study did not reach benchmark efficacy rule at 16 subjects

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).

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.

16 months

The adverse events were gathered in Common Terminology Criteria for Adverse Events v.3.0, and have been converted to v.4.0 for entry into ClinicalTrials.gov