Sorafenib (BAY 43-9006) to Treat Children With Solid Tumors or Leukemias

• Determine maximum tolerated dose and RP2D [ Time Frame: After 1 cycle of treatment ]
• Define toxicities of sorafenib administered po BID for 28 days [ Time Frame: After 1 cycle of treatment ]
• characterize pharmacokinetics [ Time Frame: During 1st cycle of treatment and prior to each cycle ]
• Determine tolerability, pharmacokinetics and pharmacodynamics(Part C) [ Time Frame: Cycle 1 and prior to cycle 3 and 4 ]

• Define antitumor activity [ Time Frame: Every odd cycle of therapy ]
• Assess biologic effect [ Time Frame: Pre-treatment and steady state ]
• Assess effect on tumor blood flow via DEMRI [ Time Frame: Pretreatment and Day 28 cycle 1 ]

Background:

• Sorafenib is an experimental anti-cancer drug that works by blocking proteins thought to be important for tumor growth. It has blocked the growth of tumors in test tubes and in some animal models.
• Sorafenib is approved for the treatment of advanced kidney cancer.
• This is the first time sorafenib is being tested in children with cancer.

Objectives:

• To determine the highest dose of sorafenib that can be safely given to children and young adults with cancer.
• To determine the side effects and benefits, if any, of sorafenib in children and young adults with cancer.
• To study how the body handles sorafenib and the drug's effects on cells and proteins in the blood.

Eligibility:

-Patients between 2 and 21 years of age with solid tumors or leukemias that do not respond to standard treatment.

Patients between 2 and 21 years of age with AML and FLT3-ITD mutation for Part C of the study.

Design:

• Patients take sorafenib tablets every day about every 12 hours in 28-day treatment cycles for a maximum of 24 cycles.
• The dose is increased in succeeding groups of 3 to 6 children until serious side effects occur. Subsequent patients then receive the drug at lower doses.
• Patients have a physical exam, blood and urine tests, and CT or MRI scans periodically to monitor safety and treatment effects. Leukemia patients also have bone marrow aspirates. Patients with a solid tumor may have an MRI. Children whose bones are still growing have X-rays of the lower legs periodically to monitor bone structure.
• Patients have additional blood studies to determine the amount of sorafenib in the blood, the effect of the drug on proteins and cells in the blood, and genetic differences that affect how individuals respond to the drug.

Background:

The ras gene product plays a critical role in cell signal transduction. Activating Ras mutations occur in 30% of all human cancers, and the ras pathway may be upregulated in absence of ras mutations. Activated Ras initiates several signaling cascades, and the best characterized is the Ras/Raf/MEK/ERK cascade. Ras initiates this pathway by recruiting Raf kinase to the plasma membrane where it is further modified for full activation. A high frequency of B-Raf mutations has recently been reported in a variety of adult solid cancers.

Sorafenib (BAY 43-9006) is a novel, orally bioavailable, bi-aryl urea, which potently inhibits wild type and mutant raf. In addition, sorafenib inhibits several receptor tyrosine kinases including human VEGFR-2, FLT3, c-KIT, and p38 alpha, suggesting that sorafenib may mediate anti-tumor activity via several additional mechanisms. In early adult clinical trials sorafenib has been well tolerated, with minimal myelosuppression. Dose-limiting toxicities were hand-foot syndrome, diarrhea, fatigue, hypertension, pain, and rash. Responses to sorafenib have been observed in early clinical trials in adults with a variety of tumors, including tumors that have not been described to harbor raf mutations. Sorafenib recently was approved by the Food and Drug Administration for treatment of refractory renal cell cancer.

OBJECTIVES:

To determine the maximum tolerated dose (MTD) of oral Sorafenib in children with refractory solid tumors or refractory leukemias.

To define the toxicities and pharmacokinetics of Sorafenib.

To evaluate the tolerability, pharmacokinetics, pharmacodynamics and activity of sorafenib administered at the MTD for refractory leukemias in patients with AML and FLT3-ITD mutations

ELIGIBILITY:

Patients (greater than or equal to 24 months to less than or equal to 21 years) with refractory solid tumors or refractory leukemias.

Patients (greater than or equal to 24 months to less than or equal to 21 years) with AML and FLT3-ITD mutation (Part C). Participation in pharmacokinetic sampling is mandatory for Part C.

DESIGN:

Sorafenib will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). Dose escalations will be performed to define the MTD.

Initially, the spectrum of toxicity and MTD will be defined in patients with solid tumors.

Patients with refractory leukemias will be entered at the solid tumor MTD, to determine whether patients with leukemia tolerate this dose level.

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of sorafenib will be studied in patients with solid tumors and leukemias.

In Part C: 14 patients will receive sorafenib at 150 mg/m(2)/dose, BID to evaluate the tolerability, pharmacokinetics, pharmacodynamics and activity of sorafenib.

• Leukemia
• With AML and FLT3-ITD Mutations

• Experimental: A
  Establlish MTD in patients with solid tumors
  Intervention: Drug: Sorafenib
• Experimental: B
  Expand MTD in patients with leukemia
  Intervention: Drug: Sorafenib
• Experimental: C
  MTD in patients with AML and FLT3-ITD mutations
  Intervention: Drug: Sorafenib

• Reuter CW, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood. 2000 Sep 1;96(5):1655-69. Review.
• Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta. 2003 Jun 5;1653(1):25-40. Review.
• Chan TL, Zhao W, Leung SY, Yuen ST; Cancer Genome Project. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003 Aug 15;63(16):4878-81.

• 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 in Section 4.1.7 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 (labs may again be repeated within 48-72 hours), then the patient is off protocol therapy. Imaging and bone marrow studies are required within 2 weeks prior to the start of protocol therapy.

The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy posted 5/11/01). 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 and C 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 enrollment.

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.

Part C: Patients with AML and FLT3-ITD mutation

Patients must have AML and documentation of a FLT3-ITD mutation by a CLIA certified laboratory.

DISEASE STATUS:

Part A: Patients with Solid Tumors

Patients with solid tumors must have either measurable or evaluable disease.

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.

Part C: Patients with AML and FLT3-ITD mutation

Patients must have greater than or equal to 5% blasts in the bone marrow. Active extramedullary disease (except for leptomeningeal disease) may also be present.

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:

1. Myelosuppressive chemotherapy or monoclonal antibody treatment: Patients must not have received myelosuppressive chemotherapy or treatment with a monoclonal antibody within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
2. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
3. 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
4. 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).
5. 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 enrollment 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:

1. Myelosuppressive chemotherapy or monoclonal antibody treatment: Patients must have had their last dose of chemotherapy at least three weeks prior to study enrollment. 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 (Gleevec). Patients must not have received treatment with a monoclonal antibody within 3 weeks of enrollment onto this study.
2. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
3. 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.
4. 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).
5. 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 enrollment.

Part C: Patients with AML and FLT3-ITD mutation

Patients with FLT3-ITD AML who relapse while receiving maintenance-like low dose chemotherapy such as dexamethasone/thioguanine, oral etoposide, or decitabine will not be required to have a waiting period before enrollment onto this study provided they meet all other inclusion criteria. (For questions regarding whether a current chemotherapy regimen can be considered maintenance like therapy, please contact the study chair to discuss prior to enrollment.)

Patients who are refractory or who relapse while not receiving maintenance-1ike therapy must have recovered from the non-hematologic toxic effects of all prior therapy before enrollment 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 such patients with AML and FLT3-ITD mutation the following applies:

1. Myelosuppressive chemotherapy: At least l4 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea or patients receiving maintenance-like low dose chemotherapy.

   Note: Cytoreduction with hydroxyurea c can be initiated and continued for up to 24 hours prior to the start of sorafenib. Maintenance-like chemotherapy can also be continued for up to 24 hours prior to the start of sorafenib.

2. .Hematopoietic growth factors: A t least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. 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.
3. Biologic (anti-neoplastic agent: A t least 7 days after the last dose of 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.
4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy e.g. tumor vaccines.
5. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
6. XRT: greater than or equal to 2 weeks for local palliative XRT (small port); greater than or equal to 24 weeks 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 weeks must have elapsed if other substantial BM radiation.
7. Stem Cell Infusion without TBI: No evidence of active graft vs. host disease and greater than or equal to 8 weeks must have elapsed since transplant or stem cell infusion.

Organ Function Requirements

Adequate Bone Marrow Function Defined As:

1. Patients with solid tumors (Part A):

   • Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL
   • Platelet count greater than or equal to 75,000/microL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).
   • Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions)

2. Patients with leukemias (Part B):

   - Blood counts are not required to be normal prior to enrollment on this trial, however, platelet count must be greater than or equal to 20,000 /microL (may receive platelet transfusions) and hemoglobin must be greater than or equal to 8.0 gm/dL (may receive RBC transfusions).

3. Patients with AML and FLT3-ITD mutation:

Blood counts are not required to be normal prior to enrollment on this trial. However, platelet count has to be greater than or equal to 20,000/mm(3) (may receive platelet 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:

1. Patients with solid tumors:

   • 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.

2. Patients with leukemias (Part B and C):

   • Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 times upper limit of normal (ULN) for age, and
   • SGPT (ALT) less than or equal to 5.0 times the ULN for age (less than or equal to 225 U/L). 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.

For Part A and B Only: 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 in Section 8.1 of the protocol and not be receiving medication for treatment of hypertension.

For Part C only: Blood Pressure Within the Upper Limit of Normal Defined As:

A blood pressure (BP) ...