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

• ClinicalTrials.gov Identifier: NCT02574728
• Recruitment Status: Recruiting
• First Posted: October 14, 2015
• Last Update Posted: August 19, 2019
• Sponsor: Emory University
• Collaborators: Cannonball Kids' Cancer Foundation; Hyundai Hope On Wheels
• Information provided by (Responsible Party): Thomas Cash, MD, Emory University

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 (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

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 Name: Cytoxan

Outcome Measures

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

• 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, 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.
• 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

Contacts

Contact: Kate Glasscox; 404-785-0002; Katherine.GlasscoxSuggs@choa.org

Contact: Study Information; AflacDevTreferral@choa.org

Locations

United States, Arizona

Phoenix Children's Hospital; Recruiting

Phoenix, Arizona, United States, 85016

Contact: Laura Evdokimo 602-933-5004 levdokimo@phoenixchildrens.com

Principal Investigator: Cynthia Wetmore, MD, PhD

United States, Delaware

Nemours/Alfred I. duPont Hospital for Children; Recruiting

Wilmington, Delaware, United States, 19803

Contact: Debra Bertz, CTR, MBA 302-651-5757 debra.bertz@nemours.org

Principal Investigator: Andrew W Walter, MD

United States, Florida

Nemour's Children's Specialty Care Jacksonville; Recruiting

Jacksonville, Florida, United States, 32207

Contact: Howard Katzenstein, MD 904-697-3985 Howard.Katzenstein@nemours.org

Principal Investigator: Howard Katzenstein, MD

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

Principal Investigator: Jaszianne Tolbert, MD

United States, Virginia

University of Virginia Health System; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: Cindy Fischer, CCRC 434-243-0901 CRB3Y@hscmail.mcc.virginia.edu

Principal Investigator: William Petersen, MD

Sponsors and Collaborators

Emory University

Cannonball Kids' Cancer Foundation

Hyundai Hope On Wheels

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
• First Posted: October 14, 2015
• Last Update Posted: August 19, 2019
• Last Verified: August 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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:

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Sirolimus; Celecoxib; Cyclophosphamide; Etoposide; Etoposide phosphate; Everolimus; 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; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic