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

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

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

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific; Recurrent Melanoma; Stage IV Melanoma; Stage III Melanoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: bevacizumab; Other: pharmacological study; Drug: imatinib mesylate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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.	Other: laboratory biomarker analysis; Correlative studies; Biological: bevacizumab; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: imatinib mesylate; Given orally; Other Names: Gleevec; CGP 57148; Glivec

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Keith Flaherty, Abramson Cancer Center of the University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: December 10, 2003
• First Submitted That Met QC Criteria: December 10, 2003
• First Posted (Estimate): December 11, 2003

Study Record Updates

• Last Update Posted (Actual): June 20, 2018
• Last Update Submitted That Met QC Criteria: May 23, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Imatinib Mesylate
• Other Study ID Numbers: NCI-2012-02564; 03903; CDR0000343804 (Registry Identifier: PDQ (Physician Data Query))