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 2 strata:
- Stratum A for recurrent/ progressive tumors
- Stratum B for recently diagnosed patients who have completed standard radiation therapy without progressive disease
- Stratum A: 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 B: 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.
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).
Research participants with high-grade glioma or diffuse intrinsic pontine glioma will receive crizotinib and dasatinib.
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 male 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
- Endpoint Classification: Safety/Efficacy Study
- Intervention Model: Single Group Assignment
- Masking: Open Label
- Primary Purpose: Treatment
About this clinical trial
Diffuse intrinsic pontine glioma (DIPG) and high-grade gliomas are fast-growing, cancerous brain tumors. High-grade gliomas are cancerous tumors that grow in the brain or spine. DIPG is a high-grade glioma that forms at the point where the brain meets the spinal cord, which is called the brainstem.
These tumors are hard to treat because surgery to remove them is often not an option, and standard radiation therapy does not usually work well. In other types of cancers, radiation therapy and chemotherapy work well because they destroy tumors by causing breaks in their DNA (genetic materials inside the tumor cells). In gliomas, it appears that the tumor is able to repair DNA damage caused by radiation therapy and chemotherapy.
Most children and young adults with DIPG and high-grade gliomas cannot be cured with current treatments. At St. Jude, researchers are determined to find new treatments for patients with DIPG and high-grade gliomas.
Purpose of this clinical trial
In this Phase I clinical trial, St. Jude researchers want to find out if a combination of two oral chemotherapy drugs, crizotinib and dasatinib, is safe for participants with DIPG and high-grade gliomas after they have received radiation therapy.
Crizotinib is approved for the treatment of lung cancer, and dasatinib is approved for the treatment of certain types of leukemia in children and adults. Neither drug is approved for treating children or adults with brain and spinal cord tumors, so the use of these drugs in this trial is investigational. Both medications are thought to block specific proteins in the body that cause cancer to grow and spread.
Two groups of participants with DIPG and high-grade gliomas will take part in this study:
- Group 1: participants whose tumors have grown after previous treatment
- Group 2: participants with newly diagnosed DIPG or high-grade glioma whose tumors have not grown after initial treatment, including radiation therapy
All participants will receive treatment with crizotinib and dasatinib once daily. Crizotinib is made as a liquid or capsule. Dasatinib is available as tablets. Participation in this trial may last up to two years, as long as the tumor is responding to the treatment and the participant is able to tolerate its side effects.
- Between 2 and 21 years of age
- Diagnosis of diffuse intrinsic pontine glioma (DIPG) or high-grade glioma
SJHG12 Quick View Sponsor
St. Jude Children's Research Hospital
ClinicalTrials.gov identifier NCT01644773 Trial start date August 2012 Estimated enrollment 50 Stydy type Interventional Study phase
- Diffuse intrinsic pontine glioma (DIPG)
- High-grade glioma
Ages 2 to 21 years Principal investigator Anna Vinitsky, MD, MS Study site St. Jude Children's Research Hospital For a consultation or to discuss SJHG12 St. Jude Brain Tumor Program
Phone: 901-595-2544 or 901-595-4599
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105 USA
Phone: 901-595-2544 or 901-595-4599
Tabatha E. Doyle, RN
Coordinator, Brain Tumor Program
262 Danny Thomas Place
Memphis, TN 38105
Phone: (901) 595-2544
FAX: (901) 595-6211
The above information is intended to provide only a basic description about a research protocol that may be currently active at St. Jude. The details made available here may not be the most up-to-date information on protocols used by St. Jude. To receive full details about a protocol and its status and or use at St. Jude, a physician must contact St. Jude directly.