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A Phase I/II Study of the RAF Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, NSC# 724772 IND# 69896) in Children With Refractory Solid Tumors or Refractory Leukemias


Phase 1
2 Years
21 Years
Not Enrolling
Both
Refractory Solid Tumors, Refractory Leukemias

Thank you

Trial Information

A Phase I/II Study of the RAF Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, NSC# 724772 IND# 69896) in Children With Refractory Solid Tumors or Refractory Leukemias


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.

Inclusion Criteria


- 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) less than or equ...

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

060233

NCT ID:

NCT01445080

Start Date:

August 2006

Completion Date:

June 2012

Related Keywords:

  • Refractory Solid Tumors
  • Refractory Leukemias
  • Inhibitor of RAS Signaling Pathway
  • Pharmacokinetics
  • Pharmacodynamics
  • Pharmacogenetics
  • MTD
  • Phase I/II
  • Pediatric
  • Solid Tumor
  • Leukemia
  • Chronic Myelogenous Leukemia
  • CML
  • Acute Lymphoblastic Leukemia
  • ALL
  • Acute Myeloid Leukemia
  • AML
  • Juevenile Myelomoncytic Leukemia
  • JMML
  • Leukemia
  • Neoplasms

Name

Location

National Cancer Institute (NCI), 9000 Rockville PikeBethesda, Maryland  20892