MDACC Study Summary NABTC07-01

Study Summary
No. NABTC07-01:.......Brain; CNS......John DeGroot......Neuro Oncology

Study Summary Title



Study Summary Number:	NABTC07-01

Study Title:	Phase I Trial of Aflibercept (VEGF Trap) with Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients with Malignant Glioma

Physician

New Patient Referral



Name:	John DeGroot	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Neuro Oncology	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-792-2883 Contact us about clinical trials

General Information



Disease Group:	Brain CNS	Supported By:	NCI/ABTC

Phase of Study:	Phase I	Return Visit:	Every 2 weeks

Treatment Agents:	Temozolomide VEGF-Trap	Home Care:	Patients will take temozolomide at home.

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	N/A


Description/ Intervention:	The goal of this clinical research study is to find the highest tolerable dose of VEGF Trap that can be given in combination with temozolomide during and after radiation therapy. The safety of this combination will also be studied.

Study Objectives / Outcomes

Primary Objectives

To define the maximum tolerated dose (MTD) of aflibercept (VEGF Trap) with radiotherapy (RT) and 6 weeks of concomitant temozolomide (TMZ) administered at 75 mg/m2/day in patients with newly-diagnosed glioblastoma (GBM).
To define the MTD of aflibercept (VEGF Trap) with adjuvant TMZ administered at 150mg/m2/day for 5 days every 28 days in patients with stable or recurrent malignant glioma (MG) after RT.
To define the MTD of aflibercept (VEGF Trap) with adjuvant TMZ administered at 100 mg/m2/day for 21 days every 28 days in patients with stable or recurrent MG after RT.
To characterize the safety profile of aflibercept (VEGF Trap) in combination with RT and concomitant TMZ in patients with newly-diagnosed GBM.
To characterize the safety profile of aflibercept (VEGF Trap) in combination with adjuvant TMZ in patients with stable or recurrent MG after RT.

Secondary Objective

To characterize the pharmacokinetic (PK) profiles of free and bound aflibercept (VEGF Trap) and TMZ in these patients.

Exploratory Objectives

To correlate tumor genotype, tumor vascularity, vascular endothelial growth factor receptor (VEGFR) and phospho-VEGFR expression, serum free and bound VEGF levels, plasma angiogenic peptides, and tumor O6-methylguanine-DNA-methyltransferase (MGMT) levels with response to therapy with aflibercept (VEGF Trap).
To evaluate the effect of treatment with aflibercept (VEGF Trap), TMZ, and RT on neurocognitive outcomes in MG patients.

Study Status Information



Study Activation / Registration Date:	10/16/2008

IRB Review and Approval Date:	07/07/2008

Study Type:	Phase I

Recruitment Status:	Open

Projected Accrual:	54 - 90

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) Patients with histologically proven intracranial GBM or gliosarcoma (GS) will be eligible for this protocol. For Arms 2 and 3, patients with anaplastic gliomas (AGs), including anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma not otherwise specified (NOS) will also be eligible.

2) All patients must sign an informed consent indicating that they are aware of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information. Patients must be registered in the ABTC Central Operations Office (ABTC COO) database prior to treatment with study drug.

3) Patients must be >/= 18 years old. Because aflibercept (VEGF Trap) interferes with growth plate maturation in animals, this agent may be inappropriate for use in patients <18 years of age. For this reason and because no dosing or adverse event (AE) data are available on the use of aflibercept (VEGF Trap) in children, patients <18 years of age are excluded from this study but may be eligible for future pediatric single-agent trials, if applicable.

4) A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required. The same type of scan, i.e., MRI or CT, must be used throughout the period of protocol treatment for tumor measurement. The use of MRI rather than CT is preferred.

5) Patients must have a life expectancy of > 12 weeks.

6) Patients must have a Karnofsky performance status of >/= 60.

7) Patients must have adequate bone marrow function (WBC > 3,000/�l, ANC > 1,500/mm^3, platelet count of > 100,000/mm^3, and hemoglobin > 10 gm/dl), adequate liver function (SGOT, SPGT and bilirubin < 2 times ULN), and adequate renal function (creatinine < 1.5 mg/dL or creatinine clearance > 60 cc/min/1.73 m^2) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

8) Urine protein:creatinine ratio (UPCR) must be </=1. Subjects with UPCR > 1 will still be eligible if 24-hour urine protein is < 500 mg.

9) Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while enrolled in the study.

10) Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 6 months after completion of aflibercept (VEGF Trap) therapy.

11) Women of childbearing potential must have a negative beta-HCG pregnancy test documented within 14 days prior to registration. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

12) Diagnosis will have been established by biopsy or resection 14-28 days prior to registration. In order to permit healing, patients should not receive Day 1 of treatment with VEGF-Trap until at least 28 days after surgery.(Arm 1 only)

13) Patients must not have had prior cranial RT. (Arm 1 only)

14) Patients must have a plan to begin partial brain RT on the same day as the first dose of TMZ. The first aflibercept (VEGF Trap) infusion will be scheduled for 2 weeks after the start of RT and TMZ. (Arm 1 only)

15) Patients must not have received prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors. (Arm 1 only)

16) Patients with AG, including AA, AO, AMO, or malignant astrocytoma NOS will be eligible for this protocol, in addition to patients with GBM and GS. (Arm 2 & 3 only)

17) Patients may have stable or recurrent disease. (Arm 2 & 3 only)

18) Patients must have an interval of 21 days or more from the completion of RT to study entry. (Arm 2 & 3 only)

19) Patients must not have received prior treatment for brain tumors, with the following exceptions: Concurrent RT and TMZ; 2 or fewer 28-day cycles of adjuvant TMZ. (Arm 2 & 3 only)

20) Patients must have recovered from the toxic effects of prior therapy: at least 23 days from prior treatment with TMZ. ( Arm 2 & 3 only)

Exclusion Criteria:

1) Patients must not have received prior Gliadel wafers.

2) Patients must not have received any investigational agents within 28 days prior to commencing study treatment.

3) Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.

4) Patients with known hypersensitivity to CHO cell products or other recombinant human antibodies, and patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to other agents used in the study. A history of hypersensitivity to a recombinant protein that occurs during or immediately after infusion might include symptoms such as: dizziness, faintness, diaphoresis, pruritus, shortness of breath; GI symptoms including nausea, vomiting, diarrhea, and abdominal cramping; rash including hives or urticaria.

5) Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.

6) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.

7) Serious or non-healing wound, ulcer, or bone fracture.

8) Patients who have a pre-operative MRI that demonstrates significant intratumoral or peritumoral hemorrhage or have a post-operative MRI that demonstrates a large amount of peri-operative parenchymal hemorrhage are not eligible. Patients may have postoperative intracavitary blood.

9) History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess gastrointestinal bleeding or diverticulitis within 6 months of treatment.

10) Patients with the following invasive procedures: a. Major surgical procedure, open biopsy or significant traumatic injury < 28 days prior to Day 1 therapy. b. Anticipation of need for major surgical procedures during the course of the study. c. Core biopsy within 7 days prior to Day 1 therapy.

11) Patients must not be pregnant/breastfeeding and must agree to practice adequate contraception. Breastfeeding should be discontinued if the mother is treated with aflibercept (VEGF Trap). Patients must not be pregnant because animal studies show that compounds with a similar mechanism of action are teratogenic; data on the teratogenicity of aflibercept (VEGF Trap) is not yet available.

12) Patients with clinically significant cardiovascular disease: a. History of ischemic or hemorrhagic stroke within past 6 months b. Uncontrolled hypertension, defined as blood pressure >140/90 mm Hg or systolic BP >180 mm Hg if diastolic blood pressure <90 mm Hg, on at least 2 repeated determinations on separate days within past 3 months c. Myocardial infarction, CABG or unstable angina within past 6 months

13) ( 12. continued) d. New York Heart Association grade III or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris within past 6 months e. Clinically significant peripheral vascular disease within past 6 months f. Pulmonary embolism, DVT, or other thromboembolic event within past 6 months.

14) Evidence of bleeding diathesis or coagulopathy or INR >1.5.

15) HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with aflibercept (VEGF Trap). Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

16) Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism.

17) Patients must not have received prior therapy with aflibercept (VEGF Trap) for any indication.

18) Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial.

19) Patients will not be excluded based on anticonvulsant use.

20) Patients on full-dose anticoagulants (e.g. warfarin, low molecular-weight heparin) are not eligible. Prophylactic doses are permitted.

Links

Registration Number: NCT00650923
Study Information on Clinical Trials Registry (clinicaltrials.gov)