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

Diffuse Intrinsic Pontine Glioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01644773
• Other study ID #: SJHG12
• Secondary ID: NCI-2012-01240
• Status: Completed
• Phase: Phase 1
• Start date: November 27, 2012
• Est. completion date: September 28, 2018

Study information

• Verified date: March 2019
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: September 28, 2018
• Est. primary completion date: March 7, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Glioma
• High-grade Glioma

Intervention

Drug:
• Crizotinib
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
• Dasatinib
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

Locations

Country	Name	City	State
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of combination crizotinib and dasatinib in stratum A patients		6 weeks after start of therapy for last enrolled participant
Primary	Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients		6 weeks after start of therapy for last enrolled participant

External Links

•   Clinical Trials Open at St. Jude
•   St. Jude Children's Research Hospital