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Version Date: 12/12/2008
Protocol Abstract and Schema
Phase I study of the Smoothened (SMO) antagonist GDC-0449 for recurrent or refractory
This is a multicenter, phase I trial for children with recurrent or refractory medulloblastoma to
recommend daily dose of GDC-0449 for a subsequent Phase II trial, evaluate toxicity and
characterize the pharmacokinetics and biologics of the GDC-0449.
• To select, based on safety and pharmacokinetics, a daily dose of GDC-0449 to
recommend for a subsequent PBTC Phase II trial of children with recurrent or refractory medulloblastoma
• To document and describe toxicities associated with GDC-0449 administered on a daily
• To characterize the pharmacokinetics (plasma and cerebrospinal fluid) of GDC-0449 in
children/adolescents with refractory medulloblastoma
• To document preliminary antitumor activity in patients with recurrent or refractory
• To identify Medulloblastoma that belong to the subset of tumors that have an activated
PTCH/SHH pathway using pathologic and genomic methods
Patients must be at least 3 years of age (≥ 3 and ≤ 21 yrs) on the date of
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.
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.
Version Date: 12/12/2008
Karnofsky Performance Scale (KPS for > 16 yrs of age) or
Lansky Performance Score (LPS for ≤ 16 years of age) ≥ 60 assessed within two
weeks prior to registration
o 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).
o Decadron dose should also be stable or decreasing for at least 1 week
XRT ≥ 3 months prior to study entry for craniospinal irradiation
(≥ 23 Gy); ≥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
o Adequate bone marrow functions for patients without bone marrow
ANC≥1000 µL Platelet count ≥ 100,000/µL (transfusion independent) Hemoglobin ≥ 8.0 gm/dL (may receive RBC transfusions)
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or A serum creatinine based on age as follows:
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, SGPT (ALT) ≤ 5 x institutional upper limit of normal (ULN) for
SGOT (AST) ≤ 5 times institutional upper limit of normal for age Serum albumin ≥ 2.5 g/dL
Version Date: 12/12/2008
Baseline Adverse Events:
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.
Off all colony forming growth factor(s) for at least 1 week prior
to registration (filgrastim, sargramostim, erythropoietin).
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.
Patients of childbearing or child fathering potential must
be willing to use a medically acceptable form of birth control, which includes
abstinence, while being treated on this study.
Signed informed consent according to institutional guidelines
must be obtained.
o Patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor
o 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
Inability to Participate:
Patients with inability to return for follow-up visits
or obtain follow-up studies required to assess toxicity to therapy.
below given criteria are confirmed by the patient history
o Malabsorption syndrome or other condition that would interfere
o History of ventricular arrhythmia requiring medication.
o History of congenital long QT syndrome
Version Date: 12/12/2008
o Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or
hypoklemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation.
o Clinically important history of liver disease, including viral or other
GDC -0449 is a novel molecule that inhibits aberrant downstream signaling in the PTCH /SHH
pathway. Preclinical studies in mouse models that spontaneously develop medulloblastoma have
demonstrated that treatment of the mice with GDC 0449 will suppress tumor formation and will
induce reduction in tumors of tumor bearing mice.
Phase I studies in adults with basal cell carcinoma have demonstrated that the drug is well
tolerated in adults and has minimal toxicity. Patients with basal cell carcinoma demonstrated
complete and partial responses. More importantly Gli-1
expression in these tumors decreased > 2
times from their baseline values.
Based on the strong preclinical rational and encouraging data from the adult phase I study we
propose a Phase I type study with GDC-0449. The initial dose for the trial will be 85 /m2 (89% of
the adult MTD). Initially, dose-limiting toxicity will comprise toxicities attributable to drug
administration occurring during the first course. Therapy may continue as long as the patient’s
disease remains stable. Although safety will be based on toxicities observed during the first
course, toxicities observed during course 2 will be classified according to whether they are dose
limiting and any chronic grade 3/4 toxicities that occur after the first course will be documented
and may warrant a review of the treatment regimen.
In consenting patients, serial plasma samples will be collected during therapy with GDC-0449 to
allow the estimation of pharmacokinetic parameters in children with recurrent medulloblastoma.
In children with Omaya reservoirs, simultaneous cerebrovascular fluid (CSF) and plasma
samples will be collected to assess GDC-0449 CSF penetration. Archival tissue samples will be
collected from patients to evaluate whether diagnostic reagents under development can detect
HH pathway activation in archival tumor tissue Schema
The drug will be administered orally on a once a day schedule continuously for 28 days in
patients with recurrent or refractory medulloblastoma. 28 days defines one course of therapy and
there are no breaks between courses. Patients may continue to receiving the protocol therapy up
to 13 courses if patient doses not meet ‘off treatment’ criteria per protocol and there are no
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