Phase I Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG)
Overview
- Phase
- Phase 1
- Intervention
- Crizotinib
- Conditions
- Diffuse Intrinsic Pontine Glioma
- Sponsor
- St. Jude Children's Research Hospital
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief 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).
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Chemotherapy
Research participants with high grade glioma or diffuse intrinsic pontine glioma will receive crizotinib and dasatinib.
Intervention: Crizotinib
Chemotherapy
Research participants with high grade glioma or diffuse intrinsic pontine glioma will receive crizotinib and dasatinib.
Intervention: Dasatinib
Outcomes
Primary Outcomes
Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients
Time Frame: 6 weeks after start of therapy for last enrolled participant
Maximum tolerated dose of combination crizotinib and dasatinib in stratum A patients
Time Frame: 6 weeks after start of therapy for last enrolled participant