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

Primary Purpose

Diffuse Intrinsic Pontine Glioma, High-grade Glioma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Crizotinib
Dasatinib
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Intrinsic Pontine Glioma

Eligibility Criteria

2 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Chemotherapy

Arm Description

Research participants with high grade glioma or diffuse intrinsic pontine glioma will receive crizotinib and dasatinib.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of combination crizotinib and dasatinib in stratum A patients
Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients

Secondary Outcome Measures

Full Information

First Posted
July 17, 2012
Last Updated
March 20, 2019
Sponsor
St. Jude Children's Research Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01644773
Brief Title
Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG)
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)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
November 27, 2012 (Actual)
Primary Completion Date
March 7, 2018 (Actual)
Study Completion Date
September 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Intrinsic Pontine Glioma, High-grade Glioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chemotherapy
Arm Type
Experimental
Arm Description
Research participants with high grade glioma or diffuse intrinsic pontine glioma will receive crizotinib and dasatinib.
Intervention Type
Drug
Intervention Name(s)
Crizotinib
Other Intervention Name(s)
PF-02341066, Xalkori®
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Other Intervention Name(s)
BMS-354825, Sprycel®
Intervention Description
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
Primary Outcome Measure Information:
Title
Maximum tolerated dose of combination crizotinib and dasatinib in stratum A patients
Time Frame
6 weeks after start of therapy for last enrolled participant
Title
Maximum tolerated dose of combination crizotinib and dasatinib in stratum B patients
Time Frame
6 weeks after start of therapy for last enrolled participant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna Vinitsky, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34586478
Citation
Gibson EG, Campagne O, Selvo NS, Gajjar A, Stewart CF. Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas. Cancer Chemother Pharmacol. 2021 Dec;88(6):1009-1020. doi: 10.1007/s00280-021-04357-4. Epub 2021 Sep 29.
Results Reference
derived
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

Learn more about this trial

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

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