Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Closed 21 and over NCI UPCC-03903 NCI-6006, NCT00074308, 6006

Objectives

1. 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.
2. Determine the response rate, time to progression, and survival of patients treated with this regimen.
3. 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.
4. Correlate clinical activity with alterations in tumor perfusion as assessed by dynamic contrast-enhanced MRI and Doppler ultrasound in patients treated with this regimen.
5. Correlate toxicity, clinical activity, and correlative endpoints with the steady-stage plasma concentration of imatinib mesylate in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• 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

Prior/Concurrent Therapy:

Biologic therapy

• 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

Chemotherapy

• 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)

Endocrine therapy

• Not specified

Radiotherapy

• More than 4 weeks since prior radiotherapy

Surgery

• More than 28 days since prior major surgical procedure or open biopsy

Other

• 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

Patient Characteristics:

Age

• 21 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• WBC at least 3,000/mm³
• Absolute granulocyte count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• No history of bleeding diathesis or coagulopathy

Hepatic

• 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

Renal

• Creatinine no greater than 2.0 times ULN

  OR

• Creatinine clearance at least 40 mL/min
• No proteinuria

  OR

• Urinary protein less than 500 mg/24 hours

Cardiovascular

• 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

Other

• 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

Expected Enrollment

A total of 3-24 patients will be accrued for the phase I portion of this study within 6 months (phase I study closed to accrual as of 8/23/04). A total of 23-40 patients will be accrued for the phase II portion of this study within 10 months.

Outcomes

Toxicity (phase I)
Progression-free survival at 8 weeks (phase II)

Response rate at 8 weeks (phase II)
Overall survival (phase II)

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.

Trial Contact Information

Trial Lead Organizations

Abramson Cancer Center of the University of Pennsylvania

Keith Flaherty, MD, Principal investigator		Ph: 215-662-8624

Registry Information
Official Title		A Phase I/II Study Of Imatinib Mesylate And Bevacizumab In Patients With Advanced Melanoma And Other Advanced Cancers
Trial Start Date		2003-10-22
Trial Completion Date		2008-03-16 (estimated)
Registered in ClinicalTrials.gov		NCT00074308
Date Submitted to PDQ		2003-11-04
Information Last Verified		2008-11-24
NCI Grant/Contract Number		CA108158

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