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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by St. Jude Children's Research Hospital
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT01644773
First received: July 17, 2012
Last updated: September 5, 2014
Last verified: September 2014
  Purpose

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).


Condition Intervention Phase
Diffuse Intrinsic Pontine Glioma
High-grade Glioma
Drug: Chemotherapy
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • Maximum tolerated dose of combination crizotinib and dasatinib in stratum A patients [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: November 2012
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Chemotherapy
Research participants with high grade glioma or diffuse intrinsic pontine glioma.
Drug: Chemotherapy

Starting dose levels:

  • Crizotinib:

    • Initial Treatment Plan: 130 mg/m^2 per dose
    • Modified Treatment Plan per Amendment 1.0: 165 mg/m^2 per dose
  • Dasatinib: 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):

  • Crizotinib: once a day for 28 days
  • Dasatinib: starting on day 3, once a day for 28 days

Cycles 2-26 (28 days each):

  • Crizotinib and dasatinib once a day
Other Names:
  • crizotinib: PF-02341066, Xalkori®
  • dasatinib: BMS-354825, Sprycel®

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).
  Eligibility

Ages Eligible for Study:   2 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
      • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01644773

Contacts
Contact: Tabatha Doyle, RN 901-595-2544 braintumors@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tabatha Doyle, RN    901-595-2544    braintumors@stjude.org   
Principal Investigator: Alberto Broniscer, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Alberto Broniscer, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01644773     History of Changes
Other Study ID Numbers: SJHG12
Study First Received: July 17, 2012
Last Updated: September 5, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Crizotinib
Dasatinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on October 20, 2014