Protocol Number: 03-C-0202

Title:

A Phase I Trial of G3139 (Bcl-2 Antisense) Combined with Cytotoxic Chemotherapy in Relapsed Childhood Solid Tumors

Number:

03-C-0202

Summary:

This study will examine the use of the experimental drug G3139 (also called BCL-2 antisense, or Genasense), in combination with the anti-cancer drugs doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan), on tumors in children. G3139 blocks the action of Bcl-2, a protein produced by the body that works to prevent cell death. Some cancer cells may have elevated Bcl-2, which protects them from dying normally, and therefore makes them more resistant to cancer treatments. G3139 blocks Bcl-2 production. Lowering Bcl-2 levels with G3139 may enhance the effectiveness of anti-cancer drugs or radiation therapy. This study will determine the following:

- The highest dose of G3139 that can be given safely to children and adolescents with cancer;

- The side effects of G3139 given together with doxorubicin and cyclophosphamide;

- The pharmacology of G3139; that is, how the body handles the drug;

- The effects of G3139 on blood levels of Bcl-2;

- The level of Bcl-2 in the child's tumor and the effects of G3139 on the Bcl-2 in the tumor;

- Whether G3139, together with doxorubicin and cyclophosphamide can inhibit the growth of the cancer.

Children with solid tumors, except central nervous system tumors and lymphomas, whose cancer no longer responds to standard treatment or for whom standard therapy is not available may be eligible for this study.

Participants will receive a continuous infusion of G3139 into a vein for 7 days. On days 5 and 6, they will also receive doxorubicin, cyclophosphamide and dexrazoxane. (The latter drug protects the heart from possible damage from doxorubicin.) After 14 days off drugs, the children will begin a second 21-day treatment cycle. Treatment will continue for up to 18 cycles (about 1 year) as long as the tumor does not worsen and there are no serious side effects. The children will be hospitalized for the first 8 or 9 days of the first cycle to monitor treatment side effects. For the infusions, children will need a central venous catheter - a plastic tube placed into a major vein in the chest. This line can stay in the body and be used for the entire treatment period to give chemotherapy or other medications and to draw blood samples. The line is usually placed under local anesthesia in the radiology department or the operating room. In addition to drug treatment, patients will have the following tests and procedures:

- Examinations by a doctor at least once a week and routine blood tests twice a week during the first 21-day treatment cycle.

- Physical examinations, routine blood tests, and imaging tests (e.g., x-rays, CT scans, MRI scans) periodically throughout the course of treatment after the first cycle to evaluate the response to treatment and treatment side effects.

- Blood samples for a pharmacology study during the first treatment cycle (optional). This requires taking 12 separate blood samples of 1/2 teaspoon each-one each on days 1, 5, and 6 of the infusion; 7 samples on day 8, when the infusion ends (every 1/2-hour for 8 hours); and two samples on day 9.

- Blood samples to test white blood cells to examine the effect of G3139 on normal cells (optional). This requires taking blood samples on days 1, 5, 6, and 8 of the first treatment cycle.

- Tumor tissue tests to determine if cancer cells have increased Bcl-2 levels (optional). These tests are performed on frozen tissue samples obtained during surgery or biopsy, if these procedures are required for the child's care during the time of this study.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA

Patients' age at the time of study entry must be older than 12 months and younger than or equal to 21.

Patients must have had histologic verification of the malignancy at original diagnosis. All solid tumors are eligible with the exclusion of lymphomas and CNS tumors.

Disease must have failed standard therapy (therapies) or be a disease for which no standard therapy exists. Patient must have a disease for which there is no known curative potential.

Karnofsky greater than or equal to 50% for patients greater than 10 years.

Lansky greater than or equal to 50 for children less than or equal to 10 years of age.

Life Expectancy: Must be greater than or equal to 8 weeks.

It is recommended, but not required, for enrolled patients to have a central venous line.

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

Myelosuppressive chemotherapy: Patients must not have received within 2 weeks of entry onto this study (6 weeks if prior nitrosourea).

Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent.

XRT: - Greater than 2 weeks for local palliative XRT (small port).

- Greater than 6 months must have elapsed for other substantial BM radiation. (Cranio-spinal XRT, TBI, greater than or equal to hemi-pelvic XRT).

Stem Cell Transplant (SCT): For autologous SCT, 6 months or more must have elapsed.

Allogeneic Transplant: For allogeneic BMT, 6 months or more must have elapsed. There must be full organ recovery and no evidence of graft versus host disease at the time of enrollment.

Concomitant Therapy:

Growth Factor(s): Must not have received within 1 week of entry onto this study. Growth factors may not be administered during the course of this study.

Study Specific: Patients may not receive any other chemotherapy, radiation therapy, or immunomodulating agents, while enrolled on study.

Chronic Medications: Patients may be on chronic medications (e.g.: steroids, narcotics, anti-epileptics) at the time of enrollment. Investigators should avoid, when possible, increasing or decreasing the doses of these medications while the patient is on study.

Adequate Bone Marrow Function Defined as:

For patients with solid tumors including status post SCT (Stratum 1):

- Peripheral absolute neutrophil count (ANC) of 1000 microliters or greater.

- Platelet count of 100,000 microliters or greater (transfusion independent).

- Hemoglobin of 8.0 gm/dL or greater (may receive RBC transfusions).

For patients with tumor metastatic to bone marrow who have granulocytopenia, anemia, and/or thrombocytopenia (Stratum 2):

- Peripheral absolute neutrophil count (ANC) of 750/microliters or greater.

- Platelet count greater than or equal to 100,000/microliters (transfusion independent).

-Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions).

Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope GFR of 70 ml/min/m(2) OR

- A serum creatinine based on age as follows:

5 years of age or less - Maximum Serum Creatinine (mg/dL) of 0.8.

Between 5 and 10 years of age - Maximum Serum Creatinine (mg/dL) of 1.0.

Between 10 and 15 years of age - Maximum Serum Creatinine (mg/dL) of 1.2

Greater than 15 years of age - Maximum Serum Creatinine (mg/dL) of 1.5.

Adequate Liver Function Defined as:

- Total bilirubin less than or equal to 1.5 times the upper limit of normal for age, and

- SGPT (ALT) less than or equal to 3 times the upper limit of normal for age.

Adequate Cardiac Function Defined as:

- Shortening fraction of 28% or greater by echocardiogram, or

- Ejection fraction of 45% or greater by MUGA.

EXCLUSION CRITERIA

Total lifetime cumulative anthracycline dose must be less than or equal to 450 mg/m(2) doxorubicin or equivalent at the time of enrollment. (Conversions: 1mg/m(2) of daunorubicin &eq; 1 mg/m(2) of doxorubicin; and 1 mg/m(2) of idarubicin &eq; 3 mg/m(2) of doxorubicin.)

Any patient with known metastases of a non-CNS tumor to the brain or spinal cord will not be eligible. CNS tumors are not eligible.

Patients with lymphomas are not eligible.

Pregnancy tests must be obtained in females of childbearing potential. Pregnant patients are ineligible for this study due to the known teratogenic effects of the cytotoxic agents and the unknown human fetal or teratogenic toxicities of G3139. Lactating women must agree not to breast-feed. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.

Patients will not be eligible for enrollment until all infections are under control.

Patients with serious infections or significant pulmonary, hepatic, renal, or other end-organ dysfunction which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate G3139 or are likely to interfere with the study procedures or results will not be eligible.

Special Instructions: Currently Not Provided

Keywords:

Apoptosis

Pharmacokinetics

Doxorubicin

Cyclophosphamide

Genasense

Recruitment Keywords:

Childhood Cancer

Childhood Solid Tumor

Conditions:

Tumors

Investigational Drug(s):

G3139

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Reed JC, Stein C, Subasinghe C, Haldar S, Croce CM, Yum S, Cohen J.

Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides.

Cancer Res. 1990 Oct 15;50(20):6565-70.

Smith MR, Abubakr Y, Mohammad R, Xie T, Hamdan M, al-Katib A.

Antisense oligodeoxyribonucleotide down-regulation of bcl-2 gene expression inhibits growth of the low-grade non-Hodgkin's lymphoma cell line WSU-FSCCL.

Cancer Gene Ther. 1995 Sep;2(3):207-12.

PMID: 8528964

Reed JC. Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am. 1995 Apr;9(2):451-73. Review. PMID: 7642473

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

Warren Grant Magnuson Clinical Center (CC)
National Institutes of Health (NIH)
Bethesda, Maryland 20892. Last update: 10/23/2004