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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
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 :	June 2015
Estimated Primary Completion Date :	June 2020
Estimated Study Completion Date :	June 2020

Arms and Interventions

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Arm

Intervention/treatment

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

Outcome Measures

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Primary Outcome Measures :

1. 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.
2. 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 :

1. 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.

Eligibility Criteria

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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

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Contacts

Contact: Kate Glasscox	404-785-0002	Katherine.GlasscoxSuggs@choa.org
Contact: Amy Autry-Bush	404-785-6011	Amy.Autry-Bush@choa.org

Locations

United States, Georgia
Children's Healthcare of Atlanta-Egleston	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kate Glasscox 404-785-0002 Katherine.GlasscoxSuggs@choa.org
Children's Healthcare of Atlanta, Scottish Rite	Recruiting
Atlanta, Georgia, United States, 30342
Contact: Kate Glasscox 404-785-0002 Katherine.GlasscoxSuggs@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: Jaszianne Tolbert, MD

Sponsors and Collaborators

Emory University

Investigators

Principal Investigator:	Thomas Cash, MD	Emory University

More Information

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Responsible Party:	Thomas Cash, MD, Assistant Professor, Emory University
ClinicalTrials.gov Identifier:	NCT02574728 History of Changes
Other Study ID Numbers:	IRB00082488
First Posted:	October 14, 2015
Last Update Posted:	March 26, 2018
Last Verified:	July 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