http://www.clinicaltrials.gov/show/NCT00061191

hase I Trial of G3139 Plus Chemotherapy to Treat Relapsed Childhood Tumors

This study is currently recruiting patients.
Sponsored by:     National Cancer Institute (NCI)
Information provided by:     Warren G Magnuson Clinical Center (CC)

Purpose

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.
Condition     Treatment or Intervention     Phase
Tumors     Drug: G3139    Phase I

MedlinePlus related topics:  Cancer;   Cancer Alternative Therapy

Study Type: Interventional
Study Design: Treatment, Safety

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

Further Study Details:

Expected Total Enrollment:  6

Study start: May 19, 2003

Chemotherapy-induced apoptosis is regulated by the expression of the Bcl-2 family of proteins. Overexpression of Bcl-2 in tumors has been associated with poor clinical response to therapy or shorter survival in patients. Dysregulation of Bcl-2 expression has been described in leukemia, lymphoma, and solid tumors, including prostate carcinoma, melanoma, and neuroblastoma. Bcl-2 overexpression has been shown in pediatric tumor cell lines, including Ewing's sarcoma, Wilms' tumor, and synovial cell sarcoma.

G3139 (Bcl-2 antisense, GenasenseTM) is an 18-base-pair phosphorothioate oligonucleotide (5'-TCTCCCAGCGTGCGCCAT-3') designed to bind the first six codons of human Bcl-2 mRNA. Down regulation of Bcl-2 in tumor cells by G3139 (Bcl-2 antisense, GenasenseTM) has increased chemotherapy-induced apoptosis in vitro and in human tumor xenograft models. G3139 (Bcl-2 antisense, GenasenseTM) alone and in combination with chemotherapy has completed Phase I and Phase II testing in adults. Dose-limiting toxicities have been thrombocytopenia, fever, hypotension, and fatigue. Target plasma G3139 (Bcl-2 antisense, GenasenseTM) concentrations have been achieved with continuous subcutaneous or intravenous infusions of greater than or equal to 5 mg/kg/day. A 40% decrease in tumor Bcl-2 was observed in adults with lymphoma treated with 1.7 mg/kg/day of G3139 (Bcl-2 antisense, GenasenseTM) in combination with dacarbazine.

In this Phase I trial of G3139 (Bcl-2 antisense, GenasenseTM) in pediatric patients with relapsed solid tumors, G3139 (Bcl-2 antisense, GenasenseTM) will be administered as a continuous infusion for seven days. Doxorubicin and cyclophosphamide will be administered on days 5 and 6 of each cycle. Dexrazoxane cardioprotectant will be administered prior to each dose of doxorubicin. Filgrastim (G-CSF) will be administered daily beginning on day 8 and continuing until the post nadir ANC is greater than 5000/mm(3). If the patient does not experience dose-limiting toxicity or progressive disease, cycles can be repeated every 21 days for a maximum of 18 cycles. Lifetime cumulative anthracycline dose will not exceed 750 mg/m2 on this trial. Three dose levels of G3139 (Bcl-2 antisense, GenasenseTM) will be studied. The spectrum of toxicity and maximum tolerated dose of G3139 (Bcl-2 antisense, GenasenseTM) in combination with doxorubicin and cyclophosphamide will be defined. The pharmacokinetics of G3139 (Bcl-2 antisense, GenasenseTM) in the pediatric population will be studied, and the biological activity of G3139 (Bcl-2 antisense, GenasenseTM) will be evaluated by studying Bcl-2 protein expression in peripheral blood mononuclear cells and, when available, tumor specimens.

Eligibility

Genders Eligible for Study:  Both

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.

Location and Contact Information

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov
TTY  1-866-411-1010

More Information

Detailed Web Page

Publications

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.

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.

Study ID Numbers:  030202; 03-C-0202
Record last reviewed:  April 21, 2004
Last Updated:  April 21, 2004
Record first received:  May 21, 2003
ClinicalTrials.gov Identifier:  NCT00061191
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-19

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2004-C-0001.html

NIH Clinical Research Studies

Protocol Number: 04-C-0001
Active Accrual, Protocols Recruiting New Patients

Title:
Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing's Sarcoma, Osteosarcoma, and Unresectable Sarcoma

Number:
04-C-0001

Summary:
This study will examine the side effects and possible benefits of the anti-cancer drugs gemcitabine (Gemzar ) and docetaxel (Taxere ) in patients with bone or soft tissue cancer (sarcoma); determine how the body absorbs and eliminates the drugs; and perform genetic studies on the tumor and try to grow the tumor in the laboratory or in animals.

Patients 10 years of age and older with recurrent osteosarcoma, Ewing's sarcoma, and inoperable or recurrent inoperable chondrosarcoma may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, and CT or MRI scans, or both.

Participants receive gemcitabine and docetaxel in 21-day cycles as follows:

- Gemcitabine is given as a 90-minute infusion on days 1 and 8 of each cycle through a catheter (thin plastic tube) placed in an arm vein.

- Docetaxel is given as a 60-minute infusion following the gemcitabine infusion on day 8 of each cycle.

- Filgrastim is given as an injection under the skin either: 1) daily, beginning the day after each docetaxel infusion and continuing until the bone marrow is recovered from chemotherapy (usually 7 to 10 days); or 2) in a long-acting form on the day after the docetaxel infusion. Filgrastim boosts production of blood cells that have been depleted as a result of chemotherapy. Patients are taught to self-administer the injections.

Treatment will continue for a total of 14 cycles or until the patient's tumor gets larger, side effects are unacceptable, the patient decides to stop treatment, or further treatment would not be in the patient's best interest.

In addition to taking the study drugs, patients undergo the following tests and procedures:

- Placement of temporary (IV line) or semi-permanent (Hickman, Broviac, or Port-a-Cath) catheters for giving chemotherapy and other drugs and for drawing blood samples.

- History and physical examination before each dose of chemotherapy to assess health status and drug side effects.

- Blood tests to measure blood counts, liver and kidney function, and electrolyte levels.

- Blood sampling for pharmacology studies on days 1 and 8 of treatment cycle 1 (6 samples on day 1; 11 samples on day 8) to study how the body handles gemcitabine and docetaxel.

- Imaging studies that may include x-rays, CT scans, MRI scans, nuclear medicine scans, and bone scans

- Tumor genetic studies. Tumor samples from patients who require surgery to remove a tumor will be grown in a test tube or in animals to define what genes are expressed (turned on) in the tumor.

At the end of chemotherapy, patients will be monitored for treatment side effects and disease progress, initially every 3 months and then every 6 months until 2 years from finishing treatment

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:

    A. Patients with recurrent high grade osteosarcoma, Ewing's sarcoma, unresectable or locally recurrent unresectable chondrosarcoma. Histological diagnosis from initial diagnosis is acceptable for local recurrences, however, biopsy confirmation is strongly recommended. For isolated pulmonary recurrences, biopsy is required. Histological diagnosis will be determined at the treating institution, central review is not required. For patients with chondrosarcoma, determination of unresectable will be made by the treating oncologist and surgeon at the treating institution.

    B. Age greater than or equal to 4 years.

    C. Measurable Disease-defined as lesions that can be measured in at least one dimension by medical imaging techniques. Ascites, pleural effusions, and bone marrow disease will not be considered measurable disease.

    D. Performance Status: Patients greater than or equal to 18 years must have an ECOG performance status of less than or equal to 2. Patients less than 18 years and greater than 10 years must have a Karnofsky Score greater than or equal to 50 percent. Patients less than or equal to 10 years must have Lansky score greater than or equal to 50.

    E. Osteosarcoma and Ewing's sarcoma: Patients must have progressed after standard therapy, and may have received no more than 2 additional salvage regimens. Chondrosarcoma: must be unresectable or locally recurrent and unable to be completely resected.

    F. Patients must have recovered (defined as toxicity less than grade 2) from toxic effects of all prior therapy before entering onto study.

    G. A treatment free interval of at least 2 weeks since the last dose of myelosuppressive therapy is required.

    H. At least 6 month interval since last dose of myeloablative therapy or total body irradiation is required.

    I. A minimum of 6 weeks since local radiation and 4 months from extensive radiation (greater than 50% of pelvis or cranial spinal radiation) is required.

    J. Patients who received filgrastim on a previous cycle of chemotherapy must be off filgrastim for at least 72 hours prior to entry onto study.

    K. Adequate bone marrow function with an ANC greater than or equal to 1500/mm3, platelet count greater than or equal to 100,000 mm3 (transfusion independent) and hemoglobin greater than or equal to 8.0 g/dl (transfusions permitted).

    L. Adequate renal function with serum normal age adjusted serum creatinine (see table below) or creatinine clearance or radioisotope GFR greater than 70 ml/min/1.73 m2. For patients over 18 years of age, creatinine must be less than or equal to upper limit of normal range.

    Less than 5 years of age with Maximum Serum Creatinine (mg/dl) of 0.8.

    Greater than or equal to 5 and less than or equal to 10 years of age with Maximum Serum Creatinine (mg/dl) of 1.0.

    Greater than 10 and less than or equal to 15 years of age with Maximum Serum Creatinine (mg/dl) of 1.2

    Greater than 15 and less than or equal to 18 years of age with Maximum Serum Creatinine (mg/dl) of 1.5

    M. Patients must have adequate liver function, defined as bilirubin within normal limits, SGPT (ALT) less than or equal to 2.5 x the upper limit of normal. For patients with documented Gilbert Syndrome, total bilirubin greater than ULN may be acceptable if the Principal Investigator in consultation with Medical Affairs, Aventis Oncology approves a special exemption for treatment on this protocol.

    N. Neuropathy (Sensory or Motor) due to prior chemotherapy, if present, must be less than or equal to grade 1. Neuropathy (Sensory or Motor) due to prior surgery or tumor involvement must be less than or equal to grade 2 and stable or improving.

    O. Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which may include abstinence, while being treated on this study and for 3 months afterwards.

    P. Informed consent: All patients or their legal guardians (if the patient is less than 18 years of age) must sign a document of informed consent indicating their awareness of the investigational nature and the risks of the study. When appropriate the patient will be included in all discussions in order to obtain assent.

    EXCLUSION CRITERIA:

    A. Pregnant or breast feeding females

    B. Prior treatment with gemcitabine or taxanes

    C. Active or uncontrolled infection

    D. History of known hypersensitivity reaction to docetaxel or other agents formulated in polysorbate 80.

    E. Recipient of prior allogeneic transplants.

Special Instructions: Currently Not Provided

Keywords:
    Antineoplastic Drugs
    Refractory Sarcomas
    Ewing Sarcoma
    Osteosarcoma
    Chondrosarcoma

Recruitment Keyword(s):
    None

Condition(s):
    Osteosarcoma
    Sarcoma, Ewing's
    Chondrosarcoma

Investigational Drug(s):
    None

Investigational Device(s):
    None

Intervention(s):
    None

Supporting Site:
    N/A

Contact(s):
    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

Citation(s):
    Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR.

    Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002 Jun 15;20(12):2824-31.

    Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9.

    Rischin D, Boyer M, Smith J, Millward M, Michael M, Bishop J, Zalcberg J, Davison J, Emmett E, McClure B. A phase I trial of docetaxel and gemcitabine in patients with advanced cancer.

    Ann Oncol. 2000 Apr;11(4):421-6.

Active Accrual, Protocols Recruiting New Patients

If you have:

    * 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.


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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10847460

Ann Oncol. 2000 Apr;11(4):421-6.     Related Articles, Links

    A phase I trial of docetaxel and gemcitabine in patients with advanced cancer.

    Rischin D, Boyer M, Smith J, Millward M, Michael M, Bishop J, Zalcberg J, Davison J, Emmett E, McClure B.

    Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Australia. drischin@petermac.unimelb.edu.au

    BACKGROUND: Docetaxel and gemcitabine are active in a broad range of malignancies. The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel and gemcitabine. PATIENTS AND METHODS: Patients with advanced cancer, WHO performance status 0-2, who had received up to one prior chemotherapy regimen were treated with gemcitabine on days 1 and 8 and docetaxel on day 8 repeated every 21 days. Prophylactic ciprofloxacin was commenced on day 11 of each cycle and continued until the neutrophil count reached 1.0 x 10(9)/l. G-CSF was not administered. Dose levels studied were docetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200 and 100/1200 mg/m2. RESULTS: Thirty-nine patients were entered and all were assessable for toxicity. The highest administered dose level was 100 mg/m2 docetaxel and 1200 mg/m2 gemcitabine with dose limiting toxicities of febrile neutropenia, grade 4 neutropenia > or = 7 days, grade 4 thrombocytopenia, grade 3 stomatitis and/or grade 3 fatigue in three out of six patients. Treatment was well tolerated (40 cycles) in the 10 patients treated at the recommended dose level (85/1200) with only a single episode of febrile neutropenia and grade 3 or 4 non-hematologic toxicity was infrequent. There was no significant pulmonary toxicity. Responses were seen in a range of malignancies including non-small-cell lung cancer. CONCLUSIONS: The recommended dose level of 85 mg/m2 docetaxel and 1200 mg/m2 gemcitabine has a favourable toxicity profile and is suitable for further investigation in phase II trials. This non-platinum containing regimen warrants further investigation as a potential alternative to platinum containing regimens in non-small-cell lung cancer and other malignancies.

    Publication Types:

        * Clinical Trial
        * Clinical Trial, Phase I


    PMID: 10847460 [PubMed - indexed for MEDLINE]