicity (Toxicity Grade ≥ 3)
Description	Highest grade toxicity per subject was counted. Toxicities were graded using Common Toxicity Criteria (CTC) v 2.0. Grade refers to the severity of the toxicity, using Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity.
Time Frame	Analysis occurs after all patients have been on study for at least 2 years. Measured from start of treatment to end of follow-up, to a maximum of 4.95 years.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment (for pre-surgery), and who additionally had surgery (post-surgery)

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
Measure Participants	52
Pre-surgery	34.6 66.5%
Post-surgery	48.9 94%

4. Secondary Outcome

Title	FDG-PET as Biological Marker of Metabolic Response(MR) During Imatinib Mesylate (IM) Treatment, in Patients With GIST Who Are naı¨ve to Tyrosine Kinase Inhibitor Therapy
Description	evaluate FDG-PET as a non-invasive functional imaging tool to assess in situ tumor metabolism (as measured by the Standardized Uptake Values of FDG in the tumor) prior to and during the administration of IM. %change in SUVmax <1 indicate decreased tumor metabolism while values >1 indicated an increase in tumor metabolism. Metabolic response by 18F-FDG PET was determined in accordance with the criteria of the European Organization for Research and Treatment of Cancer EORTC), with increases or decreases of more than 25% in SUVmax defining progressive metabolic disease (PMD) and partial metabolic response (PMR), respectively, and new lesions defining PMD.
Time Frame	change from baseline to 1 week post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PET Patricipants
Arm/Group Description	FDG-PET was done at baseline, 1-7 days after IM initiation, in patients with GIST undergoing neoadjuvant IM therapy. Tumor GLUT4 expression by immunohistochemistry (IHC) and mutation analyses were done at baseline and/or surgery. Background-subtracted SUVmax was measured in all lesions and summed; Metabolic Response (MR)based on EORTC criteria was compared to Response Evaluation Criteria in Solid Tumors (RECIST), GLUT4 expression, and KIT/PDGFRA mutation status.
Measure Participants	44
Mean (Full Range) [percentage change in SUVmax]	-59.4

Adverse Events

Time Frame	Adverse event (AE) information is collected Weeks 1, 4, 8, Months 3,8,9, then every 3 months until 2 years, then every 6 months until 5 years, then annually. (SAE = Serious Adverse Event).
Adverse Event Reporting Description	Per the protocol, toxicity data was collected via CTC 2.0 then mapped to CTCAE 4.0 to report here. Subjects experiencing more than one of a given adverse event (AE) are counted only once for that AE.
Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years.
All Cause Mortality
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	22/52 (42.3%)
Blood and lymphatic system disorders
Anemia	1/52 (1.9%)
Febrile neutropenia	2/52 (3.8%)
Cardiac disorders
Cardiac disorders - Other	1/52 (1.9%)
Gastrointestinal disorders
Colitis	1/52 (1.9%)
Esophageal fistula	1/52 (1.9%)
Gastrointestinal disorders - Other	1/52 (1.9%)
Upper gastrointestinal hemorrhage	1/52 (1.9%)
Vomiting	1/52 (1.9%)
General disorders
Fever	1/52 (1.9%)
General disorders and administration site conditions - Other	1/52 (1.9%)
Infections and infestations
Infections and infestations - Other	5/52 (9.6%)
Wound infection	3/52 (5.8%)
Investigations
Neutrophil count decreased	4/52 (7.7%)
Serum amylase increased	1/52 (1.9%)
Metabolism and nutrition disorders
Anorexia	2/52 (3.8%)
Hypocalcemia	1/52 (1.9%)
Hyponatremia	1/52 (1.9%)
Nervous system disorders
Dizziness	2/52 (3.8%)
Intracranial hemorrhage	1/52 (1.9%)
Peripheral motor neuropathy	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/52 (1.9%)
Pleural effusion	2/52 (3.8%)
Pneumonitis	1/52 (1.9%)
"Respiratory, thoracic and mediastinal disorders - Other"	1/52 (1.9%)
Vascular disorders
Capillary leak syndrome	3/52 (5.8%)
Thromboembolic event	3/52 (5.8%)
Vascular disorders - Other	1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	52/52 (100%)
Blood and lymphatic system disorders
Anemia	44/52 (84.6%)
Blood and lymphatic system disorders - Other	2/52 (3.8%)
Febrile neutropenia	1/52 (1.9%)
Cardiac disorders
Cardiac disorders - Other	2/52 (3.8%)
Palpitations	2/52 (3.8%)
Pericardial effusion	2/52 (3.8%)
Sinus tachycardia	1/52 (1.9%)
Ventricular arrhythmia	1/52 (1.9%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	1/52 (1.9%)
Hearing impaired	1/52 (1.9%)
Endocrine disorders
Hypothyroidism	1/52 (1.9%)
Eye disorders
Blurred vision	2/52 (3.8%)
Conjunctivitis	4/52 (7.7%)
Dry eye	3/52 (5.8%)
Eye disorders - Other	2/52 (3.8%)
Watering eyes	10/52 (19.2%)
Gastrointestinal disorders
Abdominal pain	10/52 (19.2%)
Ascites	1/52 (1.9%)
Constipation	8/52 (15.4%)
Diarrhea	29/52 (55.8%)
Dyspepsia	7/52 (13.5%)
Flatulence	5/52 (9.6%)
Gastric ulcer	2/52 (3.8%)
Gastrointestinal disorders - Other	7/52 (13.5%)
Mucositis oral	1/52 (1.9%)
Nausea	34/52 (65.4%)
Rectal hemorrhage	2/52 (3.8%)
Rectal pain	1/52 (1.9%)
Vomiting	17/52 (32.7%)
General disorders
Chills	3/52 (5.8%)
Fatigue	20/52 (38.5%)
Fever	7/52 (13.5%)
Non-cardiac chest pain	1/52 (1.9%)
Pain	12/52 (23.1%)
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/52 (1.9%)
Immune system disorders
Immune system disorders - Other	1/52 (1.9%)
Infections and infestations
Infections and infestations - Other	8/52 (15.4%)
Wound infection	2/52 (3.8%)
Injury, poisoning and procedural complications
Intraoperative venous injury	1/52 (1.9%)
Wound dehiscence	1/52 (1.9%)
Investigations
Alanine aminotransferase increased	11/52 (21.2%)
Alkaline phosphatase increased	11/52 (21.2%)
Aspartate aminotransferase increased	17/52 (32.7%)
Blood bilirubin increased	9/52 (17.3%)
Cholesterol high	1/52 (1.9%)
Creatinine increased	6/52 (11.5%)
Investigations - Other	5/52 (9.6%)
Lymphocyte count decreased	2/52 (3.8%)
Neutrophil count decreased	21/52 (40.4%)
Platelet count decreased	15/52 (28.8%)
Serum amylase increased	1/52 (1.9%)
Weight gain	6/52 (11.5%)
Weight loss	8/52 (15.4%)
White blood cell decreased	26/52 (50%)
Metabolism and nutrition disorders
Acidosis	1/52 (1.9%)
Anorexia	6/52 (11.5%)
Dehydration	2/52 (3.8%)
Hypercalcemia	1/52 (1.9%)
Hyperglycemia	23/52 (44.2%)
Hyperkalemia	1/52 (1.9%)
Hypermagnesemia	2/52 (3.8%)
Hypernatremia	3/52 (5.8%)
Hypertriglyceridemia	1/52 (1.9%)
Hypoalbuminemia	11/52 (21.2%)
Hypocalcemia	12/52 (23.1%)
Hypoglycemia	4/52 (7.7%)
Hypokalemia	13/52 (25%)
Hypomagnesemia	5/52 (9.6%)
Hyponatremia	6/52 (11.5%)
Hypophosphatemia	2/52 (3.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/52 (7.7%)
Bone pain	1/52 (1.9%)
Generalized muscle weakness	2/52 (3.8%)
Myalgia	15/52 (28.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	2/52 (3.8%)
Nervous system disorders
Dizziness	4/52 (7.7%)
Dysgeusia	1/52 (1.9%)
Headache	3/52 (5.8%)
Peripheral sensory neuropathy	5/52 (9.6%)
Vasovagal reaction	1/52 (1.9%)
Psychiatric disorders
Anxiety	1/52 (1.9%)
Confusion	2/52 (3.8%)
Depression	3/52 (5.8%)
Insomnia	3/52 (5.8%)
Renal and urinary disorders
Renal and urinary disorders - Other	3/52 (5.8%)
Urinary frequency	1/52 (1.9%)
Urinary incontinence	1/52 (1.9%)
Urinary tract pain	1/52 (1.9%)
Reproductive system and breast disorders
Gynecomastia	1/52 (1.9%)
Pelvic pain	1/52 (1.9%)
Reproductive system and breast disorders - Other	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/52 (1.9%)
Cough	8/52 (15.4%)
Dyspnea	6/52 (11.5%)
Epistaxis	1/52 (1.9%)
Hiccups	1/52 (1.9%)
Pleural effusion	8/52 (15.4%)
Pleuritic pain	1/52 (1.9%)
Pneumonitis	2/52 (3.8%)
Skin and subcutaneous tissue disorders
Alopecia	2/52 (3.8%)
Dry skin	1/52 (1.9%)
Nail loss	1/52 (1.9%)
Pruritus	2/52 (3.8%)
Rash maculo-papular	18/52 (34.6%)
Skin and subcutaneous tissue disorders - Other	2/52 (3.8%)
Vascular disorders
Capillary leak syndrome	28/52 (53.8%)
Flushing	1/52 (1.9%)
Hot flashes	3/52 (5.8%)
Hypertension	4/52 (7.7%)
Lymphedema	3/52 (5.8%)
Vascular disorders - Other	3/52 (5.8%)

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.