Imatinib Mesylate and Bevacizumab in Treating Patients With Advanced Melanoma or Other Advanced Cancers

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of combining imatinib mesylate with bevacizumab in treating patients who have advanced melanoma or other metastatic or unresectable cancer. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Bevacizumab may stop the growth of tumor cells by stopping blood flow to the tumor. Combining imatinib mesylate with bevacizumab may kill more tumor cells

Detailed Description
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OBJECTIVES: I. Determine the tolerability, maximum tolerated dose, and lowest biologically active dose of imatinib mesylate and bevacizumab in patients with advanced melanoma or other advanced cancers. II. Determine the response rate, time to progression, and survival of patients treated with this regimen. III. Correlate clinical activity with inhibition of platelet-derived growth factor receptor beta, vascular endothelial growth factor receptor, flt-1, and markers of angiogenesis in patients treated with this regimen. IV. Correlate clinical activity with alterations in tumor perfusion as assessed by dynamic contrast-enhanced MRI and Doppler ultrasound in patients treated with this regimen. V. Correlate toxicity, clinical activity, and correlative endpoints with the steady-stage plasma concentration of imatinib mesylate in patients treated with this regimen. OUTLINE: This is a dose-escalation, open-label study. PHASE I (closed to accrual as of 8/23/04): Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of imatinib mesylate and bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients receive imatinib mesylate and bevacizumab as in phase I at the MTD.

Official Title
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A Phase I/II Study Of Imatinib Mesylate And Bevacizumab In Patients With Advanced Melanoma And Other Advanced Cancers

Conditions
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Recurrent Melanoma, Stage III Melanoma, Stage IV Melanoma, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: imatinib mesylate
* Biological: bevacizumab
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of 1 of the following: Metastatic or unresectable malignancy for which standard curative or palliative measures do not exist or are no longer effective (phase I) (phase I study closed to accrual as of 8/23/04) Melanoma (phase I and II) Measurable disease (phase II) No history or clinical evidence of CNS disease, including primary brain tumor or brain metastases Performance status - ECOG 0-1 More than 3 months WBC at least 3,000/mm^3 Absolute granulocyte count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No history of bleeding diathesis or coagulopathy Bilirubin no greater than 1.5 times upper limit of normal (ULN) AST and ALT no greater than 2.5 times ULN INR no greater than 1.5 APTT normal Creatinine no greater than 2.0 times ULN Creatinine clearance at least 40 mL/min No proteinuria Urinary protein less than 500 mg/24 hours No history of stroke No uncontrolled hypertension within the past 6 months Blood pressure less than 150/100 mm Hg on a stable antihypertensive regimen None of the following within the past 6 months: Myocardial infarction Unstable angina New York Heart Association class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Grade II or greater peripheral vascular disease Transient ischemic attack Cerebrovascular accident Other arterial thromboembolic event Other clinically significant cardiovascular disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for at least 3 months after study participation No seizures not controlled with standard medical therapy No prior allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biological composition to imatinib mesylate No serious, nonhealing wound, ulcer, or bone fracture No ongoing or active infection requiring parenteral antibiotics No significant traumatic injury within the past 28 days No psychiatric illness or social situation that would preclude study compliance No other concurrent uncontrolled illness More than 4 weeks since prior immunotherapy More than 8 weeks since prior monoclonal antibody therapy No concurrent prophylactic granulocyte or platelet colony-stimulating factors More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No more than 1 prior cytotoxic chemotherapy regimen for advanced disease (phase II) More than 4 weeks since prior radiotherapy More than 28 days since prior major surgical procedure or open biopsy Recovered from prior therapy No concurrent chronic daily aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs known to inhibit platelet function No recent or concurrent full-dose anticoagulants (except as required to maintain patency of preexisting permanent indwelling IV catheters) or thrombolytic agent No concurrent grapefruit juice No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational or commercial agents or therapies directed at the malignancy No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: imatinib mesylate<br>* Given orally<br>* Other names: Glivec;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD, Defined as One Dose Level Below the Dose That Induced DLT in at Least One Third of Patients at a Dose Level, Graded According to NCI CTCAE Version 3.0 (Phase I) |  | Up to 28 days | 
| Progression-free Survival at 16 Weeks (Phase II) | Progression Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate at 8 Weeks, Evaluated Using RECIST (Phase II) | Response and progression was evaluated in this study using Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | 8 weeks | 
| Overall Survival (Phase II) | Kaplan-Meier estimates of overall survival and 95% confidence intervals will be calculated. | Up to 6 years |