Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma
Primary Purpose
Recurrent Childhood Medulloblastoma
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Pharmacological Study
Vismodegib
Sponsored by
About this trial
This is an interventional treatment trial for Recurrent Childhood Medulloblastoma
Eligibility Criteria
Inclusion Criteria:
- Patients with a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive, or refractory to standard therapy and for which there is no known curative therapy
Patient must have adequate archival formalin fixed, paraffin embedded (FFPE) primary tumor material for biology studies; specifically, adequate archival FFPE tumor material is either:
- An FFPE block, preferably in which tumor occupies an area of at least 10x10 mm if available, and is free of surgical or processing artifacts; tumor in the submitted FFPE block must not have been obtained from the CUSA trap OR
- Preferably15x5µm sections if available from an FFPE tissue block conforming to the above criteria AND
- Tissue submission must be accompanied by a copy of the pathology report
- Patients must have bi-dimensionally measureable disease in the brain or spinal cord defined as at least one lesion that can be accurately measured in at least 2 planes in order to be eligible for this study
- Patients must have a body surface area (BSA) of >= 0.67m^2 and at most 2.5m^2
- Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration; this is to be documented in the database
- Karnofsky performance status of >= 50% in patients > 16 years, or Lansky performance status of >= 50% in patients >= 3 yrs and =< 16 years, assessed within two weeks prior to registration
- Must have recovered from prior treatment-related toxicity; no other myelosuppressive chemotherapy or immunotherapy within 4 weeks prior to study entry (6 weeks if prior nitrosurea)
- Decadron dose should also be stable or decreasing for at least 1 week (7days) prior to starting therapy
- Radiation therapy (XRT) >= 3 months prior to study entry for craniospinal irradiation; >= 8 weeks for local irradiation to primary tumor; >= 2 weeks prior to study entry for focal irradiation for symptomatic metastatic sites
- Off all colony stimulating factors > 1 week prior to study entry (granulocyte colony stimulating factor [GCSF], granulocyte macrophage colony stimulating factor [GM CSF], erythropoietin)
- Prior therapy will include primary therapy (including radiation therapy and chemotherapy) and a maximum of 2 additional salvage therapies; patients can enroll on the protocol after failure on primary therapy
- Absolute neutrophil count (ANC) >= 1000 µL
- Platelet count >= 50,000/uL (transfusion independent)
- Hemoglobin >= 8.0 gm/dL (may receive red blood cell [RBC] transfusions)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 or a serum creatinine =< 1.5 mg/dL
- Serum Total Bilirubin =< 1.5 x upper limit of normal (ULN) for age
- Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 times institutional ULN for age
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times institutional ULN for age
- Alkaline Phosphatase =< 1.5 times institutional ULN
- Serum albumin >= 2.5 g/dL
- Patient must have recovered from the significant acute toxicities of all prior therapy before entering this study and meet all other eligibility criteria specified in the Inclusion and Exclusion Criteria
- Pregnancy should be avoided for 12 months after the last dose of GDC-0449 for females of child-bearing potential; female patients of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment
- Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the of GDC-0449 to cause spontaneous abortion or birth defects; female patients are required to use two forms of acceptable contraception, including one barrier method during participation in the study and for the 12 months following the last dose; all patients should receive contraceptive counseling either by the investigator, or by an obstetrician (OB), gynecologist or other physician who is qualified in this area of expertise; if a woman of childbearing potential believes that her contraceptive method has failed, emergency contraception should be considered; if a patient is suspected to be pregnant, GDC-0449 should be immediately discontinued; in addition, a positive urine test must be confirmed by a serum pregnancy test; if it is confirmed that the patients is not pregnant, the patient may resume dosing with GDC-0449; if a female patient becomes pregnant during therapy or within 12 months after the last dose of GDC-0449, or if the female partner of a male patient exposed to the drug becomes pregnant while the male patient is receiving GDC-0449 or within 12 months after the last dose of GDC-0449, the investigator must be notified in order to facilitate outcome follow-up; female patients should not breastfeed a baby while on this study; female patients must NEVER donate ova while being treated with GDC-0449; all sexually active male subjects (including those who have undergone vasectomy) should utilize a barrier form of contraception during study treatment and for 12 months after the last dose as it is not known whether GDC-0449 that may be present in seminal fluid would cause serious or life-threatening birth defects in a fetus born to the female partner of a male subject; males should also not donate sperm during treatment or up to 12 months after the last dose
- Signed informed consent must be obtained including for pharmacokinetic study according to institutional guidelines
Exclusion Criteria:
- Central nervous system (CNS) embryonal tumor other than medulloblastoma; for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), primitive neuroectodermal tumor (PNET) from a non-cerebellar site within the central nervous system, ependymoblastoma, or medulloepithelioma
- Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results
- Patients receiving any other anticancer or investigational drug therapy, or warfarin
- Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
Other: below given criteria are confirmed by the patient history
- Inability to swallow capsules
- Malabsorption syndrome or other condition that would interfere with enteral absorption
- History of congestive heart failure
- History of ventricular arrhythmia requiring medication
- Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation
- Clinically important history of liver disease, including viral or other hepatitis or cirrhosis
Sites / Locations
- Children's Hospital Los Angeles
- Lucile Packard Children's Hospital Stanford University
- Children's National Medical Center
- Lurie Children's Hospital-Chicago
- National Cancer Institute Pediatric Oncology Branch
- Memorial Sloan-Kettering Cancer Center
- Duke University Medical Center
- Cincinnati Children's Hospital Medical Center
- Children's Hospital of Philadelphia
- Children's Hospital of Pittsburgh of UPMC
- St. Jude Children's Research Hospital
- Texas Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (vismodegib)
Arm Description
Patients receive vismodegib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Objective Response (CR+PR) Sustained for ≥ 8 Weeks
Objective response is either a complete response or a partial response sustained for 8 weeks in a patient. The objective response rate will be reported separately for patients of each stratum. CR is complete disappearance of all enhancing tumor. PR is >= 50% reduction in tumor size.
Pharmacokinetics (Plasma) of GDC-0449
plasma GDC-0449 concentration of day 21 in first course
Secondary Outcome Measures
Progression-free Survival
Progression-free survival (PFS) is measured from the date of initial treatment with GDC-0449 until the earliest of progression or death on study. PFS is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment. Kaplan-Meier method is used to estimate the progression-free survival.
Duration of Objective Response
The duration of objective response is measured from the initial scan documenting complete or partial response that was subsequently confirmed until the earlier of documented progression or death on study. Duration of objective response is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment.
Pharmacokinetic Parameters of Vismodegib, CSF Penetration
The estimated median of cerebrospinal fluid (CSF) drug penetration is reported when expressed as an AUC ratio of CSF vismodegib to that of unbound drug in plasma.
Full Information
NCT ID
NCT01239316
First Posted
November 10, 2010
Last Updated
December 10, 2015
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01239316
Brief Title
Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma
Official Title
A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Children With Recurrent or Refractory Medulloblastoma
Study Type
Interventional
2. Study Status
Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
August 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
5. Study Description
Brief Summary
This phase II trial studies how well vismodegib works in treating younger patients with recurrent or refractory medulloblastoma. Vismodegib may slow the growth of tumor cells.
Detailed Description
PRIMARY OBJECTIVES:
I. Estimate the efficacy of GDC-0449 (vismodegib) treatment for pediatric patients with recurrent or refractory medulloblastoma, as measured by the sustained objective response rates for patients without (stratum A) and with (stratum B) evidence of activation of Hedgehog (Hh) signaling pathway in their tumors.
II. Characterize the pharmacokinetics (plasma) of GDC-0449 in children/adolescents with refractory medulloblastoma.
III. To document pathologic and genomic methods to identify medulloblastomas with activation of the Hh signaling pathway.
SECONDARY OBJECTIVES:
I. Document and describe toxicities associated with GDC-0449 administered on a daily schedule.
II. Estimate the duration of objective response and progression-free survival (PFS).
III. Characterize the pharmacokinetics (cerebrospinal fluid) of GDC-0449 in children/adolescents with refractory medulloblastoma.
OUTLINE: This is a multicenter study. Patients are stratified according to evidence of activation of Hedgehog signaling pathway in their tumors (without vs with vs unknown).
Patients receive vismodegib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Plasma and cerebrospinal fluid samples are collected periodically for pharmacokinetic and other correlative studies.
After completion of study treatment, patients are followed up every other month for up to 12 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Childhood Medulloblastoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (vismodegib)
Arm Type
Experimental
Arm Description
Patients receive vismodegib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Vismodegib
Other Intervention Name(s)
Erivedge, GDC-0449, Hedgehog Antagonist GDC-0449
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Objective Response (CR+PR) Sustained for ≥ 8 Weeks
Description
Objective response is either a complete response or a partial response sustained for 8 weeks in a patient. The objective response rate will be reported separately for patients of each stratum. CR is complete disappearance of all enhancing tumor. PR is >= 50% reduction in tumor size.
Time Frame
Up to 12 months
Title
Pharmacokinetics (Plasma) of GDC-0449
Description
plasma GDC-0449 concentration of day 21 in first course
Time Frame
up to 12 month
Secondary Outcome Measure Information:
Title
Progression-free Survival
Description
Progression-free survival (PFS) is measured from the date of initial treatment with GDC-0449 until the earliest of progression or death on study. PFS is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment. Kaplan-Meier method is used to estimate the progression-free survival.
Time Frame
From start of treatment up to 2 years
Title
Duration of Objective Response
Description
The duration of objective response is measured from the initial scan documenting complete or partial response that was subsequently confirmed until the earlier of documented progression or death on study. Duration of objective response is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment.
Time Frame
From start of treatment up to 2 years
Title
Pharmacokinetic Parameters of Vismodegib, CSF Penetration
Description
The estimated median of cerebrospinal fluid (CSF) drug penetration is reported when expressed as an AUC ratio of CSF vismodegib to that of unbound drug in plasma.
Time Frame
up to 12 month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive, or refractory to standard therapy and for which there is no known curative therapy
Patient must have adequate archival formalin fixed, paraffin embedded (FFPE) primary tumor material for biology studies; specifically, adequate archival FFPE tumor material is either:
An FFPE block, preferably in which tumor occupies an area of at least 10x10 mm if available, and is free of surgical or processing artifacts; tumor in the submitted FFPE block must not have been obtained from the CUSA trap OR
Preferably15x5µm sections if available from an FFPE tissue block conforming to the above criteria AND
Tissue submission must be accompanied by a copy of the pathology report
Patients must have bi-dimensionally measureable disease in the brain or spinal cord defined as at least one lesion that can be accurately measured in at least 2 planes in order to be eligible for this study
Patients must have a body surface area (BSA) of >= 0.67m^2 and at most 2.5m^2
Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration; this is to be documented in the database
Karnofsky performance status of >= 50% in patients > 16 years, or Lansky performance status of >= 50% in patients >= 3 yrs and =< 16 years, assessed within two weeks prior to registration
Must have recovered from prior treatment-related toxicity; no other myelosuppressive chemotherapy or immunotherapy within 4 weeks prior to study entry (6 weeks if prior nitrosurea)
Decadron dose should also be stable or decreasing for at least 1 week (7days) prior to starting therapy
Radiation therapy (XRT) >= 3 months prior to study entry for craniospinal irradiation; >= 8 weeks for local irradiation to primary tumor; >= 2 weeks prior to study entry for focal irradiation for symptomatic metastatic sites
Off all colony stimulating factors > 1 week prior to study entry (granulocyte colony stimulating factor [GCSF], granulocyte macrophage colony stimulating factor [GM CSF], erythropoietin)
Prior therapy will include primary therapy (including radiation therapy and chemotherapy) and a maximum of 2 additional salvage therapies; patients can enroll on the protocol after failure on primary therapy
Absolute neutrophil count (ANC) >= 1000 µL
Platelet count >= 50,000/uL (transfusion independent)
Hemoglobin >= 8.0 gm/dL (may receive red blood cell [RBC] transfusions)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 or a serum creatinine =< 1.5 mg/dL
Serum Total Bilirubin =< 1.5 x upper limit of normal (ULN) for age
Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 times institutional ULN for age
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times institutional ULN for age
Alkaline Phosphatase =< 1.5 times institutional ULN
Serum albumin >= 2.5 g/dL
Patient must have recovered from the significant acute toxicities of all prior therapy before entering this study and meet all other eligibility criteria specified in the Inclusion and Exclusion Criteria
Pregnancy should be avoided for 12 months after the last dose of GDC-0449 for females of child-bearing potential; female patients of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment
Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the of GDC-0449 to cause spontaneous abortion or birth defects; female patients are required to use two forms of acceptable contraception, including one barrier method during participation in the study and for the 12 months following the last dose; all patients should receive contraceptive counseling either by the investigator, or by an obstetrician (OB), gynecologist or other physician who is qualified in this area of expertise; if a woman of childbearing potential believes that her contraceptive method has failed, emergency contraception should be considered; if a patient is suspected to be pregnant, GDC-0449 should be immediately discontinued; in addition, a positive urine test must be confirmed by a serum pregnancy test; if it is confirmed that the patients is not pregnant, the patient may resume dosing with GDC-0449; if a female patient becomes pregnant during therapy or within 12 months after the last dose of GDC-0449, or if the female partner of a male patient exposed to the drug becomes pregnant while the male patient is receiving GDC-0449 or within 12 months after the last dose of GDC-0449, the investigator must be notified in order to facilitate outcome follow-up; female patients should not breastfeed a baby while on this study; female patients must NEVER donate ova while being treated with GDC-0449; all sexually active male subjects (including those who have undergone vasectomy) should utilize a barrier form of contraception during study treatment and for 12 months after the last dose as it is not known whether GDC-0449 that may be present in seminal fluid would cause serious or life-threatening birth defects in a fetus born to the female partner of a male subject; males should also not donate sperm during treatment or up to 12 months after the last dose
Signed informed consent must be obtained including for pharmacokinetic study according to institutional guidelines
Exclusion Criteria:
Central nervous system (CNS) embryonal tumor other than medulloblastoma; for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), primitive neuroectodermal tumor (PNET) from a non-cerebellar site within the central nervous system, ependymoblastoma, or medulloepithelioma
Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results
Patients receiving any other anticancer or investigational drug therapy, or warfarin
Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
Other: below given criteria are confirmed by the patient history
Inability to swallow capsules
Malabsorption syndrome or other condition that would interfere with enteral absorption
History of congestive heart failure
History of ventricular arrhythmia requiring medication
Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation
Clinically important history of liver disease, including viral or other hepatitis or cirrhosis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amar Gajjar
Organizational Affiliation
Pediatric Brain Tumor Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Lucile Packard Children's Hospital Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Lurie Children's Hospital-Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
National Cancer Institute Pediatric Oncology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
26169613
Citation
Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, Packer RJ, Goldman S, Prados MD, Desjardins A, Chintagumpala M, Takebe N, Kaste SC, Rusch M, Allen SJ, Onar-Thomas A, Stewart CF, Fouladi M, Boyett JM, Gilbertson RJ, Curran T, Ellison DW, Gajjar A. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015 Aug 20;33(24):2646-54. doi: 10.1200/JCO.2014.60.1591. Epub 2015 Jul 13.
Results Reference
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Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma
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