Malignant Glioma of Brain
Conditions
Keywords
Panitumumab, Vectibix, Irinotecan, CPT-11, Camptosar, Malignant glioma, Glioblastoma multiforme, Gliosarcoma, Duke, Vredenburgh, Pro00015447
Brief summary
This is a phase II study of the combination of panitumumab with irinotecan in malignant glioma patients. The primary objective of the study is to determine the activity of the combination of panitumumab with irinotecan as measured by 6-month progression-free survival. Secondary objectives include the following- to determine the safety of panitumumab in combination with irinotecan in patients with malignant glioma; to determine the effect of panitumumab in combination with irinotecan on corticosteroid dose for each patient; to explore any relationship between epidermal growth factor receptor (EGF-R) mutational analysis and efficacy or toxicity; and, to determine the response rate and overall survival of recurrent glioblastoma (GBM) patients treated with panitumumab in combination with irinotecan. The patients will have histologically documented grade 4 malignant gliomas (glioblastoma multiforme or gliosarcoma) that have failed at least one prior chemotherapy regimen and all patients will have received radiation therapy. This study will investigate second or greater line of therapy for recurrent grade 4 malignant glioma. The patient population will include 32 patients. The patients will undergo a baseline magnetic resonance imaging (MRI) as well as a MRI after every six-week cycle to determine response and progression. After 16 patients with recurrent GBM are treated, an interim analysis will be conducted. The most common side effects associated with panitumumab have been dermatological (skin) problems such as erythema (redness of the skin), acneiform rash (skin eruptions of the face), skin exfoliation, pruritus (itching), skin fissures (skin tears), xerosis (dryness of the eye, skin, or mouth), and rash. The most common side effects associated with irinotecan have been decreased blood counts of platelets (increased risk of bleeding), white blood cells (increased risk of infection), red blood cells (anemia); diarrhea, constipation, nausea, vomiting, tiredness, fever, mouth sores, dehydration (excessive loss of body fluids), rash, itching, changes in skin color, swelling, numbness, tingling, dizziness, confusion, low blood pressure, sweating, hot flashes, hair loss, inflammation of the liver, flu-like symptoms, decreased urine output, shortness of breath, and pneumonia (inflammatory disease of the lungs).
Interventions
DRUGIrinotecan
Irinotecan: for those patients on an enzyme-inducing anti-epileptic drug (EIAED), irinotecan will be dosed at 340 mg/m2 every other week. For those not on an EIAED, irinotecan will be dosed at 125 mg/m2. Treatment on both drugs will continue until tumor progression or unacceptable toxicity.
DRUGPanitumumab
Panitumumab, 6 mg/kg, as an intravenous infusion every other week. Treatment on both drugs will continue until tumor progression or unacceptable toxicity.
Sponsors
Amgen
Annick Desjardins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed diagnosis of primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients with recurrent disease whose diagnostic pathology confirmed grade IV malignant glioma (glioblastoma multiforme or gliosarcoma) will not need re-biopsy. * Age ≥ 18 years. * Evidence of measurable recurrent or residual primary central nervous system (CNS) neoplasm on contrast-enhanced MRI * An interval of at least 4 weeks between prior surgical resection, or major surgery requiring general anesthesia or 1 week between prior biopsy or minor surgical procedures and study enrollment. The subjects must have recovered from all surgery related toxicities. * An interval of at least 12 weeks between prior radiotherapy or 4 weeks from prior monthly chemotherapy, or 7 days from daily chemotherapy. * The lab values following the prior chemotherapy must return to the baseline prior to study enrollment. * Karnofsky ≥ 70%. * Hematocrit ≥ 29%, absolute neutrophil count (ANC) ≥ 1,500 cells/μl, platelets ≥ 125,000 cells/μl. * Serum creatinine ≤ 1.5 mg/dl, serum magnesium, potassium, calcium, chloride, and sodium ≥ the lower limit of normal, serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal. * Signed informed consent approved by the Institutional Review Board prior to patient entry. * If sexually active, patients will take contraceptive measures for the duration of the treatments, and for 6 months afterwards.
Exclusion criteria
* Pregnancy or breast feeding * Co-medication that may interfere with study results; e.g. immuno¬suppressive agents other than corticosteroids. * Active infection requiring intravenous antibiotics. * uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) homozygous for the 7/7 genotype. * Pre-existing diarrhea greater than Grade 1. Panitumumab-Specific Concerns: \[Subjects meeting any of the following criteria are ineligible for study entry\] * Prior anti-epidermal growth factor receptor (EGFr) antibody therapy or treatment with small molecule EGFr inhibitors * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrollment. * History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan. * History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results. * Subject unwilling or unable to comply with study requirements * Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. * Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment. * Known positive test(s) for human immunodeficiency virus infection, hepatitis C virus, acute or chronic active hepatitis B infection(testing is not required in the absence of clinical suspicion) * Patients with a history of deep venous thrombosis, pulmonary embolism or on therapeutic anti-coagulation. * Known allergy or hypersensitivity to any component of the study treatment(s) * Active infection requiring systemic intravenous treatment of any uncontrolled infections ≤14 days prior to enrollment/randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Progression-free Survival (PFS) | 6 months | Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), and 3) concomitant steroid use (as reported by the investigator). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Panitumumab in Combination With Irinotecan | 16 months | Number of participants experiencing a toxicity ≥ grade 3 as graded per CTCAE v.3.0 |
| Effect of Panitumumab in Combination With Irinotecan on Corticosteroid Dose | Baseline and Day 29 | Average change in corticosteroid dose from baseline to the end of cycle 1. |
| One-Year Overall Survival | 1 year | Percentage of participants surviving 12 months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of the death due to any cause. |
| Objective Response Rate | 16 months | Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. A complete response is defined as the disappearance of all enhancing rumor and mass effect, off all corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. A partial response is defined as greater than or equal to 50% reduction in tumor size on MR (magnetic resonance) / CT(computed tomography) by bi-dimensional measurement on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. |
| Median Overall Survival (OS) | 18 months | Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve. |
| Relationship Between Epidermal Growth Factor Receptor (EGF-R) Mutational Analysis and Efficacy or Toxicity | 16 months | Number of participants with an abnormal fluorescence in situ hybridization (FISH) interpretation that 1) survived \< 6 months and 2) experienced a ≥ grade 3 toxicity as graded per CTCAE v.3.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab and Irinotecan Panitumumab in Combination with Irinotecan : Panitumumab, 6mg/kg, as an intravenous infusion every other week in combination with Irinotecan (dose dependent upon whether the patient is taking an enzyme-inducing anti-epileptic drug \[EIAED\]). On an enzyme-inducing anti-epileptic drug (EIAED), irinotecan will be dosed at 340 mg/m2 every other week. Not on an EIAED, irinotecan will be dosed at 125 mg/m2. Treatment will continue until tumor progression or unacceptable toxicity. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Panitumumab and Irinotecan |
|---|---|
| Age Continuous | 48.73 years STANDARD_DEVIATION 14.58 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 1 / 16 |
Outcome results
Primary
6-month Progression-free Survival (PFS)
Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), and 3) concomitant steroid use (as reported by the investigator).
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab and Irinotecan | 6-month Progression-free Survival (PFS) | 12.5 percentage of participants |
Secondary
Effect of Panitumumab in Combination With Irinotecan on Corticosteroid Dose
Average change in corticosteroid dose from baseline to the end of cycle 1.
Time frame: Baseline and Day 29
Population: Insufficient data to analyze the effect of the treatment regimen on corticosteroid dose. Data was not collected for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab and Irinotecan | Effect of Panitumumab in Combination With Irinotecan on Corticosteroid Dose | NA mg |
Secondary
Median Overall Survival (OS)
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab and Irinotecan | Median Overall Survival (OS) | 4.6 months |
Secondary
Objective Response Rate
Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. A complete response is defined as the disappearance of all enhancing rumor and mass effect, off all corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. A partial response is defined as greater than or equal to 50% reduction in tumor size on MR (magnetic resonance) / CT(computed tomography) by bi-dimensional measurement on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.
Time frame: 16 months
Population: 2 patients' response was unknown due to withdrawal from the study before an MRI was performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab and Irinotecan | Objective Response Rate | 0 participants |
Secondary
One-Year Overall Survival
Percentage of participants surviving 12 months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of the death due to any cause.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab and Irinotecan | One-Year Overall Survival | 12.5 percentage of participants |
Secondary
Relationship Between Epidermal Growth Factor Receptor (EGF-R) Mutational Analysis and Efficacy or Toxicity
Number of participants with an abnormal fluorescence in situ hybridization (FISH) interpretation that 1) survived \< 6 months and 2) experienced a ≥ grade 3 toxicity as graded per CTCAE v.3.0
Time frame: 16 months
Population: Insufficient data to analyze the relationship between EGF-R analysis and efficacy or toxicity. Data was not collected for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab and Irinotecan | Relationship Between Epidermal Growth Factor Receptor (EGF-R) Mutational Analysis and Efficacy or Toxicity | Abnormal FISH Interpretation & ≥ grade 3 toxicity | NA participants |
| Panitumumab and Irinotecan | Relationship Between Epidermal Growth Factor Receptor (EGF-R) Mutational Analysis and Efficacy or Toxicity | Abnormal FISH Interpretation & Survived <6 months | NA participants |
Secondary
Safety of Panitumumab in Combination With Irinotecan
Number of participants experiencing a toxicity ≥ grade 3 as graded per CTCAE v.3.0
Time frame: 16 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab and Irinotecan | Safety of Panitumumab in Combination With Irinotecan | 10 participants |