RATIONALE: SU011248 may stop the growth of tumor cells by blocking the enzymes necessary for their growth. It is not yet known if SU011248 is effective in treating malignant gastrointestinal stromal tumors.

PURPOSE: Randomized phase III trial to study the effectiveness of SU011248 in treating patients who have malignant gastrointestinal stromal tumors that have not responded to imatinib mesylate.

Condition	Treatment or Intervention	Phase
gastrointestinal stromal tumor	Drug: SU011248  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare the time to tumor progression in patients with imatinib mesylate-resistant or -intolerant malignant gastrointestinal stromal tumor treated with SU011248 vs placebo.

Secondary

• Compare other measures of antitumor efficacy of these regimens in these patients.
• Compare pain control, analgesic usage, tumor-related signs and symptoms, health status, and performance status in patients treated with these regimens.
• Determine the safety and tolerability of SU011248 in these patients.
• Correlate plasma concentration of this drug with efficacy and safety parameters in these patients.
• Correlate potential biomarkers with clinical outcomes in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to prior imatinib mesylate response or intolerance (progressive disease within 6 months of the start of therapy vs progressive disease beyond 6 months from the start of therapy vs intolerance) and baseline MPQ score based on the median value of the worst daily pain over a 7-day period before randomization (0 vs ≥ 1). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral SU011248 once daily on days 1-28.
• Arm II: Patients receive oral placebo once daily on days 1-28. In both arms, courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Patients in arm II with disease progression who meet all eligibility criteria for further treatment may crossover to arm I to receive open-label treatment with SU011248.

Quality of life is assessed on days 1 and 28 of each course and at the end of study treatment.

Patients are followed at 30 days and then every 2 months for up to 3 years.

PROJECTED ACCRUAL: A total of 357 patients (238 in arm I and 119 in arm II) will be accrued for this study within 18 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant gastrointestinal stromal tumor
• Not amenable to surgery, radiotherapy, or combined modality therapy with curative intent
• Imatinib mesylate-resistant or -intolerant disease (last dose administered ≥ 2 weeks ago)
• Failed prior imatinib mesylate therapy, defined by disease progression during treatment OR significant toxicity during treatment that precludes further treatment
• Must have radiological confirmation of disease progression
• Intolerance to prior imatinib mesylate, defined by 1 of the following:
• Life-threatening adverse events at any dose (attempt to dose reduce or rechallenge not required)
• Unacceptable toxicity induced by a moderate dose (e.g., 400 mg/day), specifically grade 3 toxicity OR grade 2 toxicity that is unacceptable to the patient (e.g., nausea) that persists despite standard countermeasures
• Unidimensionally measurable disease
• At least 1 tumor mass ≥ 20 mm by conventional radiographic techniques or MRI OR ≥ 10-16 mm by spiral CT scan
• Tumor evaluation by positron-emission tomography scan or ultrasound may not substitute for MRI or CT scan
• The following are considered non-measurable disease:
• Bone lesions
• Ascites
• Peritoneal carcinomatosis or miliary lesions
• Pleural or pericardial effusions
• Lymphangitis of the skin or lung
• Cystic lesions
• Irradiated lesions
• Disease documented by indirect evidence only (e.g., laboratory tests, such as alkaline phosphatase)

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm ^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL

Hepatic

• PT and PTT ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (5 times ULN for abnormalities due to underlying malignancy)
• Bilirubin ≤ 1.5 times ULN
• Albumin ≥ 3.0 g/dL

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• LVEF > lower limit of normal by MUGA scan
• Cardiac troponin T AND/OR cardiac troponin I ≤ ULN
• No ongoing cardiac dysrhythmias ≥ grade 2
• No atrial fibrillation of any grade
• No prolongation of the QTc interval to > 450 msec for males or > 470 msec for females
• None of the following conditions within the past 12 months:
• Myocardial infarction
• Severe or unstable angina
• Symptomatic congestive heart failure
• Cerebrovascular accident
• Transient ischemic attack
• Deep vein thrombosis
• Other thromboembolic event

Pulmonary

• No pulmonary embolism within the past 12 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 30 days after study participation
• Amylase and lipase ≤ 1.0 times ULN
• Adrenocorticotrophic hormone (ACTH) stimulation test normal
• HIV negative
• No AIDS-related illness
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• No immunotherapy since last dose of imatinib mesylate
• No concurrent biological response modifiers
• No concurrent immunotherapy

Chemotherapy

• No chemotherapy or chemoembolization therapy since last dose of imatinib mesylate
• No concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• No prior radiotherapy to areas of measurable disease where progression has occurred in patients with imatinib mesylate-resistant disease
• No concurrent radiotherapy to the sole site of measurable disease
• Concurrent palliative radiotherapy allowed provided no measurable lesions (target lesions) are included in the irradiated field

Surgery

• More than 12 months since prior coronary/peripheral artery bypass graft
• No prior surgery or cryotherapy on areas of measurable disease where progression has occurred in patients with imatinib mesylate-resistant disease
• No concurrent surgery to the sole site of measurable disease

Other

• Recovered from all prior therapy
• No investigational anticancer agent since last dose of imatinib mesylate
• No concurrent participation in another clinical trial
• No other concurrent anticancer therapy
• No other concurrent investigational drugs

California
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-7059,  United States; Recruiting
New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021-6007,  United States; Recruiting

Study chairs or principal investigators

Robert Maki, MD, PhD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   
David R. D'Adamo, MD, PhD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   
Peter Rosen, MD,  Principal Investigator,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000370830; MSKCC-04028; PFIZER-A6181004; UCLA-0311021-01; NCT00085618
Record last reviewed:  July 2004
Last Updated:  December 6, 2004
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085618
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08