Sirolimus in Combination With Metronomic Chemotherapy in Children With Recurrent and/or Refractory Solid and CNS Tumors - Full Text View

Purpose

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	Intervention	Phase
Cancer	Drug: Sirolimus Drug: Celecoxib Drug: Etoposide Drug: Cyclophosphamide	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: No masking 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

Resource links provided by NLM:

Drug Information available for: Etoposide Sirolimus Etoposide phosphate Everolimus Temsirolimus Celecoxib

Genetic and Rare Diseases Information Center resources: Soft Tissue Sarcoma Osteosarcoma Ewing Sarcoma Ewing's Family of Tumors Neuroblastoma Wilms' Tumor Perlman Syndrome

U.S. FDA Resources

Further study details as provided by Thomas Cash, MD, Emory University:

Primary Outcome Measures:

Change in radiographic response to treatment for solid tumors [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.


Estimated Enrollment:	60
Study Start Date:	June 2015
Estimated Study Completion Date:	June 2020
Estimated Primary Completion Date:	June 2020 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Oral sirolimus, celecoxib, etoposide, and cyclophoshphamide 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 Name: Cytoxan

Arms

Assigned Interventions

Experimental: Oral sirolimus, celecoxib, etoposide, and cyclophoshphamide

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 Name: Cytoxan

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.

Eligibility


Ages Eligible for Study:	12 Months to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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
Extracranial solid tumors including neuroblastoma
Bone tumors (osteosarcoma, Ewing sarcoma)
Rhabdomyosarcoma
Soft tissue sarcomas
Wilms tumor
Other rare solid tumors

Participants must have had a histologic verification of malignancy at original diagnosis or relapse, except in participants with intrinsic brain stem tumors, optic pathway gliomas, or participants with pineal tumors and elevations of serum or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) or beta-HCG (beta-human chorionic gonadotropin).

Karnofsky performance level of greater than or equal to 50 percent for participants greater than 16 years of age at the time of screening
Lansky performance level of greater than or equal to 50 percent for participants 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
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
Uncontrolled infection
Participants who in the opinion of the investigator may not be able to comply with the safety monitoring requirements

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02574728

Contacts


Contact: Jaclyn Smith, MBA	404-785-0692	jaclyn.smith@choa.org

Locations


United States, Georgia
Children's Healthcare of Atlanta-Egleston	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jaclyn Smith, MBA 404-785-0692 jaclyn.smith@choa.org
Children's Healthcare of Atlanta, Scottish Rite	Recruiting
Atlanta, Georgia, United States, 30342
Contact: Jaclyn Smith, MBA 404-785-0692 jaclyn.smith@choa.org
Principal Investigator: Thomas Cash, MD
United States, Missouri
Children's Mercy Hospital	Recruiting
Kansas City, Missouri, United States, 64108
Contact: Amber Jenkins, MSc, CCRC 816-302-6891 amjenkins@cmh.edu
Contact: Allie Bruce 816-302-6892 albruce@cmh.edu
Principal Investigator: Keith August, MD, MS

Sponsors and Collaborators

Emory University

Investigators


Principal Investigator:	Thomas Cash, MD	Emory University

More Information


Responsible Party:	Thomas Cash, MD, Assistant Professor, Emory University
ClinicalTrials.gov Identifier:	NCT02574728 History of Changes
Other Study ID Numbers:	IRB00082488
Study First Received:	October 2, 2015
Last Updated:	February 14, 2017

Keywords provided by Thomas Cash, MD, Emory University:


Pediatrics Brain Tumors Neuroblastoma Osteosarcoma	Ewing's Sarcoma Rhabdomyosarcoma Wilms Tumors Soft Tissue Sarcomas

Additional relevant MeSH terms:


Cyclophosphamide Sirolimus Everolimus Celecoxib Etoposide phosphate Etoposide Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists	Antineoplastic Agents, Phytogenic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antineoplastic Antifungal Agents Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on June 23, 2017

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