| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to confirm that the addition of rindopepimut/GM-CSF to adjuvant temozolomide improves overall survival in patients with newly diagnosed, resected, EGFRvIII positive glioblastoma who have undergone gross-total resection. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
• Compare Progression-Free Survival between the two treatment arms
• Further characterize the safety and tolerability profile of the rindopepimut vaccination in combination with temozolomide
• Assess health-related quality of life and symptom severity/interference using the patient-reported tools, QLQ-C30/BN20 and MDASI-BT.
• Compare objective tumor response rates between the two treatment arms (applicable only for patients with evaluable disease at study entry, as defined per RANO criteria).
Correlative Objectives:
• Further characterize the EGFRvIII-specific immune response to rindopepimut vaccinations and the overall immunogenicity of the vaccine
• Assess whether treatment with rindopepimut/GM-CSF results in elimination of EGFRvIII expression |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 radiation therapy dose (usually 60 Gy) and concomitant TMZ chemotherapy (75mg/m2 body surface area per day). Patients who received an incomplete course or lower dose of temozolomide may be eligible, provided all other entry criteria are
met.
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) Radiographic imaging from the post-operative period (ideally obtained within 72 hours of surgery, but acceptable if obtained up to the initiation of chemoradiation) and post-chemoradiation period (within 14 days of completion of chemoradiation) available for submission to the independent review committee. If multiple scans are performed within the period after surgery but prior to chemoradiation, all should be
submitted. (Note: Although the preferred imaging modality is MRI, in certain circumstances where MRI is not possible for a particular patient, CT scans may be utilized. However, contrast-enhanced scans are required and the same imaging modality must be used from the post-chemoradiation scan throughout the study.)
6) No unequivocal radiographic progression of disease during the pre-study chemoradiation period. This assessment should be based on review of the latest interpretable scan performed within the time interval between surgery and the first day of chemoradiation, as compared to the post-chemoradiation (baseline) scan.
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 |
|
| E.4 | Principal 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, or infratentorial disease
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. Infection controlled by therapy will not be exclusionary 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, cured early-stage prostate cancer in a
patient with PSA level less than ULN, or other carcinoma in situ that has
been adequately treated and cured.
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary end point is overall survival defined as the time from date of randomization to death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Progression free survival (PFS), defined as the time from randomization to the date of progression (recurrence in the case of fully resected disease) or death due to any cause. An external, independent review of radiologic imaging, blinded to treatment allocation and investigator assessments, will be performed.
• Safety profile characterized by type, frequency, severity and relationship to investigational therapy of adverse events and laboratory abnormalities
• Health-related quality of life and symptom severity and interference, as per the patient-reported tools, QLQ-C30/BN20 and MDASI-BT.
• Objective tumor response rate (applicable only for patients with evaluable disease at study entry, as defined per RANO criteria).
Correlative Endpoint:
• Specific humoral immune responses to EGFRvIII
• Post-treatment EGFRvIII expression status, assessed via biopsies or resection samples of recurrent tumor tissue. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Greece |
| Italy |
| Austria |
| Netherlands |
| New Zealand |
| Australia |
| Brazil |
| Colombia |
| Czech Republic |
| Germany |
| Hungary |
| India |
| Spain |
| Thailand |
| Israel |
| Mexico |
| Peru |
| Poland |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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