An International, Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma (The “ACT IV” Study)
Trial Purpose and Description
This is an international, multicenter, double-blind clinical trial of rindopepimut in which up to 440 patients with newly diagnosed, resected, EGFRvIII positive glioblastoma will, after completion of standard chemoradiation, be randomized to receive either rindopepimut/GM-CSF or control (KLH), in combination with standard adjuvant temozolomide. Randomization will occur in a 1:1 ratio and will be stratified according to MGMT status (methylated/unmethylated/unknown), EORTC (adapted) RPA class (III or IV) (Mirimanoff, Gorlia et al. 2006) and geographical region (North America/Western Europe vs. Other).
After completion of screening assessments and determination of eligibility, enrolled patients will be randomized to receive two “priming” doses of either rindopepimut/GM-CSF vaccination or control vaccination (KLH) (hereafter referred to as “double-blind vaccine”) in a double-blind fashion. Approximately one week later, monthly cycles of TMZ will be given in combination with double-blind vaccine. TMZ will continue in accordance with local standards of care with a goal of six to twelve cycles, or until intolerance or disease progression. Greater than twelve cycles of temozolomide may be considered for individual patients on a case-by case basis after discussion with Celldex (or designee). Double-blind vaccine will continue every 28 days during and following TMZ, until intolerance or disease progression.
Screening assessments will include central review of tumor tissue including pathologic confirmation of glioblastoma, EGFRvIII expression status, and MGMT promoter methylation status. Brain MRIs from the post-operative period (ideally obtained with 72 hours of surgery) and post-chemoradiation period (within 1-14 days of completion of chemoradiation) will be obtained, and brain MRI will be conducted approximately every 12 weeks until disease progression, and whenever progression is suspected based on clinical symptoms. (Note: In certain circumstances where MRI is not possible for a particular patient, CT scans may be utilized. However, the same imaging modality must be used from the post-chemoradiation scan throughout the study.) For the purpose of treatment decisions, progression will be assessed by the treating investigator. For the analysis of the study endpoints (progression-free survival and tumor response), an external, independent review of radiologic imaging, blinded to treatment allocation and investigator assessments, will be performed. In all cases, progression-free survival and tumor response will be assessed using the RANO response criteria for high-grade gliomas (Wen, Macdonald et al. 2010), which considers radiologic imaging, neurological status, and steroid dosing. Additionally, health-related quality of life will be assessed in a subset of patients (those who speak a language in which the questionnaire(s) are validated) via the EORTC core Quality of Life Questionnaire (QLQ-C30) and Brain Cancer Module (BN20), while the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) will be utilized to capture patient self reports of symptom severity and interference with daily activities throughout the treatment period. Humoral immunologic response will be measured at baseline and at selected times following vaccination and at the time of disease progression. HLA typing will also be performed at baseline. Safety will be evaluated throughout the trial by the incidence of adverse events, physical examination findings, vital signs and clinical laboratory test results. Adverse events will be graded for severity using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0, and collection of adverse events will continue until 28 days after the last dose of trial treatment or until the initiation of subsequent anticancer treatment, whichever occurs first. Any serious adverse event occurring any time after the reporting period must be promptly reported if a causal relationship to study treatment (double-blind vaccine) is suspected. If a tumor biopsy or resection is performed upon progression, all attempts should be made to send tissue to the sponsor-designated centralized laboratory for repeat analysis of EGFRvIII expression and possibly other tumor or immune markers. Following documentation of disease progression, all patients will be followed every 12 weeks for survival status until study closure.
An independent data monitoring committee (DMC) will be convened for this study and will act in an advisory capacity to the sponsor with respect to safeguarding the interests of study patients, assessing interim safety and efficacy data, and for monitoring the overall conduct of the study.
- 18 Years and older
Patients may be included in the study only if they meet all of the following inclusion criteria at the time of randomization:
1) Histologically confirmed, newly diagnosed, de novo glioblastoma including the following recognized variants of glioblastoma: small cell glioblastoma, giant cell glioblastoma, gliosarcoma and glioblastoma with oligodendroglial component (central pathologic review will be performed and histologic confirmation will be required prior to study entry).
2) Attempted surgical resection followed by conventional chemoradiation, consisting of radiotherapy at a minimally acceptable total dose of at least 90% of the planned dose (approximately 60 Gy) of absorbed radiation, concurrent with temozolomide at a targeted dose of 75 mg/m2
3) Tumor tissue specimens (paraffin-embedded) from surgical resection must be available for central pathology review, MGMT status determination and analysis of EGFRvIII status. body surface area per day. Patients who received an incomplete course of temozolomide may be eligible, provided inclusion criterion 7 is met.
4) Documented EGFRvIII positive tumor status, determined by polymerase chain reaction (PCR) assay on tumor tissue, performed at a sponsor-designated central laboratory.
5) Brain MRIs from the post-operative period (ideally obtained within 72 hours of surgery) and post-chemoradiation period (within 1-14 days of completion of chemoradiation) available for submission to the independent review committee by the time of randomization. (Note: In certain circumstances where MRI is not possible for a particular patient, CT scans may be utilized. However, the same imaging modality must be used from the post-chemoradiation scan throughout the study.)
6) No evidence of progressive disease from the post-operative period to the post-chemoradiation period, based on changes in the neurologic exam, steroid use, or evident radiographic progression, according to RANO criteria.
7) Candidate for, and agrees to receive, adjuvant (maintenance) temozolomide therapy.
8) Systemic corticosteroid therapy at ≤2 mg of dexamethasone or equivalent per day for at least 3 days prior to randomization
9) WHO-ECOG Performance Status (Appendix 3) ≤ 2 throughout the week prior to randomization.
10)Men or women who are 18 years of age or older
11) Patients of childbearing/ reproductive potential should use highly effective method of birth control as defined by the investigator, for example those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.
12) Personally signed and dated informed consent document indicating that the patient has been informed of and agreed with all pertinent aspects of the study
Exclusion Criteria :
Patients will be excluded from the study for any of the following reasons:
1) Stereotactic biopsy only (without further surgical resection)
2) Presence of diffuse leptomeningeal disease or gliomatosis cerebri
3) History, presence, or suspicion of metastatic disease
4) Patients who have received any additional treatment for glioblastoma, aside from surgical resection and chemoradiation with temozolomide. Agents used for diagnosis, imaging or visualization, even if investigational, are not exclusionary. Exclusionary treatments would include, but are not limited to: stereotactic radiosurgery, placement of Gliadel® (carmustine; BCNU) wafers, any other any other intratumoral or intracavity treatment, receipt of other chemotherapies, bevacizumab, or investigational agents.
5) Active systemic infection requiring treatment. A patient with an infection controlled by therapy will not be excluded provided it is not consistent with exclusion criterion 7.
6) History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with PSA level less than ULN.
7) Severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or trial drug administration or could interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into the trial. This includes but is not limited to the following:
a) HIV, or chronic hepatitis B or hepatitis C infection,
b) Immunosuppressive disease,
c) Chronic renal disease / failure,
d) Concurrent neurodegenerative disease,
e) Cardiovascular: uncontrolled hypertension, unstable angina, myocardial infarction or symptomatic congestive heart failure within the past 12 months or serious uncontrolled cardiac arrhythmia,
f) Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol.
8) Planned major surgery.
9) Evidence of current drug or alcohol abuse.
10)Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 7 days prior to starting treatment (Priming Day 1).
11)Known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins.
- Celldex Therapeutics
- May 2012
- Last Updated:
- Study HIC#:
Clinicaltrials.gov ID: Yale9431225