Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma

PRIMARY OBJECTIVES:

I. Estimate the efficacy of GDC-0449 (vismodegib) treatment for pediatric patients with
recurrent or refractory medulloblastoma, as measured by the sustained objective response
rates for patients without (stratum A) and with (stratum B) evidence of activation of
Hedgehog (Hh) signaling pathway in their tumors.

II. Characterize the pharmacokinetics (plasma) of GDC-0449 in children/adolescents with
refractory medulloblastoma.

III. To document pathologic and genomic methods to identify medulloblastomas with activation
of the Hh signaling pathway.

SECONDARY OBJECTIVES:

I. Document and describe toxicities associated with GDC-0449 administered on a daily
schedule.

II. Estimate the duration of objective response and progression-free survival (PFS).

III. Characterize the pharmacokinetics (cerebrospinal fluid) of GDC-0449 in
children/adolescents with refractory medulloblastoma.

OUTLINE: This is a multicenter study. Patients are stratified according to evidence of
activation of Hedgehog signaling pathway in their tumors (without vs with vs unknown).

Patients receive vismodegib orally (PO) once daily (QD) on days 1-28. Treatment repeats
every 28 days for up to 26 courses in the absence of disease progression or unacceptable
toxicity.

Plasma and cerebrospinal fluid samples are collected periodically for pharmacokinetic and
other correlative studies.

After completion of study treatment, patients are followed up every other month for up to 12
months.

Inclusion Criteria:

- Patients with a histologically confirmed diagnosis of medulloblastoma that is
recurrent, progressive, or refractory to standard therapy and for which there is no
known curative therapy

- Patient must have adequate archival formalin fixed, paraffin embedded (FFPE) primary
tumor material for biology studies; specifically, adequate archival FFPE tumor
material is either:

- An FFPE block, preferably in which tumor occupies an area of at least 10x10 mm
if available, and is free of surgical or processing artifacts; tumor in the
submitted FFPE block must not have been obtained from the CUSA trap OR

- Preferably15x5µm sections if available from an FFPE tissue block conforming to
the above criteria AND

- Tissue submission must be accompanied by a copy of the pathology report

- Patients must have bi-dimensionally measureable disease in the brain or spinal cord
defined as at least one lesion that can be accurately measured in at least 2 planes
in order to be eligible for this study

- Patients must have a body surface area (BSA) of >= 0.67m^2 and at most 2.5m^2

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration; this is to be documented in the database

- Karnofsky performance status of >= 50% in patients > 16 years, or Lansky performance
status of >= 50% in patients >= 3 yrs and =< 16 years, assessed within two weeks
prior to registration

- Must have recovered from prior treatment-related toxicity; no other myelosuppressive
chemotherapy or immunotherapy within 4 weeks prior to study entry (6 weeks if prior
nitrosurea)

- Decadron dose should also be stable or decreasing for at least 1 week (7days) prior
to starting therapy

- Radiation therapy (XRT) >= 3 months prior to study entry for craniospinal
irradiation; >= 8 weeks for local irradiation to primary tumor; >= 2 weeks prior to
study entry for focal irradiation for symptomatic metastatic sites

- Off all colony stimulating factors > 1 week prior to study entry (granulocyte colony
stimulating factor [GCSF], granulocyte macrophage colony stimulating factor [GM CSF],
erythropoietin)

- Prior therapy will include primary therapy (including radiation therapy and
chemotherapy) and a maximum of 2 additional salvage therapies; patients can enroll on
the protocol after failure on primary therapy

- Absolute neutrophil count (ANC) >= 1000 µL

- Platelet count >= 50,000/uL (transfusion independent)

- Hemoglobin >= 8.0 gm/dL (may receive red blood cell [RBC] transfusions)

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >=
70ml/min/1.73 m^2 or a serum creatinine =< 1.5 mg/dL

- Serum Total Bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5
times institutional ULN for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2.5 times institutional ULN for age

- Alkaline Phosphatase =< 1.5 times institutional ULN

- Serum albumin >= 2.5 g/dL

- Patient must have recovered from the significant acute toxicities of all prior
therapy before entering this study and meet all other eligibility criteria specified
in the Inclusion and Exclusion Criteria

- Pregnancy should be avoided for 12 months after the last dose of GDC-0449 for females
of child-bearing potential; female patients of childbearing potential must not be
pregnant or breast-feeding; female patients of childbearing potential must have a
negative serum or urine pregnancy test within 24 hours prior to beginning treatment

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours
prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or
urine) will be administered every 4 weeks if their menstrual cycles are regular or
every 2 weeks if their cycles are irregular while on study within the 24-hour period
prior to the administration of GDC-0449; prior to dispensing GDC-0449, the
investigator must confirm and document the patient's use of two contraceptive
methods, dates of negative pregnancy test, and confirm the patient's understanding of
the of GDC-0449 to cause spontaneous abortion or birth defects; female patients are
required to use two forms of acceptable contraception, including one barrier method
during participation in the study and for the 12 months following the last dose; all
patients should receive contraceptive counseling either by the investigator, or by an
obstetrician (OB), gynecologist or other physician who is qualified in this area of
expertise; if a woman of childbearing potential believes that her contraceptive
method has failed, emergency contraception should be considered; if a patient is
suspected to be pregnant, GDC-0449 should be immediately discontinued; in addition, a
positive urine test must be confirmed by a serum pregnancy test; if it is confirmed
that the patients is not pregnant, the patient may resume dosing with GDC-0449; if a
female patient becomes pregnant during therapy or within 12 months after the last
dose of GDC-0449, or if the female partner of a male patient exposed to the drug
becomes pregnant while the male patient is receiving GDC-0449 or within 12 months
after the last dose of GDC-0449, the investigator must be notified in order to
facilitate outcome follow-up; female patients should not breastfeed a baby while on
this study; female patients must NEVER donate ova while being treated with GDC-0449;
all sexually active male subjects (including those who have undergone vasectomy)
should utilize a barrier form of contraception during study treatment and for 12
months after the last dose as it is not known whether GDC-0449 that may be present in
seminal fluid would cause serious or life-threatening birth defects in a fetus born
to the female partner of a male subject; males should also not donate sperm during
treatment or up to 12 months after the last dose

- Signed informed consent must be obtained including for pharmacokinetic study
according to institutional guidelines

Exclusion Criteria:

- Central nervous system (CNS) embryonal tumor other than medulloblastoma; for example,
patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), primitive
neuroectodermal tumor (PNET) from a non-cerebellar site within the central nervous
system, ependymoblastoma, or medulloepithelioma

- Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
that would compromise the patient's ability to tolerate protocol therapy or would
likely interfere with the study procedures or results

- Patients receiving any other anticancer or investigational drug therapy, or warfarin

- Patients with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy

- Other: below given criteria are confirmed by the patient history

- Inability to swallow capsules

- Malabsorption syndrome or other condition that would interfere with enteral
absorption

- History of congestive heart failure

- History of ventricular arrhythmia requiring medication

- Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined
as less than the lower limit of normal for the institution despite adequate
electrolyte supplementation

- Clinically important history of liver disease, including viral or other
hepatitis or cirrhosis