Sorafenib and Topotecan in Refractory/Recurrent Pediatric Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborators:
Pediatric Cancer Foundation
Bayer
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01683149
First received: September 7, 2012
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

H. Lee Moffitt Cancer Center and Research Institute will be the Sunshine Project Coordinator, but will not be recruiting locally.

The purpose of this research study is to establish a dose of the combination of drugs, Topotecan and Sorafenib in children. This will be called the maximum tolerated dose. The chemotherapy in this study is a combination of Topotecan and Sorafenib. The investigators are trying to find the highest dose of Topotecan and Sorafenib that can be given safely to children with Refractory or Recurrent Pediatric Solid Malignancies. The investigators will do this by testing different doses of these drugs in different groups of children. The investigators will also study how the body processes these drugs.


Condition Intervention Phase
Solid Tumor
Drug: Topotecan
Drug: Sorafenib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I, Traditional 3+3, Trial of PO Sorafenib and Topotecan in Refractory or Recurrent Pediatric Solid Malignancies

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    Establish the recommended phase II dose of the combination of topotecan and sorafenib in children. This will be the maximum tolerated dose.


Secondary Outcome Measures:
  • Time to Progression (TTP) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Determine Time to Progression (TTP) for all patients, comparing TTP on study to TTP on previous regimen. This study will use the (RECIST 1.1) Response Evaluation Criteria in Solid Tumors from the NCI for assessment of radiographic response in patients with solid tumors and in order to determine if patients have met off study criteria, i.e. disease progression. Progressive Disease (PD): At least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions, or evidence of laboratory or clinical progression.

  • The Number of Participants with Adverse Events as a Measure of Safety and Feasibility [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    Describe the toxicity as per NCI Common Toxicity Criteria, version 4.0 (CTCAE 4.0).


Estimated Enrollment: 25
Study Start Date: January 2013
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Combination Chemotherapy

Combination Chemotherapy: Topotecan and Sorafenib. Participants will receive the treatment in cycles. Every cycle is 28 days long. For the first cycle participants will get the chemotherapy drugs:

  • Topotecan PO (by mouth) once daily on days 1-5 and days 8-12
  • Sorafenib PO (by mouth) twice daily (BID), continuously on days 2-28 of cycle one and days 1-28 on each additional cycle.
  • Level -1: Topotecan 1.0 mg/m^2: Sorafenib 100 mg/m^2 BID
  • Level -2: Topotecan 0.8 mg/m^2: Sorafenib 100 mg/m^2 BID
  • Level 1: Topotecan 1.0 mg/m^2: Sorafenib 150 mg/m^2 BID
  • Level 2: Topotecan 1.4 mg/m^2: Sorafenib 150 mg/m^2 BID
  • Level 3: Topotecan 1.4 mg/m^2: Sorafenib 200 mg/m^2 BID
  • Level 4: Topotecan 1.8 mg/m^2: Sorafenib 200 mg/m^2 BID
Drug: Topotecan
Topotecan will be given by mouth as outlined in treatment arm.
Other Name: Topoisomerase-I inhibitor
Drug: Sorafenib
Sorafenib will be given by mouth as outlined in treatment arm.
Other Name: BAY 43-9006

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Life expectancy of at least 12 weeks (3 months)
  • Must have had relapsed or refractory solid tumor malignancy, or a relapsed or refractory central nervous system malignancy AND must have received at least one prior course of therapy for their malignancy.
  • Patients with a solid tumor must have radiographic evidence of disease. Bone only disease is acceptable if biopsy proven but will not be eligible for response criteria by RECIST 1.1. Ideally patients will have disease evaluable by RECIST 1.1.
  • Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
  • Karnofsky ≥ 50 for patients > 16 years of age, and Lansky ≥ 50 for patients ≤ 16 years of age.
  • Prior Therapy: Patients with solid tumors must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    1. Previous Sorafenib or Topotecan: Patients may not have previously been treated with sorafenib. Patients may have been previously treated with topotecan provided it was in combination with other agents and the most recent dose was more than 6 months from study entry. Patients in whom disease has progressed on single agent topotecan will not be eligible for this study.
    2. Myelosuppressive Chemotherapy: Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks or nitrosourea within 6 weeks of entry onto this study.
    3. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration.
    4. Biologic (anti-neoplastic agent): At least 21 days or 5 half lives (whichever is greater duration) since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    5. Radiation Therapy (XRT): ≥ 4 wks for local palliative XRT (small port); ≥ 3 months must have elapsed if prior TBI, or craniospinal XRT or if ≥ 50% radiation of pelvis; ≥ 6 weeks must have elapsed if other substantial bone marrow (BM) radiation.
    6. Stem Cell Transplant or Rescue without total body irradiation (TBI): For allograft: no evidence of active graft vs. host disease and ≥ 3 months must have elapsed since stem cell transplantation (SCT). Autologous transplant recipients must be transfusion independent and not require growth factors for >4 weeks.
  • All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate will be obtained according to local Institutional Review Board (IRB) guidelines. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.
  • Organ Function Requirements - Adequate Bone Marrow Function Defined As:

    1. Peripheral absolute neutrophil count (ANC) ≥ 1500/μL.
    2. Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
    3. Hemoglobin ≥ 10.0 gm/dL (may receive red blood cell transfusions)
    4. Patients with known bone marrow metastatic disease will be eligible for study. These patients must not be known to be refractory to red cell or platelet transfusion. If dose limiting hematologic toxicity is observed, all subsequent patients enrolled at the dose level must not have bone marrow metastatic disease.
  • Adequate Renal Function Defined As: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m^2, or serum creatinine based on age/gender as defined in the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC).
  • Adequate Liver Function Defined As:

    1. Bilirubin (sum of conjugated + unconjugated) ≤ upper limit of normal (ULN) for age
    2. Alanine transaminase (ALT) ≤ upper limit of normal for age
    3. All clinically significant chemistries excluding alkaline phosphatase, uric acid, aspartic transaminase (AST) and lactate dehydrogenase (LDH) must be grade 1 or less
  • Adequate Cardiac Function Defined As:

    1. Normal 12 lead EKG with corrected QT interval (QTc) < 450 msec, and either:
    2. Shortening fraction ≥ 28% or left ventricular ejection fraction ≥ 50%.
    3. Systolic Blood Pressure and Diastolic Blood Pressure ≤ 95th percentile for age and gender
  • Adequate Pulmonary Function Defined As: No evidence of dyspnea at rest, and a resting pulse oximetry > 92%.
  • All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less at the time of enrollment, signing the Informed Consent Form (ICF).
  • Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.
  • Prothrombin time-international normalized ratio (PT-INR) ≤ 1.5 X ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN.
  • Participants (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 30 days after the last dose of study drug.
  • Must be able to swallow and retain oral medication

Exclusion Criteria:

  • Previous assignment to treatment during this study
  • Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management
  • Evidence or history of bleeding diathesis or coagulopathy
  • Any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 2 or higher within 4 weeks of treatment; any other hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks of treatment
  • Have used strong cytochrome P450 3A4 (CYP3A4) inducers (eg, phenytoin, carbamazepine, phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before treatment
  • Any previously untreated or concurrent cancer that is distinct in primary site or histology from the primary. Patients surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form)
  • Presence of a non-healing wound, non-healing ulcer, or bone fracture
  • History of organ allograft. (Including corneal transplant)
  • Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
  • Women who are pregnant or breast-feeding
  • Inability to comply with the protocol and/or not willing or not available for follow-up assessments
  • Any condition which, in the investigator's opinion, makes the patient unsuitable for trial participation
  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: NCT01683149

Contacts
Contact: Kathleen Manning 813-745-3073 dale.barrios@moffitt.org
Contact: Damon Reed, M.D. 813-745-7412 kathleen.manning@moffitt.org

Locations
United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Trang Nguyen    323-361-7309    trnguyen@chla.usc.edu   
Principal Investigator: Leo Mascarenhas, M.D.         
Sub-Investigator: Venkatramani Rajkumar, M.D.         
Sub-Investigator: David Tisher, M.D.         
Sub-Investigator: William May, M.D.         
Sub-Investigator: Girish Dhall, M.D.         
Sub-Investigator: Nathan Robinson, M.D.         
United States, Connecticut
Connecticut Childrens Medical Center Recruiting
Hartford, Connecticut, United States, 06106
Contact: Michael Isakoff, M.D.    860-545-9637    misakoff@ccmckids.org   
Principal Investigator: Michael Isakoff, M.D.         
Sub-Investigator: Andrea Orsey, M.D.         
Sub-Investigator: Nehal Parikh, M.D.         
Sub-Investigator: Donna Boruchov, M.D.         
Sub-Investigator: Eileen Gillan, M.D.         
Sub-Investigator: Kerry Moss, M.D.         
United States, Delaware
Nemours/Alfred I. duPont Hospital for Children, Delaware Recruiting
Wilmington, Delaware, United States, 19803
Contact: Debra J. Bertz    302-651-5757    debra.bertz@nemours.org   
Principal Investigator: Edward A. Kolb, M.D.         
Sub-Investigator: Gregory Griffin, M.D.         
Sub-Investigator: Robin Miller, M.D.         
Sub-Investigator: Emi Caywood, M.D.         
Sub-Investigator: Jonathan Powell, M.D.         
Sub-Investigator: Andrew Walter, M.D.         
United States, Florida
University of Florida, Gainesville Recruiting
Gainesville, Florida, United States, 32610
Contact: Ashley Bayne    352-265-0027    abayne@ufl.edu   
Principal Investigator: Joanne Lagmay, M.D.         
Sub-Investigator: Lamis Eldjerou, M.D.         
Sub-Investigator: John Fort, M.D.         
Sub-Investigator: Tung Wynn, M.D.         
Sub-Investigator: William Slayton, M.D.         
Nemours Children's Clinic, Jacksonville Recruiting
Jacksonville, Florida, United States, 32207
Contact: Ingrid Ingram    904-697-3985    iingram@nemours.org   
Principal Investigator: Scott Bradfield, M.D.         
Sub-Investigator: Paul Pitel, M.D.         
Sub-Investigator: Eric Sandler, M.D.         
Sub-Investigator: Manisha Bansal, M.D.         
Sub-Investigator: Michael Joyce, M.D.         
Sub-Investigator: Cynthia Gauger, M.D.         
University of Miami, Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Myriam Zayas    305-243-7846    MZayas2@med.miami.edu   
Principal Investigator: John M. Goldberg, M.D.         
All Children's Hospital, St. Petersburg Recruiting
St. Petersburg, Florida, United States, 33701
Contact: Ashley Repp    727-767-4784    ashley.repp@allkids.org   
Principal Investigator: Damon Reed, M.D.         
Principal Investigator: Gergory Hale, M.D.         
United States, New York
Montefiore Medical Center, Children's Hospital at Montefiore Recruiting
Bronx, New York, United States, 10467
Contact: Noam Zeffren    718-741-2356    nzeffren@montefiore.org   
Principal Investigator: Jonathan Gill, M.D.         
United States, Utah
Primary Children's Medical Center/Utah Recruiting
Salt Lake City, Utah, United States, 84113
Contact: Melissa Bolton    801-213-3909    melissa.bolton@hsc.utah.edu   
Principal Investigator: Holly Spraker-Perlman, M.D.         
Sub-Investigator: Richard Lemons, M.D., Ph.D.         
Sub-Investigator: Jennifer Wright, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Pediatric Cancer Foundation
Bayer
Investigators
Principal Investigator: Damon Reed, M.D. H. Lee Moffitt Cancer Center and Research Institute
Principal Investigator: G. Douglas Letson, M.D. H. Lee Moffitt Cancer Center and Research Institute
  More Information

No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01683149     History of Changes
Other Study ID Numbers: MCC-16963, ONC-2011-49, Sunshine Project 002
Study First Received: September 7, 2012
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Refractory
Relapsed
Recurrent
Pediatric
Malignancy

Additional relevant MeSH terms:
Neoplasms
Topotecan
Topoisomerase I Inhibitors
Sorafenib
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014