Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG)
Condition: Diffuse Intrinsic Pontine Glioma; High-grade Glioma
MeSH terms: Glioma; Diffuse Intrinsic Pontine Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      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).
    

Detailed description: 
      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).
    

Intervention name(s): Crizotinib; Dasatinib
Intervention type(s): Drug; Drug
Intervention description(s): Starting dose level:
Initial Treatment Plan: 130 mg/m^2 per dose
Modified Treatment Plan per Amendment 1.0: 165 mg/m^2 per dose
The dose of a single agent will be increased by approximately 30% in each subsequent cohort until the MTD of this combination is reached.
The doses of each agent will not exceed their single-agent MTD already determined for children with recurrent solid tumors.
Cycle 1 (28 days): once a day for 28 days
Cycles 2-26 (28 days each): once a day; Starting dose level: 50 mg/m^2 per dose
The dose of a single agent will be increased by approximately 30% in each subsequent cohort until the MTD of this combination is reached.
The doses of each agent will not exceed their single-agent MTD already determined for children with recurrent solid tumors.
Cycle 1 (28 days): starting on day 3, once a day for 28 days
Cycles 2-26 (28 days each): once a day
Other intervention name(s): PF-02341066; Xalkori®; BMS-354825; Sprycel®
Intervention MeSH terms: Dasatinib; Crizotinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment