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

PURPOSE: Phase I trial to study the effectiveness of intravenous VEGF Trap in treating patients who have relapsed or refractory advanced solid tumors or non-Hodgkin's lymphoma.

Condition	Treatment or Intervention	Phase
Cancer	Drug: VEGF Trap  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: growth factor antagonist therapy  Procedure: targeted fusion protein therapy	Phase I

Further Study Details: 

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.

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

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

New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting

Study chairs or principal investigators

Jakob Dupont, MD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers  CDR0000360856;  MSKCC-03137; REGENERON-VGFT-ST-0202
Record last reviewed  April 2004
ClinicalTrials.gov Identifier  NCT00083213
ClinicalTrials.gov processed this record on 2004-08-31

This study will investigate the combined use of temozolomide (TMZ) and O6-benzylguanine (O6BG) for treating cancer. TMZ is an anti-cancer drug approved to treat certain brain tumors in adults. TMZ loses its effectiveness over time because a protein called AGT makes the tumor resistant to the drug. O6BG inactivates AGT and, therefore, may prolong TMZ's effectiveness.

Children and young adults under age 21 with various types of cancer (brain, liver, bone and others) for whom standard treatment was not successful may be eligible for this study. Participants will receive TMZ capsules by mouth and an intravenous (through a vein) infusion of O6BG 5 days in a row every month for up to 12 months. Blood will be drawn on days 3 and 5 of the first course of treatment to measure AGT levels. Also on day 5 of the first treatment course, 16 blood samples (1 teaspoon each) will be taken over a 48-hour period to study how the two drugs work in the body. If possible, a heparin lock will be placed in the vein to avoid having multiple needle sticks. A tissue biopsy (removal of a small piece of tumor) may be taken if the tumor is close to the skin and not near a vital organ. The sample will be used to evaluate the effect of O6BG on AGT levels.

A doctor will see the patients weekly. Routine blood tests will be done twice a week. MRI or CT scans will be done before treatment begins and every 1 to 2 months during treatment to measure the size of the tumor. Patients with a brain tumor will also have a magnetic resonance spectroscopic test (similar to MRI) every 1 to 2 months to measure chemicals in the tumor. Patients will complete a Quality of Life Assessment questionnaire about the effect of the illness on the patient's behavior and everyday activities.

Potential benefits to patients in this study are tumor shrinkage and symptom improvement, such as pain relief. Because this is an experimental therapy, however, the likelihood of tumor shrinkage cannot be predicted.

Condition	Treatment or Intervention	Phase
Brain Neoplasm Embryonal Neoplasm Ewing's Sarcoma Germ Cell Neoplasm Liver Neoplasm Nephroblastoma Osteosarcoma Rhabdomyosarcoma Sarcoma	Drug: O(6) Benzylguanine	Phase I

Further Study Details: 

Temozolomide is a prodrug that spontaneously degrades to the active metabolite, MTIC, under physiologic conditions. MTIC is an alkylating agent that preferentially methylates the O(6)-position on guanine. The DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase (AGT) removes the methyl group from the O(6)-position of guanine, repairing the lesion produced by MTIC. AGT is expressed in many tumors and has been associated with tumor resistance and poor clinical response to methylating agents, such as the nitrosoureas and temozolomide. O(6)-Benzylguanine (O(6)BG) is an AGT substrate that permanently inactivates AGT. O(6)BG depletes tumor AGT, blocks repair of the lesion produced by temozolomide and thereby enhances its cytotoxicity.

A pediatric phase I trial using the combination of temozolomide and O(6)BG on a daily times 5 days schedule every 4 weeks will be conducted in children with refractory solid tumors and brain tumors to determine the maximum tolerated dose (MTD) of temozolomide when given in combination with a biologically active dose of O(6)BG. Pharmacokinetic studies of O(6)BG and temozolomide will also be performed.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
1. Age: Patients must be less than or equal to 21 years of age.
2. Histological diagnosis: Patients must have a histologically confirmed solid tumor, which may include, but is not limited to, rhabdomyosarcoma and other soft tissue sarcomas, Ewing's family tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors or primary brain tumor. For patients with brainstem gliomas or optic gliomas, the requirement for histological confirmation may be waived.
3. Prior therapy:
3.1 The patient's tumor must be refractory to standard treatment. Patients must have no known potentially curative therapy available to them. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities.
3.2 Patients must have had their last dose of limited-field radiation therapy at least four weeks prior to study entry. Patients who have received extensive prior radiation therapy (craniospinal radiation, total body radiation, or radiation to more than half of the pelvis) must be at least 4 months post-completion of radiation therapy. Patients must have received their last dose of chemotherapy at least three weeks prior to study entry (four weeks for nitrosoureas), and their last investigational therapy at least four weeks prior to study entry.
3.3 Patients must have recovered from the toxic effects of all prior therapy prior to entry onto this trial.
3.4 Patients with brain tumors who are receiving corticosteroids for the control of tumor-associated edema must be on a stable or decreasing dose for at least 1 week prior to study enrollment.
3.5 Patients who have previously received temozolomide are eligible if they have not received the drug in the past 3 months and they did not experience severe toxicities during their previous course of therapy with temozolomide. Severe toxicity is defined as any grade 4 non-hematologic toxicity or failure to recover (to grade less than or equal to 1 level) from any non-hematologic or hematologic toxicity within six weeks of receiving temozolomide. Patients who received temozolomide in combination with other agents that were designed to inactivate AGT are not eligible for this trial.
3.6 Patients should be off colony stimulating factors such as G-CSF, GM-CSF, and Epo for at least one week prior to study entry.
4. Measurable/Evaluable disease: Patients must have measurable or evaluable disease. There must be evidence of progressive disease on prior chemotherapy or radiation therapy or persistent disease after surgery.
5. Performance status: Patients should have an ECOG performance status of 0, 1, or 2 and a life expectancy of at least eight (8) weeks. Patients who are unable to walk because of paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose of calculating the performance score.
6. Hematological function: Patients must have adequate bone marrow function defined as a peripheral absolute granulocyte count of greater than 1500/mm(3), hemoglobin greater than 8 gm/dL, and platelet count greater than 100,000/mm(3).
7. Hepatic function: Patients must have adequate liver function, defined as bilirubin within normal limits and SGPT less than 2 times the upper limit of normal.
8. Renal function: Patients must have an age-adjusted normal serum creatinine or a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).
9. Patients must be able to swallow capsules.
10. Informed consent: All patients or their legal guardians (if the patient is less than 18 years old) must sign a document of informed consent indicating their understanding of the investigational nature and their risks of this study before any protocol related studies are performed. When appropriate, pediatric patients will be included in all discussions in order to obtain verbal assent.
11. Durable Power of Attorney (DPA): Assignment of a DPA to a family member or guardian should be offered to all patients 18 to 21 years of age who have a brain tumor.
EXCLUSION CRITERIA:
1. Patients currently receiving other investigational chemotherapeutic agents.
2. Patients with a history of myeloablative therapy requiring bone marrow or stem cell transplantation within the previous 4 months.
3. Pregnant or breast-feeding females are excluded.
4. Clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate this therapy or are likely to interfere with the study procedures or results.
5. Patients with a history of hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol (PEG).

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers  000105;  00-C-0105
Study Start Date April 4, 2000
Record last reviewed  March 1, 2004
Last Updated  March 1, 2004
ClinicalTrials.gov Identifier  NCT00005019
ClinicalTrials.gov processed this record on 2004-08-31