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Sirolimus in Combination With Metronomic Therapy in Children With Recurrent and Refractory Solid Tumors: A Phase I Study

Phase 1
30 Years
Open (Enrolling)
Ewing's Sarcoma, Osteosarcoma, Astrocytoma, Atypical Teratoid/Rhabdoid Tumor, Ependymoma, Germ Cell Tumor, Glioma, Medulloblastoma, Rhabdoid Tumor, Retinoblastoma, Clear Cell Sarcoma, Renal Cell Carcinoma, Wilms Tumor, Hepatoblastoma, Neuroblastoma, Rhabdomyosarcoma

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Trial Information

Sirolimus in Combination With Metronomic Therapy in Children With Recurrent and Refractory Solid Tumors: A Phase I Study

Sirolimus, is a potent immunosuppressive drug that is approved for use in prevention against
allograft rejection following solid organ transplant. It has anti-tumor effects mainly by
blocking signals which drive cells from G1 to S phase during cell cycle through inhibition
of mTOR, thus inhibiting cell growth. Sirolimus, as well as other mTOR inhibitors, has
shown anti-tumor activity in pediatric solid tumor xenografts. Children with relapsed
and/or refractory solid tumors are in need of novel therapeutic approaches. One option for
these patients is the use of prolonged exposure to low dose antiangiogenic chemotherapy,
with agents such as etoposide and cyclophosphamide. In this phase I trial the feasibility
and optimal dosing for daily sirolimus, in combination with daily celecoxib, and low dose
etoposide alternating with cyclophosphamide, will be determined in children with relapsed
and refractory solid tumors. p70S6 kinase inhibition will be used as a surrogate for mTOR
inhibition. The potential immunosuppressive effect of sirolimus administered on this
schedule will be assessed by serial lymphocyte subsets and assessment of memory T cell

Inclusion Criteria:

- must be <=30 years of age at time of study enrollment

- histologic verification of malignancy at original diagnosis or relapsis except in
patients with intrinsic brain stem tumors, optic pathway gliomas or patients wtih
pineal tumors and evaluations of serum or CSF alpha-fetoprotein or beta-HCG

- measurable or evaluable disease

- disease state must be one for which there is no known curative therapy

- Performance level >=50%

- Patients must have fully recovered from acute toxic effects of all prior
chemotherapy, immunotherapy or radiotherapy

- no evidence of acute graft vs. host disease and >=3 months since transplant

- organ function as defined in eligibility section of protocol

Exclusion Criteria:

- patients cannot be pregnant or breast-feeding

- patients must agree to use of an effective contraceptive method

- no growth factors that support platelet or white cell number or function for at least
7 days prior to enrollment

- patients receiving corticosteroids who have not been on a stable or decreasing dose
of corticosteroid for the prior 7 days are not eligible

- patients receiving any other investigational drugs

- patients receiving any other anti-cancer drugs

- patients who have an uncontrolled infection

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD)

Outcome Description:

estimate the maximum tolerated dose (MTD) and recommended Phase II dose of sirolimus administered orally once daily for 42 days in combination with metronomic chemotherapy in children with recurrent or refractory solid tumors.

Outcome Time Frame:

2 years after treatment starts

Safety Issue:


Principal Investigator

Howard Katzenstein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Healthcare of Atlanta


United States: Institutional Review Board

Study ID:




Start Date:

April 2011

Completion Date:

April 2021

Related Keywords:

  • Ewing's Sarcoma
  • Osteosarcoma
  • Astrocytoma
  • Atypical Teratoid/Rhabdoid Tumor
  • Ependymoma
  • Germ Cell Tumor
  • Glioma
  • Medulloblastoma
  • Rhabdoid Tumor
  • Retinoblastoma
  • Clear Cell Sarcoma
  • Renal Cell Carcinoma
  • Wilms Tumor
  • Hepatoblastoma
  • Neuroblastoma
  • Rhabdomyosarcoma
  • pediatrics
  • sirolimus
  • relapse
  • Astrocytoma
  • Carcinoma
  • Carcinoma, Renal Cell
  • Ependymoma
  • Glioma
  • Medulloblastoma
  • Wilms Tumor
  • Neuroblastoma
  • Osteosarcoma
  • Retinoblastoma
  • Rhabdomyosarcoma
  • Neoplasms, Germ Cell and Embryonal
  • Hepatoblastoma
  • Sarcoma, Clear Cell
  • Rhabdoid Tumor
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma



Children's Healthcare of AtlantaAtlanta, Georgia  30342