Clinical trial NCT01331135: Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
Official title: Sirolimus in Combination With Metronomic Therapy in Children With Recurrent and Refractory Solid Tumors: A Phase I Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Keywords: pediatrics
sirolimus
relapse
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Children's Healthcare of Atlanta
First posted: 2011-04-07
Enrollment: 18
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The best treatment for recurrent cancers or those that do not respond to therapies is not known. Typically, patients with these cancers receive a combination of cancer drugs (chemotherapy), surgery, or radiation therapy. These treatments can prolong their life but may not offer a long-term cure.

This study proposes using a drug called Sirolimus in combination with common chemotherapy drugs to treat patients with recurrent and refractory solid tumors. Sirolimus has been found to inhibit cell growth and to have anti-tumor activity in pediatric solid tumors in previous studies and, therefore, has the potential to increase the effectiveness of the chemotherapy drugs when given together.

This study wil investigate the highest dose of Sirolimus that can be given orally with other oral chemotherapy drugs. Cohorts of 2 subjects will be started at the minimum dose. The dose will be increased in the next 2 subjects as long as there were no major reactions in the previous groups. This study will also seek to learn more about the side effects of sirolimus when used in this combination and what effects the drug has on the white cells and the immune system. Successful use of this drug will impact the cancer population greatly by providing an increased chance of survival to those with resistant or recurrent cancers.

Detailed description: 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 number.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: 2 years after treatment starts
Secondary outcomes:
measure: define and describe toxicities of sirolimus
timeFrame: 2 years post treatment
measure: anti-tumor activity of sirolimus
timeFrame: 2 years post treatment
measure: evaluate correlation of p70S6 kinase activity
timeFrame: 2 years post treatment
measure: evaluate risk of infection
timeFrame: 2 years post treatment
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
Study officials:
affiliation: Children's Healthcare of Atlanta
name: Muna Qayed, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Qayed M, Cash T, Tighiouart M, MacDonald TJ, Goldsmith KC, Tanos R, Kean L, Watkins B, Suessmuth Y, Wetmore C, Katzenstein HM. A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors. Pediatr Blood Cancer. 2020 Apr;67(4):e28134. doi: 10.1002/pbc.28134. Epub 2019 Dec 25.