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 EGFRvIII positive glioblastoma who have undergone gross-total resection.
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
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
Background summary
The rationale for the therapeutic use of rindopepimut/GM-CSF to treat
glioblastoma has several foundations. Given that glioblastoma is highly
infiltrative and cannot be completely resected even when diagnosed very early,
the treatment of glioblastoma remains palliative in that no current treatments
are curative. Rindopepimut is a vaccine designed to generate an immune response
against the tumor-specific antigen EGFRvIII. In the setting of
EGFRvIII-positive glioblastomas, this immune response is intended to prevent
the expansion of tumor cells that remain after surgery and radiochemotherapy in
order to increase Progression Free Survival (PFS) and Overall Survival (OS).
The aim of this randomized trial is to assess the therapeutic activity of
rindopepimut/GM-CSF with adjuvant Temozolomide (TMZ) in patients with newly
diagnosed, surgically resected, EGFRvIII-positive glioblastoma.
Study objective
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 EGFRvIII positive glioblastoma who have undergone
gross-total resection.
Study design
This is a multicenter, double-blind, clinical trial of rindopepimut in which up
to 440 eligible patients with newly diagnosed, resected, EGFRvIII-positive
glioblastoma will, after completion of standard chemoradiation, be randomized
to receive and start either rindopepimut/GM-CSF or control (KLH), in
combination with standard adjuvant TMZ. Randomization will occur in a 1:1 ratio
and will be stratified according to country, age, mini-mental status
examination (MMSE) and MGMT promotor methylation status.
Intervention
.Beginning 7-14 days after completion of standard chemoradiation therapy,
patients will receive two priming doses of double-blind vaccine (either
rindopepimut/GMCSF or KLH) via intradermal injection, two weeks apart (on
Priming Days 1 and 15). Patients randomized to receive rindopepimut will
receive a total of 0.8 ml containing approximately 500 mcg rindopepimut and 150
mcg GM-CSF, while patients randomized to control will receive 0.8 ml containing
100 mcg of KLH. Adjuvant Temozolomide / Vaccine Phase (TMZ-V)
* TMZ will begin no sooner than 28 days after completion of concomitant
temozolomide radiation therapy and no sooner than six days after the last
priming dose of double-blind vaccine, and only when the absolute neutrophil
count (ANC) is -1000/*l and the platelet count is -100,000/*l
.* TMZ will be dosed on days 1-5 of repeated 28-day cycles. A temozolomide dose
of 150 mg/m2 body surface area per day will typically be given for the first
cycle of TMZ. This dose may increase to 200 mg/m2 body surface area per day in
subsequent TMZ cycles, in the absence of Grade 3 and 4 hematological toxicity
(nadir) and adequate count recovery after the first cycle. Any change in weight
of more than 10% will require re-calculation of the administered TMZ dose;
otherwise, dosing may be based on the baseline weight. The total dose of TMZ
shall be rounded as necessary to accommodate available pill strengths. TMZ
should continue for a minimum of six cycles and up to a maximum of 12 cycles,
until patient refusal, intolerance or progression in accordance with local
standards of care. Greater than twelve cycles of TMZ may be considered for
individual patients on a case-by case basis after discussion with Celldex (or
designee).
* During TMZ, double-blind vaccine should be administered on the 22nd day of
each TMZ cycle (-3/+1 days). Vaccine Maintenance Therapy (VMT)
* Following completion or discontinuation of TMZ for reason other than tumor
progression, double-blind vaccine maintenance therapy (VMT) will begin with the
first VMT dose 28 days (±3 days) after last vaccination administered during the
TMZ component of trial therapy. Double-blind vaccine will continue monthly (Day
1±3 days of each 28 day cycle) until patient refusal, intolerance or tumor
progression.
Study burden and risks
A detailed risk/benefit analysis for the use of Rindopepimut/GM-CSF in the
study population is available on Section 7.7 of the Rindopepimut Investigator
Brochure. Extracts of this section are presented below.
Rindopepimut is a vaccine designed to generate an immune response against
EGFRvIII, the most frequent EGFR mutation. The EGFR mutant EGFRvIII, which is
present in 25-30% of glioblastomas (Humphrey, Wong et al. 1990), has been
associated with poor long term survival, and a prognosis independent of
previously identified prognostic factors, including gross total resection
(Pelloski, Ballman et al. 2007).
Rindopepimut, in combination with GM-CSF, has been administered as an
intradermal vaccine to a total of 125 patients with glioblastoma. The clinical
experience includes the phase II ACT III study sponsored by Celldex, three
studies (ACTIVATE, ACT II and ZAP-IT) conducted under an Investigator-Initiated
IND, and a few patients treated under compassionate use. Nearly all of these
patients have received rindopepimut for first-line treatment of surgically
resected EGFRvIII-positive glioblastoma, with or without adjuvant (maintenance)
TMZ following standard chemoradiation. Thus far, rindopepimut has demonstrated
potential clinical benefit in the form of apparent prolongation of
progression-free survival and overall survival, with a favorable safety
profile.
The addition of rindopepimut to standard surgery, chemoradiation and adjuvant
temozolomide monotherapy has been associated with fairly minimal toxicity, as
compared to standard cytotoxics. In the experience with 125 patients to date,
the most frequently reported treatment-related adverse events have been
mild/moderate injection site reactions, chiefly localized erythema and
pruritus, which generally resolved without the need for intervention.
Hypersensitivity-like reactions (including symptoms such as pruritus, erythema,
rash, perioral numbness, lightheadedness, shortness of breath, edema, mylagia,
and increases in temperature, pulse and blood pressure) have occurred, but were
generally mild to moderate in severity and transient, resolving spontaneously
or with routine supportive care.
The clinical experience to date provides strong evidence for potential clinical
benefit with an acceptable risk profile.Taken together, available information
suggests that the benefit/risk ratio for rindopepimut therapy is acceptable for
further development.
Fourth Avenue 119
Needham MA 02494
US
Fourth Avenue 119
Needham MA 02494
US
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Age
Inclusion criteria
1.Histologically confirmed, newly diagnosed, de novo glioblastoma
including the following variants of glioblastoma: small cell glioblastoma,
giant cell glioblastoma, gliosarcoma and glioblastoma with
oligodendroglial component.
2. Attempted surgical resection followed by convential chemoradiation, consisting of radiotherapy at a minimally acceptable total dose of at least 90% of the planned radiation therapy dose (usually 60Gy and concomitant TMZ chemotherapy (75 mg/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.
4. Documented EGFRvIII positive tumor status, determined by reverse transcriptase 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-chemoradiationperiod (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 * 2 throughout the 7 days prior to randomization.
10. Men or woman 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
D5a. In English
1. Stereotactic biopsy only (without further surgical resection).
2. Presence of diffuse leptomeningeal disease, gliomatosis cerebri or infra-tentorial disease
3.History, presence, or suspicion of metastatic disease
4. Patients who have received an additional treatment for glioblastoma, aside from surgical resection
and chemoradiation with TMZ. 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 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 cancer or 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) Known (no need for active screening) HIV or chronic hepatitis B or
hepatitis C infection,
b) Immuno-deficiency 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 KLH, GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast-derived products, or a history of anaphylactic reactions to shellfish proteins.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-006068-32-NL |
| ClinicalTrials.gov | NCT01480479 |
| CCMO | NL42432.000.13 |