This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT This is a multicenter, open-label, two-part, safety and efficacy study, with exploratory pharmacodynamics, of IV temsirolimus given as a 60-minute infusion once a week to children with relapsed/refractory solid tumors. For both Part 1 (Phase 1)and Part 2 (Phase 2&), a cycle is defined as 3 weeks of once weekly dosing (approximately 21 days). Subjects age 1 to 21 years will be eligible to enroll in the study. We are only participating in Part 2. Please note that Part 1 of the study is complete and that this application pertains to Part 2 of the study.Part 2 will verify the safety of the selected dose, 75 mg/m2, and obtain preliminary antitumor activity of temsirolimus in three groups of children with refractory or relapsed pediatric solid tumors. Subjects with the following tumor types will be enrolled: neuroblastoma, rhabdomyosarcoma, and highgrade gliomas. The study design of Part 2 is based on the Simon Two-Stage Design. For each group, the sample size for the first stage is at least 12 evaluable subjects, and the sample size for the second stage is at least 13 evaluable subjects. A total of approximately 25 subjects will be enrolled in each of the three groups.HYPOTHESIS We aim to verify the safety of the selected dose of 75 mg/m2, and obtain preliminary information on the antitumor activity of temsirolimus in three groups of pediatric subjects with refractory or relapsed pediatric solid tumors. Approximately 25 subjects will be enrolled in each tumor group.In addition, Part 2 will explore the effects of temsirolimus on proteins in the mTOR signaling pathway in bone marrow (if available). Measurement of changes in the phosphorylation levels of proteins in the mTOR pathway including, but not limited to S6RP, 4EBP1, eIF4E, and AKT in bone marrow biopsies following treatment with temsirolimus will reflect the level of inhibition of temsirolimus at the target as well as provide evidence of biologically active doses.
SPECIFIC AIMS Primary Aims1. To obtain preliminary information on the anti-tumor activity of IV temsirolimus in children with relapsed/refractory neuroblastoma, high-grade glioma, and rhabdomyosarcoma. Anti-tumor activity will be assessed by determining the percentage of subjects exhibiting objective response (CR + PR) within 12 weeks.Secondary Aims1. To verify the safety of the selected dose. 2. To evaluate the percentage of subjects exhibiting freedom from progression (disease stabilization defined as CR+VGPR+MR+PR+SD for subjects with neuroblastoma and CR+PR+SD for all other subjects)at 3 months. 3. To determine the multiple-dose pharmacokinetics of temsirolimus in children with once-weekly IV treatment. 4. To determine the effects of IV temsirolimus on changes in the mTOR signaling pathway in the bone marrow.BACKGROUND AND SIGNIFICANCE Approximately 12,400 children and adolescents younger than 20 years old are diagnosed with some type of cancer each year. Of these, approximately 2,300 children and adolescents die of cancer each year making cancer the most common cause of disease-related mortality for children 1 to 19 years of age. There are 12 major types of childhood cancers, and of these leukemias and brain and other central nervous system tumors (ie, gliomas and medullablastomas)account for over 50% of the new cases. The remainder of new cases included extracranial tumors such as neuroblastomas, Wilms tumors, and rhabdomyosarcomas.From 1975 through 1998,the incidence of children diagnosed with all forms of invasive cancer increased from 11.4 cases per 100,000 children to 15.2 cases per 100,000 children. Although improvements in imaging equipment and treatments have resulted in an overall decline in mortality and increased survival, approximately half of all children with malignant solid tumors will experience relapse and, of these children, less than 10% will achieve long-term survival after standard multimodal therapy.Temsirolimus (sirolimus 42-ester with 2,2-bis(hydroxymethyl)-propionic acid(an ester of sirolimus) Rapamune ), an immunosuppressive agent approved for the prophylaxis of organ rejection in subjects receiving renal transplants. Temsirolimus is being developed as a cytostatic agent to delay the time to tumor recurrence or progression or to increase survival in adult subjects with various malignancies, when used as a single agent or in combination with other anticancer agents. Similar to sirolimus, temsirolimus binds to the immunophilin FK-506-binding protein 12 (FKBP-12) and forms an intracellular complex. This temsirolimus / FKBP-12 complex blocks the activity of mammalian target of Rapamycin (mTOR), a serine/threonine kinase, and subsequently inhibits key signaling pathways, including those regulated in part by p70S6 kinase and 4EBP1. Inhibition of these proteins results in decreased translation of mRNA with a 5'terminal oligopolypyrimidine tract and CAP-dependent translation of proteins that are required for cell cycle progression, which ultimately results in a block in the G1 phase of the cell cycle. The mTOR pathway also is downstream of PI3-kinase and the proto-oncogene serine/threonine kinase AKT/PKB. In response to growth stimulation, PI3-kinase phosphorylates mTOR through the AKT pathway and also mediates phosphorylation of S6- kinase. The tumor suppressor gene PTEN (a protein and lipid phosphatase) functions as a negative regulator of PI3- kinase by dephosphorylating the second messenger, PIP3, thus resulting in the inhibition of AKT phosphorylation and consequently in the inhibition of mTOR and S6-kinase. Mutations or deletions in the PTEN gene result in the activation of PI3-kinase pathway and selective upregulation of the AKT/mTOR pathway.9-11 PTEN mutations/deletions have been associated with several human cancers.12-16 Preliminary in vitro findings in several tumor types show a correlation between PTEN loss or AKT activation and sensitivity to growth inhibition by temsirolimus. Both preclinical data and preliminary results of ongoing clinical trials in adults are providing increasing evidence of the antitumor effects of temsirolimus. In a Phase 1 study with a daily x 5 days every 2 weeks dosing schedule (3066K1-100-US), minor anti-tumor responses and/or prolonged (greater than 4 months) stable disease have been reported in several tumor types including soft tissue sarcoma, non-small cell lung cancer, thyroid cancer, cervical cancer, endometrial cancer, head and neck cancer, glioma, pleomorphic adenoma with brain metastases and renal carcinoma. With the IV temsirolimus weekly schedule (3066K1-101-EU), tumor shrinkage has been reported in patients with renal cancer, breast cancer, and neuroendocrine tumor of the lung. The planned 2-part study is designed to assess the safety and activity of IV temsirolimus in children. In some subjects the effects of temsirolimus on changes in the activity of proteins in the mTOR pathway in the bone marrow will be explored. Measurement of the change in the phosphorylation levels of S6RP following treatment with temsirolimus will reflect the level of inhibition of temsirolimus at the target as well as provide evidence of biologically active doses. Other biomarkers will be explored, including 4EBP, eIF4E, AKT and PTEN if sufficient tissue is available.Biomarkers of Temsirolimus Activity One of the objectives of Part 2 of this study is to evaluate possible correlations between clinical response to temsirolimus in subjects with neuroblastoma, high-grade gliomas, or rhabdomyosarcoma and changes in the mTOR pathway proteins. It has been demonstrated that resistance to the rapamycin family may be a result of defects or mutations in mTOR mediated down-stream effect or molecules, including S6K1 and 4E-BP1. As such, measurement of baseline levels or changes in phosphorylation status of these proteins may help identify tumors that are sensitive to temsirolimus treatment.
Showing the most recent 10 out of 459 publications
