Clinical trial NCT00083213: Intravenous VEGF Trap in Treating Patients With Relapsed or Refractory Advanced Solid Tumors or Non-Hodgkin's Lymphoma
Official title: An Open Label, Sequential Cohort Dose-Escalation Safety, Tolerability and Pharmacokinetic Study of VEGF Trap Administered Intravenously in Patients With Advanced Solid Tumors or Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Keywords: recurrent grade 1 follicular lymphoma
stage IV grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
stage IV grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
stage IV grade 3 follicular lymphoma
recurrent adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
recurrent adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
recurrent adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
recurrent mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
unspecified adult solid tumor, protocol specific
recurrent adult soft tissue sarcoma
recurrent adult primary liver cancer
advanced adult primary liver cancer
recurrent cervical cancer
stage IVA cervical cancer
stage IVB cervical cancer
fallopian tube cancer
ovarian sarcoma
recurrent ovarian epithelial cancer
stage IV ovarian epithelial cancer
recurrent endometrial carcinoma
stage IV endometrial carcinoma
recurrent uterine sarcoma
stage IV uterine sarcoma
recurrent ovarian germ cell tumor
stage IV ovarian germ cell tumor
ovarian stromal cancer
recurrent vaginal cancer
stage IVA vaginal cancer
stage IVB vaginal cancer
recurrent prostate cancer
stage IV prostate cancer
recurrent penile cancer
stage IV penile cancer
recurrent malignant testicular germ cell tumor
stage III malignant testicular germ cell tumor
recurrent bladder cancer
stage IV bladder cancer
recurrent vulvar cancer
stage IVB vulvar cancer
distal urethral cancer
proximal urethral cancer
recurrent urethral cancer
urethral cancer associated with invasive bladder cancer
primary peritoneal cavity cancer
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
stage IV marginal zone lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
stage IV adult soft tissue sarcoma
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-05-19
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: VEGF Trap may stop the growth of solid tumors or non-Hodgkin's lymphoma by stopping blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of intravenous VEGF Trap in treating patients with relapsed or refractory advanced solid tumors or non-Hodgkin's lymphoma.

Detailed description: OBJECTIVES:

Primary

* Determine the safety and tolerability of intravenous VEGF Trap in patients with relapsed or refractory advanced solid tumors or non-Hodgkin's lymphoma.

Secondary

* Determine the maximum tolerated intravenous dose of this drug in these patients.
* Determine the pharmacokinetics of this drug in these patients.
* Determine the ability of this drug to bind circulating vascular endothelial growth factor in these patients.
* Determine, preliminarily, the ability of this drug to alter tumor blood flow and tumor vascular permeability in these patients.
* Determine whether antibodies to this drug develop in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive VEGF Trap IV over 1 hour on days 1 and 15 for a total of 2 doses.

Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 6 patients are treated at that dose level.

In the absence of dose-limiting toxicity, patients with stable disease or partial or complete remission may continue to receive VEGF Trap on a separate extension protocol.

Patients are followed at weeks 1, 3, and 7 and then at 3 months.

PROJECTED ACCRUAL: A maximum of 25 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed diagnosis of one of the following:

  * Non-Hodgkin's lymphoma
  * Primary or metastatic solid tumor located, by radiography, in at least one of the following sites:

    * Liver
    * Soft tissue
    * Pelvis
    * Other site that is suitable for delayed contrast-enhanced MRI (e.g., peripheral lung field)
* Relapsed or refractory (including unresectable) disease

  * Patients with solid tumors must have failed all curative chemotherapeutic regimens
  * Patients with non-Hodgkin's lymphoma must be refractory to at least 2 standard chemotherapeutic regimens and rituximab
* Not amenable to available conventional therapies AND no standard therapy exists
* Measurable disease
* No prior or concurrent CNS metastases (brain or leptomeningeal)
* No primary intracranial tumor by MRI or CT scan
* No histologically confirmed squamous cell carcinoma of the lung

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-2

Life expectancy

* Not specified

Hematopoietic

* WBC ≥ 3,500/mm\^3
* Absolute neutrophil count ≥ 1,500/mm\^3
* Hemoglobin ≥ 9.0 g/dL
* Platelet count ≥ 100,000/mm\^3
* No severe or uncontrolled hematologic condition

Hepatic

* Bilirubin ≤1.5 times upper limit of normal (ULN)
* AST and ALT ≤ 2.5 times ULN
* PT and PTT normal
* INR normal
* Hepatitis B surface antigen negative
* Hepatitis C antibody negative

Renal

* Creatinine ≤ ULN
* Urine protein/creatinine ratio ≤ 1
* No severe or uncontrolled renal condition

Cardiovascular

* No clinically significant acute electrocardiographic abnormalities
* LVEF normal by echocardiogram or MUGA within the past 12 months if there was prior exposure to anthracyclines
* No untreated or uncontrolled hypertension

  * No blood pressure \> 150/100 mm Hg (despite treatment)
* No isolated systolic hypertension (i.e., systolic blood pressure \> 180 mm Hg on at least 2 determinations \[on separate days\] within the past 3 months)
* No New York Heart Association class II - IV heart disease
* No active coronary artery disease requiring acute medical management
* No angina requiring acute medical management
* No congestive heart failure requiring acute medical management
* No ventricular arrhythmia requiring acute medical management
* No stroke or transient ischemic event within the past 6 months
* No prior or concurrent peripheral vascular disease

  * No angiographically or ultrasonographically documented arterial or venous occlusive event
  * No symptomatic claudication
* No symptomatic orthostatic hypotension
* No other severe or uncontrolled cardiovascular condition

Pulmonary

* No severe or uncontrolled pulmonary condition
* No pulmonary embolism within the past 6 months

Immunologic

* HIV negative
* No severe or uncontrolled immunologic condition
* No active current infection requiring antibiotics
* No prior hypersensitivity reaction to any recombinant proteins, including VEGF Trap

Other

* No severe or uncontrolled gastrointestinal or musculoskeletal condition
* No psychiatric condition or adverse social circumstance that would preclude study participation
* No other condition that would preclude study participation
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective double-barrier contraception during and for 3 months after study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

* See Disease Characteristics
* No prior participation in a VEGF Trap, interleukin-1 Trap, or interleukin-4/13 Trap clinical trial
* At least 3 weeks since prior immunotherapy and recovered
* No concurrent epoetin alfa, filgrastim (G-CSF), or sargramostim (GM-CSF)

Chemotherapy

* See Disease Characteristics
* At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy

* No concurrent adrenal corticosteroids except low-dose replacement therapy
* No concurrent systemic hormonal contraceptive agents

Radiotherapy

* At least 3 weeks since prior radiotherapy and recovered

Surgery

* At least 3 weeks since prior major or laparoscopic surgery and recovered
* More than 6 months since prior surgical procedure for correction or prophylaxis of peripheral vascular insufficiency or cerebral ischemic events

Other

* More than 30 days since prior investigational drugs
* No concurrent anticoagulant or antiplatelet drugs (e.g., warfarin, heparin, or aspirin) other than low-dose (1 mg) warfarin for maintaining patency of venous access devices
* No concurrent non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 (COX-2) inhibitors
* No other concurrent anticancer investigational agents
* No other concurrent anticancer therapy

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan - Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: William P. Tew, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010 Jan 10;28(2):207-14. doi: 10.1200/JCO.2009.22.9237. Epub 2009 Nov 30.
citation: Wang-Gillam A, Tew WP, Rothenberg ML, Dupont J, Cooper W, Sternas L, Buzenet G, Sosman JA, Spriggs DR, Lockhart AC. A phase I study of subcutaneously administered aflibercept (VEGF trap) in a new formulation in patients with advanced solid tumors. Invest New Drugs. 2012 Oct;30(5):1958-61. doi: 10.1007/s10637-011-9753-y. Epub 2011 Oct 15.