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Phase I, Traditional 3+3, Trial of PO Sorafenib and Topotecan in Refractory or Recurrent Pediatric Solid Malignancies

Phase 1
3 Years
18 Years
Open (Enrolling)
Solid Tumor

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Trial Information

Phase I, Traditional 3+3, Trial of PO Sorafenib and Topotecan in Refractory or Recurrent Pediatric Solid Malignancies

This protocol will evaluate a combination of a targeted agent, sorafenib, and a cytotoxic
agent with broad spectrum activity, topotecan, in relapsed and refractory childhood solid

Patients will be enrolled in a traditional 3+3 phase I design to receive increasing doses of
topotecan daily x 5 days on weeks 1 and 2 and sorafenib twice daily by mouth continuously.
The duration of each treatment cycle will last 28 days.

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®)

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)

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

- 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

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

Establish the recommended phase II dose of the combination of topotecan and sorafenib in children. This will be the maximum tolerated dose.

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Damon Reed, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

November 2015

Related Keywords:

  • Solid Tumor
  • Refractory
  • Relapsed
  • Recurrent
  • Pediatric
  • Malignancy
  • Neoplasms



University of Miami, Sylvester Comprehensive Cancer CenterMiami, Florida  33136
University of Florida, GainesvilleGainesville, Florida  32611
Nemours Children's Clinic, JacksonvilleJacksonville, Florida  32207
All Children's Hospital, St. PetersburgSt. Petersburg, Florida  33701
Montefiore Medical Center, Children's Hospital at MontefioreBronx, New York  10467