Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Diffuse Intrinsic Pontine Glioma, Gliosarcoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of vorinostat and to see how well it works when given together with radiation therapy followed by maintenance therapy with vorinostat in treating younger patients with newly diagnosed diffuse intrinsic pontine glioma (a brainstem tumor). Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with radiation therapy may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: l. To estimate the maximum tolerated dose (MTD) or recommend a phase 2 dose of vorinostat given concurrently with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). II. To define and describe the toxicities of vorinostat given concurrently with radiation in children with newly diagnosed DIPG. III. To determine, in the context of this phase I/II trial, the anti-tumor activity of combining vorinostat with radiation, followed by maintenance vorinostat for twelve courses, in children with newly diagnosed DIPG, as measured by 12-month event-free survival (EFS) and overall survival (OS). IV. To determine the toxicities of vorinostat for 12 additional courses after completion of vorinostat and radiation. SECONDARY OBJECTIVES: I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMCs) before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation. II. To measure histone deacetylase 2 (HDAC2) levels and assess histone acetylation in PBMCs before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation. III. To quantify deoxyribonucleic acid (DNA) repair proteins from the NHEJ and homologous recombination repair (HHR) pathways in tumors by either Western analysis or immunohistochemistry, if paraffin-embedded tumor is available. OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study. Patients receive vorinostat orally (PO) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients undergo 3-dimensional (3D) conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. Patients then receive maintenance therapy comprising vorinostat PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal radiation therapy
RADIATIONIntensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGVorinostat
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
37 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are eligible without histologic confirmation; patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, or anaplastic mixed glioma; patients with juvenile pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible; patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician * Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 for patients =\< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score * Patients must not have received any prior treatment except dexamethasone and/or surgery * Peripheral absolute neutrophil count (ANC) \>= 1000/uL * Platelet count \>= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment) * Hemoglobin \>= 8.0 g/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 based on age/gender as follows: * 0.8 mg/dL (3 to \< 6 years of age) * 1 mg/dL (6 to \< 10 years of age) * 1.2 mg/dL (10 to \< 13 years of age) * 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to \< 16 years of age) * 1.7 mg/dL (male) or 1.4 mg/dL (female) (\>= 16 years of age) * Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 110 U/L; for the purpose of this study, the ULN for SGPT (ALT) is 45 U/L * Serum albumin \>= 2 g/dL * Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants (with the exception of valproic acid) and seizures are well controlled * Patients must be able to swallow capsules or liquids; patients dependent on nasogastric (NG) tube feeding are not permitted to receive protocol therapy * Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date
Exclusion criteria
* Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method * Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment * Patients who are currently receiving another investigational drug are not eligible * Patients who are currently receiving other anti-cancer agents are not eligible * Patients must not currently be receiving enzyme inducing anticonvulsants * Patients on valproic acid must discontinue valproic acid for at least 2 weeks before starting protocol therapy * Patients receiving coumadin, heparin, low-molecular weight heparin, or any other anti-coagulants are not eligible for study entry * Patients receiving acetylsalicylic acid (ASA) (\> 81 mg/day), non-steroidal anti-inflammatory drugs, clopidogrel (Plavix), dipyridamole (Persantine), or any other drug that inhibits platelet function are not eligible for study entry * Patients who have an uncontrolled infection are not eligible * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Toxicity During Maintenance Therapy | Planned 12 months of maintenance with Vorinostat | Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience |
| Maximum Tolerated Dose (MTD) of Vorinostat | Planned 7 weeks during chemoradiotherapy | The dose of vorinostat in mg/sqm/day to be administered with combination chemotherapy and radiation therapy |
| Event-Free Survival | 2 years after study enrollment | Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first. |
| Incidence of Toxicity During Chemoradiation Therapy | Planned 7 weeks during chemoradiotherapy | Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years after study enrollment | Time from enrollment to death or last follow-up, whichever occurs first. |
| Change in H3 and H4 Acetylation Levels in PBMCs | Baseline to up to 7 weeks | Degree of acetylation in peripheral blood monocytes will be divided into quartiles and coded as none, mild, moderation or marked. |
| Change in NHEJ Activity in PBMCs | Baseline to up to 7 weeks | Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points. |
| Levels of DNA Repair Proteins in Paraffin-embedded Blocks, Measured Via Immunohistochemistry or Western Analysis | Baseline | For immunohistochemistry from tumor blocks, the intensity will be graded from 1 to 3; for Western analysis, a percentage of the intensity relative to the tumor with the highest level will be measured. |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
Phase I /II study. Phase I determined Maximum Tolerated Dose between the first 2 treatment arms; zero patients completed therapy. Study was closed, then reopened to accrual. Phase II enrolled an additional 67 patients. Overall, 79 patients were enrolled but only 2 patients completed all 12 cycles of maintenance chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Phase I Vorinostat 180 mg/m^2 Patients in phase I received vorinostat at 180 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
3-Dimensional Conformal Radiation Therapy: Undergo 3D conformal radiation therapy
Intensity-Modulated Radiation Therapy: Undergo intensity-modulated radiation therapy
Laboratory Biomarker Analysis: Correlative studies
Vorinostat: Given PO | 6 |
| Arm 2 Phase 1 Vorinostat 230 mg/m^2 Patients received a higher dose of vorinostat at 230 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
3-Dimensional Conformal Radiation Therapy: Undergo 3D conformal radiation therapy
Intensity-Modulated Radiation Therapy: Undergo intensity-modulated radiation therapy
Laboratory Biomarker Analysis: Correlative studies
Vorinostat: Given PO | 6 |
| Arm 3 Phase II Evaluation Vorinostat 230 mg/m^2 Patients received a higher dose of vorinostat at 230 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/ day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
3-Dimensional Conformal Radiation Therapy: Undergo 3D conformal radiation therapy
Intensity-Modulated Radiation Therapy: Undergo intensity-modulated radiation therapy
Laboratory Biomarker Analysis: Correlative studies
Vorinostat: Given PO | 67 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 5 |
| Overall Study | Death | 0 | 0 | 5 |
| Overall Study | Lack of Efficacy | 4 | 5 | 44 |
| Overall Study | No treatment | 0 | 0 | 1 |
| Overall Study | Patient refuses further therapy | 1 | 0 | 7 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1 Phase I Vorinostat 180 mg/m^2 | Arm 2 Phase 1 Vorinostat 230 mg/m^2 | Arm 3 Phase II Evaluation Vorinostat 230 mg/m^2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 66 Participants | 78 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 6 years | 9 years | 6 years | 6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 15 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 51 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 9 Participants | 10 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 47 Participants | 58 Participants |
| Region of Enrollment Australia | 0 participants | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Puerto Rico | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 5 participants | 5 participants | 62 participants | 62 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 36 Participants | 44 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 31 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 6 | 6 / 6 | 62 / 65 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 51 / 65 |
| serious Total, serious adverse events | 6 / 6 | 5 / 6 | 55 / 65 |
Outcome results
Primary
Event-Free Survival
Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first.
Time frame: 2 years after study enrollment
Population: One patient enrolled on Arm 3 was withdrawn from study prior to the start of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase 1 Study Participants | Event-Free Survival | 0 percent probability |
| Arm 2, Phase I Vorinostat 230 mg/m^2 | Event-Free Survival | 0 percent probability |
| Arm 3, Phase II Evaluation Vorinostat 230 mg/m^2 | Event-Free Survival | 3.1 percent probability |
Primary
Incidence of Toxicity During Chemoradiation Therapy
Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience
Time frame: Planned 7 weeks during chemoradiotherapy
Population: All patients enrolled on Arm 1 and 2 received at least one dose of chemoradiation therapy. Two patients enrolled on arm 3 did not receive protocol therapy prior to date of removal from protocol therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase 1 Study Participants | Incidence of Toxicity During Chemoradiation Therapy | 5 Participants |
| Arm 2, Phase I Vorinostat 230 mg/m^2 | Incidence of Toxicity During Chemoradiation Therapy | 2 Participants |
| Arm 3, Phase II Evaluation Vorinostat 230 mg/m^2 | Incidence of Toxicity During Chemoradiation Therapy | 24 Participants |
Primary
Incidence of Toxicity During Maintenance Therapy
Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience
Time frame: Planned 12 months of maintenance with Vorinostat
Population: All patients enrolled on arm 1 and 2 received at least one dose of maintenance therapy. Seven patients enrolled on arm 3 did not receive maintenance therapy prior to date of removal from protocol therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase 1 Study Participants | Incidence of Toxicity During Maintenance Therapy | 6 Participants |
| Arm 2, Phase I Vorinostat 230 mg/m^2 | Incidence of Toxicity During Maintenance Therapy | 4 Participants |
| Arm 3, Phase II Evaluation Vorinostat 230 mg/m^2 | Incidence of Toxicity During Maintenance Therapy | 39 Participants |
Primary
Maximum Tolerated Dose (MTD) of Vorinostat
The dose of vorinostat in mg/sqm/day to be administered with combination chemotherapy and radiation therapy
Time frame: Planned 7 weeks during chemoradiotherapy
Population: All patients enrolled on arm 1 and 2 who received at least 85% of the planned doses of radiation therapy and chemotherapy in the chemoradiotherapy portion of the study or who experienced DLT after after receiving at least one dose of chemoradio therapy and completing 7 weeks fo follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase 1 Study Participants | Maximum Tolerated Dose (MTD) of Vorinostat | 230 mg/m^2 |
Secondary
Change in H3 and H4 Acetylation Levels in PBMCs
Degree of acetylation in peripheral blood monocytes will be divided into quartiles and coded as none, mild, moderation or marked.
Time frame: Baseline to up to 7 weeks
Population: Due to budgetary issues the planned laboratory testing was not performed and no data were collected
Secondary
Change in NHEJ Activity in PBMCs
Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points.
Time frame: Baseline to up to 7 weeks
Population: Due to budgetary issues the planned laboratory testing was not performed and no data were collected
Secondary
Levels of DNA Repair Proteins in Paraffin-embedded Blocks, Measured Via Immunohistochemistry or Western Analysis
For immunohistochemistry from tumor blocks, the intensity will be graded from 1 to 3; for Western analysis, a percentage of the intensity relative to the tumor with the highest level will be measured.
Time frame: Baseline
Population: Due to budgetary issues the planned laboratory testing was not performed and no data were collected
Secondary
Overall Survival
Time from enrollment to death or last follow-up, whichever occurs first.
Time frame: 2 years after study enrollment
Population: One patient enrolled on Arm 3 was withdrawn from study prior to the start of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase 1 Study Participants | Overall Survival | 22 percent probability |
| Arm 2, Phase I Vorinostat 230 mg/m^2 | Overall Survival | 0 percent probability |
| Arm 3, Phase II Evaluation Vorinostat 230 mg/m^2 | Overall Survival | 3.1 percent probability |