AflacST1502: Sirolimus in Combination With Metronomic Chemotherapy in Children With Recurrent and/or Refractory Solid and CNS Tumors

Sponsor

Emory University (Other)

Overall Status

Recruiting

CT.gov ID

NCT02574728

Collaborator

Cannonball Kids' Cancer Foundation (Other), Hyundai Hope On Wheels (Other)

Enrollment

Locations

Arm

103

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to determine the efficacy of daily sirolimus and celecoxib, with low dose etoposide alternating with cyclophosphamide for pediatric participants with relapsed or refractory tumors.

Condition or Disease	Intervention/Treatment	Phase
Cancer	Drug: Sirolimus Drug: Celecoxib Drug: Etoposide Drug: Cyclophosphamide	Phase 2

Detailed Description

This study aims to learn if the combination of oral sirolimus once daily with celecoxib, and with oral etoposide alternating every 21 days with oral cyclophosphamide (metronomic chemotherapy) is effective in shrinking relapsed or refractory tumors in pediatric participants. In addition, this study seeks to learn the length of time this combination can keep the tumor from growing, learn more about the side effects of sirolimus when used in this combination, and to learn if the sirolimus is working by evaluating blood and tumor tissue.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

AflacST1502: A Phase II Study of Sirolimus in Combination With Metronomic Chemotherapy in Children With Recurrent and/or Refractory Solid and CNS Tumors

Study Start Date :

Jun 1, 2015

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral sirolimus, celecoxib, etoposide, and cyclophosphamide Participants in this group will receive oral sirolimus and celecoxib in addition to cycles of oral etoposide and cyclophosphamide for up to two years.	Drug: Sirolimus The starting dose for sirolimus is 2 mg/m2 once daily. The dose of sirolimus will be individually adjusted to achieve a target serum trough concentration in the range of 10-15 ng/ml. Sirolimus will be given by mouth every day for six weeks (every six weeks is called one cycle) for up to two years or 16 cycles. Other Names: Rapamune rapamycin Drug: Celecoxib Celecoxib 100 mg will be given by mouth twice a day for six weeks (every six weeks is called one cycle) for up to two years or 16 cycles. Drug: Etoposide Etoposide 50 mg/m2 (maximum dose 100 mg) will be given daily by mouth for the first 3 weeks of a 6 week cycle. Six week cycles will be repeated for up to two years or 16 cycles. Other Names: Etopophos Toposar Drug: Cyclophosphamide Cyclophosphamide 2.5 mg/Kg (maximum dose 100 mg) will be given daily by mouth for the second 3 weeks of a 6 week cycle. Six week cycles will be repeated for up to two years or 16 cycles. Other Names: Cytoxan

Arm

Intervention/Treatment

Experimental: Oral sirolimus, celecoxib, etoposide, and cyclophosphamide

Participants in this group will receive oral sirolimus and celecoxib in addition to cycles of oral etoposide and cyclophosphamide for up to two years.

Drug: Sirolimus

The starting dose for sirolimus is 2 mg/m2 once daily. The dose of sirolimus will be individually adjusted to achieve a target serum trough concentration in the range of 10-15 ng/ml. Sirolimus will be given by mouth every day for six weeks (every six weeks is called one cycle) for up to two years or 16 cycles.

Other Names:

Rapamune

rapamycin

Drug: Celecoxib

Celecoxib 100 mg will be given by mouth twice a day for six weeks (every six weeks is called one cycle) for up to two years or 16 cycles.

Drug: Etoposide

Etoposide 50 mg/m2 (maximum dose 100 mg) will be given daily by mouth for the first 3 weeks of a 6 week cycle. Six week cycles will be repeated for up to two years or 16 cycles.

Other Names:

Etopophos

Toposar

Drug: Cyclophosphamide

Cyclophosphamide 2.5 mg/Kg (maximum dose 100 mg) will be given daily by mouth for the second 3 weeks of a 6 week cycle. Six week cycles will be repeated for up to two years or 16 cycles.

Other Names:

Cytoxan

Outcome Measures

Primary Outcome Measures

Change in radiographic response to treatment for solid tumors [Baseline, End of Treatment (Up to 2 years)]
Radiographic response to treatment will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) for participants with solid tumors via CT or MRI scan. A complete response (CR) is a disappearance of all target and non-target lesions. Partial response (PR) is at least a 30% decrease in the disease measurement compared to the baseline measurement. Stable disease (SD) is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD) taking as reference the smallest disease measurement since baseline. Progressive disease (PD) is at least a 20% increase in the disease measurement compared to baseline, or the appearance of one or more new lesions, or evidence of laboratory or clinical progression.
Change in radiographic response to treatment for central nervous system (CNS) tumors [Baseline, End of Treatment (Up to 2 years)]
Radiographic response to treatment will be assessed for participants with CNS tumors via CT or MRI scan. Response criteria are assessed based on the lesion of the longest diameter and its longest perpendicular diameter. Development of new disease or progression in any established lesions is considered progressive disease, regardless of response in other lesions. Complete response (CR) is the the disappearance of all target lesions. Partial response (PR) is greater than or equal to 50% decrease decrease in the sum of the products of the two perpendicular diameters of all target lesions, taking into reference the baseline measurement. Stable disease (SD) is neither a sufficient decrease in the sum of the products of the two perpendicular diameters of all target lesions to qualify for PR, nor sufficient increase in a single target lesion to qualify for progressive disease (PD).

Secondary Outcome Measures

Number of adverse events [Baseline, End of Treatment (Up to 2 years)]
The adverse events associated with sirolimus in combination with metronomic chemotherapy administered on this schedule will be defined and evaluated throughout the treatment period.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Months to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants with any of the following tumors who have experienced relapse following front-line therapy, or who are refractory to front-line therapy, and participants with tumors that carry a poor prognosis and have no known standard curative therapy
Brain tumors of all World Health Organization (WHO) grades, except diffuse intrinsic pontine glioma (DIPG)
Extracranial solid tumors including histiocytoses
Participants must have had a histologic verification of malignancy at original diagnosis or relapse, except in participants with optic pathway gliomas, or participants with pineal tumors and elevations of serum or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) or beta-human chorionic gonadotropin (beta-HCG)
Tissue blocks or slides must be sent
Participants must have radiographically measurable disease at the time of study enrollment to be eligible. Patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG+) evaluable disease are eligible. Measurable disease in patients with CNS involvement is defined as tumor that is measurable (≥ 10 mm) in two perpendicular diameters on MRI and visible on more than one slice. For all patients, tumors that are located in a previously irradiated area may be considered measurable if the lesion has shown tumor growth after radiation or has been biopsied and proven to have active disease.
Participant's current disease state must be one for which there is no known curative therapy
Karnofsky performance level of greater than or equal to 50 percent for participants who are greater than 16 years of age at the time of screening
Lansky performance level of greater than or equal to 50 percent for participants who are less than or equal to 16 years of age at the time of screening
Fully recovered from acute toxic effects of all prior anti-cancer therapy
Adequate bone marrow function as deemed by the protocol at the time of screening
Adequate renal function as deemed by the study protocol at the time of screening
Adequate liver function as deemed by the study protocol at the time of screening
Serum triglyceride level ≤300 mg/dL and serum cholesterol ≤ 300 mg/dL
Random or fasting blood glucose within the upper normal limits for age
Adequate pulmonary function as deemed by the study protocol at the time of screening

Exclusion Criteria:

Women who are currently pregnant or breastfeeding
Receiving corticosteroids who have not been on a stable dose for at least 7 days
Currently receiving enzyme inducing anticonvulsants
Currently receiving receiving potent CYP3A4 (enzyme) inducers or inhibitors
Currently receiving another investigational drug
Currently receiving any other anti-cancer agents
The use of cannabis oil is prohibited during the first 2 cycles of this protocol. Patients must be off of cannabis oil for 3 days prior to enrollment.
Uncontrolled infection
Participants who in the opinion of the investigator may not be able to comply with the safety monitoring requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	Nemours/Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
3	Children's Healthcare of Atlanta-Egleston	Atlanta	Georgia	United States	30322
4	Children's Healthcare of Atlanta, Scottish Rite	Atlanta	Georgia	United States	30342
5	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
6	University of Virginia Health System	Charlottesville	Virginia	United States	22908