Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG)



Status:Completed
Conditions:Brain Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:2 - 21
Updated:3/24/2019
Start Date:November 27, 2012
End Date:September 28, 2018

Use our guide to learn which trials are right for you!

Phase I Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG)

This is a phase I study to find the highest tolerable dose of crizotinib and dasatinib given
in combination to patients with diffuse intrinsic pontine glioma (DIPG) and other types of
high grade gliomas (HGG). Participants will receive escalating doses until the highest dose
is determined. Participants will be enrolled in two strata: stratum A for recurrent/
progressive tumors and stratum B for recently diagnosed patients who have completed standard
radiation therapy without progressive disease. Up to 7 dosage levels will be tested. Both
drugs are taken orally daily, once per day. Correlative pharmacokinetic and biology studies
are planned, as well as advanced methods of magnetic resonance imaging (MRI).

The Rolling 6 design will be used to estimate the maximum tolerated dose (MTD) and determine
the dose-limiting toxicity (DLT) of the combination of escalating doses of crizotinib and
dasatinib. Our goal is to accrue research participants for both stratum A and B. However, it
is our expectation that the accrual of research participants to stratum B will proceed at a
slower pace. Therefore, initially the strategy of dose escalation will be exclusively based
on research participants treated at stratum A until the MTD of this combination is reached.
Until the MTD of this combination is reached for research participants in stratum A, accrual
of research participants in stratum B will be allowed at the highest dosage level which has
already been deemed to be safe (i.e., no DLTs in three research participants or ≤ 1 DLT in
six research participants). No research participants will be accrued to stratum B until at
least one dosage level has been confirmed to be safe in stratum A. Once the MTD for stratum A
is reached, we will accrue research participants at this same dosage level to stratum B
following the rules of the Rolling 6 design. If the MTD for stratum A is well tolerated among
research participants in stratum B, we will proceed with dose escalation for research
participants in stratum B based on the same rules of the Rolling 6 design. This strategy is
based on the premise that research participants who are more heavily pre-treated (stratum A)
may not tolerate therapy as well as those with minimal previous treatment (stratum B).

Primary Objectives:

- To estimate the MTD of the combination of crizotinib (c-Met and ALK inhibitor) and
dasatinib (bcr-abl, PDGFRA and B, src, lck, yes, and c-kit inhibitor) in pediatric
research participants with recurrent or progressive DIPG and other HGGs (stratum A).

- To estimate the MTD of the combination of crizotinib and dasatinib in research
participants with DIPG or HGG who completed RT within a short interval prior to
enrollment but have not experienced disease progression (stratum B).

Inclusion Criteria: ALL RESEARCH PARTICIPANTS

- Diagnosis of high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). If
histologic confirmation was obtained, diagnosis must be one of the following:
anaplastic astrocytoma (WHO grade 3), anaplastic oligodendroglioma (WHO grade 3),
anaplastic oligoastrocytoma (WHO grade 3), anaplastic ganglioglioma (WHO grade 3),
pleomorphic xanthoastrocytoma with anaplastic features (WHO grade 3), malignant
glioneuronal tumor, glioblastoma, or gliosarcoma (WHO grade 4)

- Age > or = 2 years and < or = 21 years

- Performance score > or = 50 (Lansky for research participants < or = 16 years and
Karnofsky for those > 16 years).

- Adequate organ function at the time of enrollment as follows:

- Bone marrow: Hemoglobin > or = 8g/dL [may have received packed red blood cell
transfusion], absolute neutrophil count (ANC) > or = 1000/mm^3, platelets > or =
100,000/mm^3 [transfusion independent])

- Renal: Normal serum creatinine based on age as shown below or GFR >
70ml/min/1.73m^2:

- Age < or = 5 years: 0.8 mg/dL maximum

- Age 5 to 10 years: 1.0 mg/dL maximum

- Age 10 to 15 years: 1.2 mg/dL maximum

- Age > 15 years: 1.5 mg/dL maximum

- Hepatic: SGPT and SGOT < 3x the institutional upper limit of normal (ULN), total
bilirubin concentration < 1.5x the institutional ULN, albumin > or = 2g/dL

- Female research participants > or = 10 years of age or post-menarchal must not be
pregnant (confirmed by serum or urine pregnancy test within 1 week of study
enrollment) or breastfeeding

- Female research participants of childbearing age or males research participants of
child fathering potential must agree to use safe contraceptive methods for the
duration of the study and for 3 months thereafter

Inclusion Criteria: STRATUM A

- Diagnosis of recurrent or progressive HGG or DIPG.

- Neurological deficits must be stable on a fixed or decreasing dose of dexamethasone
for ≥7 days before study enrollment.

- Recovery to ≤ grade 1 from all significant toxicities of previous therapies.

- Irradiation: Interval from the last dose of local radiation therapy (RT), craniospinal
RT, and palliative RT for symptomatic disease > or = 3 months, > or = 6 months, and >
or = 2 weeks before study enrollment, respectively

- Myelosuppressive chemotherapy: Interval > or = 6 weeks and > or = 4 weeks from last
dose of nitrosourea and other chemotherapy drugs before study enrollment,
respectively. However, interval must be > or = 1 week from last dose of oral etoposide
and other drugs administered at low doses (metronomic regimen) before study enrollment

- Small-Molecule Inhibitors: Interval > or = 1 week from last dose before study
enrollment. If a previously used agent has a prolonged half-life, the appropriate
interval will be determined after consultation with the principal investigator

- Monoclonal Antibodies: Interval > or = 3 half-lives before study enrollment. Such
cases will need to be discussed with the principal investigator

- High-Dose Chemotherapy with Stem-Cell Rescue: Interval > or = 3 months before study
enrollment

- Cancer Vaccines and Convection-Enhanced Therapies: Interval > or = 1 month before
study enrollment

- Growth Factors: Interval > or = 1 week and > or = 2 weeks before study enrollment for
standard and long-acting growth factors (e.g., pegfilgrastim), respectively

Inclusion Criteria: STRATUM B

- Completion of local RT with or without concomitant chemotherapy including temozolomide
and radiosensitizing agents (e.g., carboplatin, vorinostat) outside the context of a
clinical trial. Any agent administered during RT should have a short half-life so that
it should already be completely eliminated by the start of this therapy. If other
agents were used concurrently with RT, they will need to be discussed with the
principal investigator to assess eligibility

- Interval > or = 4 weeks and < or = 8 weeks from the completion of radiochemotherapy

Exclusion Criteria: ALL RESEARCH PARTICIPANTS

- Metastatic disease for stratum B only

- Concomitant use of other anticancer (except for corticosteroids) or experimental
agents

- Use of enzyme-inducing anticonvulsants (EIACs). A minimum interval of 10 days between
the last dose of EIAC and start of this therapy will be required for research
participants who were previously receiving such medications.

- Pregnant or lactating patients

- Research participants with other clinically significant medical disorders that could
compromise their ability to tolerate protocol therapy or would interfere with the
study procedures or results

- Prior therapy with a PDGFR or c-Met inhibitor

- Original treatment design: Body surface area ≥ 1.8m2on dosage levels 3b, 4, and 5

- Modified treatment design: Body surface area < 0.55 m^2 for all dosage levels
We found this trial at
1
site
262 Danny Thomas Pl
Memphis, Tennessee 38105
(901) 495-3300
Principal Investigator: Anna Vinitsky, MD
Phone: 901-595-2544
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
?
mi
from
Memphis, TN
Click here to add this to my saved trials