PATIENT ELIGIBILITY:
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. If more than 7 calendar days elapse between the date eligibility studies outlined were obtained and the start date of treatment, then the following studies must be repeated prior to treatment: CBC with differential, bilirubin, ALT (SGPT) and serum creatinine, lipase and amylase. If any of these repeat laboratory studies are outside the parameters required for eligibility, then the patient is off protocol therapy.
The eligibility criteria listed below are interpreted literally and cannot be waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical or research record which will serve as the source document for verification at the time of audit.
INCLUSION CRITERIA (refers to both Parts A & B of the study, unless otherwise indicated):
Age: Patients must be greater than or equal to 24 months and less than or equal to 21 years of age at the time of study entry.
Diagnosis:
Part A: Patients with Solid Tumors
Patients with solid tumors must have had histologic verification of solid tumor malignancy at either original diagnosis or relapse.
Part B Patients with Leukemias
Patients with leukemias must have histologically-confirmed acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia (CML) in blast crisis.
DISEASE STATUS:
Part A: Patients with Solid Tumors Patients with solid tumors must have either measurable or evaluable disease. This should be documented with the appropriate imaging studies within 14 days prior to enrollment on the trial.
Part B: Patients with Leukemias
Patients with leukemias must have greater than 25% blasts in the bone marrow (M3 bone marrow). Active extramedullary disease (except for leptomeningeal disease) may also be present. Patients with JMML have to meet diagnostic criteria for JMML, and the requirement of greater than 25% blasts in the bone marrow does not apply to patients with JMML.
Therapeutic Options: 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.
Performance Level: Karnofsky greater than or equal to 50% for patients greater than 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
PRIOR THERAPY:
Part A - Patients with Solid Tumors
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. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will be used for toxicity assessment. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home page (http://ctep.info.nih.gov). Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion Criteria. For patients with solid tumors the following applies:
a) Myelosuppressive chemotherapy or monoclonal antibody treatment: Patients must not have received myelosuppressive chemotherapy or treatment with a monoclonal antibody within 3 weeks of entry onto this study (6 weeks if prior nitrosourea).
b) Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
c) Biologic (anti-neoplastic agent): At least 7 days 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
d) Radiation Therapy: greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 3 months must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation (skull, spine, pelvis, ribs).
e) Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and greater than or equal to 3 months must have elapsed since the transplant.
Part B: Patients with Leukemias Patients with leukemias must have recovered from the non-hematologic toxic effects of all prior therapy before entry onto this trial. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will be used for toxicity assessment. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home page (http://ctep.info.nih.gov). Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion Criteria. For patients with leukemia the following applies:
a) Myelosuppressive chemotherapy or monoclonal antibody treatment: Patients must have had their last dose of chemotherapy at least three weeks prior to study entry. Patients with acute promyelocytic leukemias (APL) must be refractory to treatment with retinoic acid and arsenic trioxide. Patients with Philadelphia (Ph) chromosome positive CML must be refractory to imatinab (GleevecTM). Patients must not have received treatment with a monoclonal antibody within 3 weeks of entry onto this study.
b) Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
c) Biologic (anti-neoplastic agent): At least 7 days 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.
d) Radiation Therapy: greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 3 months must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation (skull, spine, pelvis, ribs).
e) Stem cell or bone marrow transplant: Patients who previously received myeloablative therapy followed by a bone marrow or stem cell transplant are eligible if the transplant was performed at least 3 months before study entry.
Organ Function Requirements
Adequate Bone Marrow Function Defined As:
a) Patients with solid tumors:
-Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/micro
-Platelet count greater than or equal to 75,000/micro (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment) .
-Hemoglobin = 8.0 gm/dL (may receive RBC transfusions)
b) Patients with leukemias:
-Blood counts are not required to be normal prior to entry on this trial, however, platelet count must be greater than or equal to 20,000 /micro (may receive platelet transfusions) and hemoglobin must be greater than or equal to 8.0 gm/dL (may receive RBC transfusions).
Adequate Renal Function Defined as:
-Creatinine clearance or radioisotope GFR greater than or equal to 70 ml/min/1.73 m(2) or
-A serum creatinine based on age/gender as follows:
Age 2 to less than 6 years = Maximum Serum Creatinine (mg/dL) male 0.8 and female 0.8.
Age 6 to less than 10 years = Maximum Serum Creatinine (mg/dL) male 1 and female 1.
Age 10 to less than 13 years = Maximum Serum Creatinine (mg/dL) male 1.2 and female 1.2.
Age 13 to less than 16 years = Maximum Serum Creatine (mg/dL) male 1.5 and female 1.4.
Age greater than or equal to 16 years = Maximum Serum Creatinine (mg/dL) male 1.7 and female 1.4.
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
Adequate Liver Function Defined As:
Bilirubin (sum of conjugated + unconjugated) less than or equal to upper limit of normal (ULN) for age, and
SGPT (ALT) less than or equal to ULN for age. For the purpose of this study, the ULN for SGPT is 45 U/L.
Serum albumin greater than or equal to 2 g/dL.
Normal PT, PTT, and INR for patients on prophylactic anticoagulation only.
Normal serum lipase and amylase.
Adequate Pulmonary Function Defined As:
No evidence of dyspnea at rest, no exercise intolerance and a pulse oximetry greater than 94% if there is clinical indication for determination.
Diastolic Blood Pressure Within The Upper Limit Of Normal Defined As:
A diastolic blood pressure (DBP) less than or equal to the 95th percentile for age and gender (Appendix V) measured as described in Section 8.1 and not be receiving medication for treatment of hypertension.
Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
EXCLUSION CRITERIA:
Pregnancy or Breast-feeding Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
Patients with leukemia will be excluded from Part A (or the dose escalation component) of the trial. However, once the dose finding component of the trial is completed, and the MTD is established in patients with refractory solid tumors, 6 patients with refractory leukemia will be enrolled at the MTD to assess tolerability in Part B of the study.
Concomitant Medications:
Growth factor(s): Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
Investigational Drugs: Patients who are currently receiving another investigational drug.
Anti-cancer Agents: Patients who are currently receiving other anticancer agents.
Study Specific: Sorafenib is predominantly metabolized via CYP3A4, and patients who take cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), rifampin, grape fruit juice, or St. Johns Wort will not be eligible for the trial.
Infection: Patients who have an uncontrolled infection.
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
Patients with baseline hypertension greater than grade 1.
Inability to swallow tablets.
Prior treatment with Sorafenib.
Patients must not have any evidence of bleeding diathesis.
Patients with brain tumors or known metastasis to the brain will be excluded from trial participation.
Patients must not be on therapeutic anticoagulation. Prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for PT, INR or PTT are met.
Patients with active leptomeningeal leukemia: (CSF WBC greater than 5/micro and unequivocal confirmation of leukemic blasts in the CSF by morphologic demonstration on a CSF cytocentrifuge specimen).
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009