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>>E.5.1 Primary end point(s): Time to objective demonstration of disease progression or death,
measured from time of randomization (progression free survival, PFS),
>>D.3.1 Product name: DCVax-L
D.3.4 Pharmaceutical form: Suspension for injection
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: NA
D.3.9.3 Other descriptive name: AUTOLOGOUS DENDRITIC CELLS LOADED WITH AUTOLOGOUS TUMOR CELL LYSATE
D.3.9.4 EV Substance Code: SUB99905
D.3.10 Strength
D.3.10.1 Concentration unit: Other
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 1250000
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: No
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): Yes
D.3.11.3.1 Somatic cell therapy medicinal product: Yes
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Suspension for injection
D.8.4 Route of administration of the placebo: Intradermal use
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Glioblastoma multiforme
E.1.1.1 Medical condition in easily understood language: Brain cancer, stage 4
E.1.1.1 Medical condition in easily understood language (de): Gehirnkrebs, Stage 4
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: 20.0
E.1.2 Level: PT
E.1.2 Classification code: 10018337
E.1.2 Term: Glioblastoma multiforme
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: Yes
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of this study is to compare progression free
survival (PFS) between patients in the DCVax-L cohort and patients in
the placebo cohort in patients with no evidence of disease progression at
baseline.
E.2.2 Secondary objectives of the trial: The secondary objective of this study is to compare Overall Survival (OS)
between patients in the DCVax-L group and patients in the placebo
group in patients with no evidence of disease progression at baseline.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: Determined at pre-screening
• Patients ≥18 and ≤70 years of age at time of surgery
• Patients must be able to understand and sign the informed consent indicating that they are aware of the investigational nature of this study. The consent for tumor donation may be signed by a legally authorized representative (LAR) if allowed by the institution.
• Patients must have a life expectancy of ≥8 weeks
Determined at or around surgery, and prior to pre-leukapheresis visit
• Primary therapy must consist of surgical resection with the intent for a gross or near gross total resection of the contrast-enhancing tumor mass as confirmed by central review, followed by external beam radiation therapy and concurrent temozolomide chemotherapy. Patients who have a resection with original intent for gross or near gross total resection where the surgery can be said to be beyond biopsy are eligible. Central confirmation is not required prior to the pre-leukapheresis visit, but is required before the patient can proceed to leukapheresis. Patients having a biopsy only will be excluded. Patients may be screened if they have had a previous biopsy and are scheduled for a subsequent gross or near gross total resection prior to commencement of other therapies.
• Patients with newly diagnosed, unilateral GBM (Grade IV) without metastases are eligible for this protocol. An independent central neuropathologist will review this diagnosis during the enrollment process. This confirmation is not required prior to the pre-leukapheresis visit, but is required before the patient can proceed to leukapheresis.
• All Patients must have sufficient tumor lysate protein that was generated from the surgically obtained tumor material. This determination will be made by the contracted manufacturer and communicated to the clinical site through the Sponsor, or its designee. This confirmation is not required prior to the pre-leukapheresis visit, but is required before the patient can proceed to leukapheresis.
Determined at pre-leukapheresis visit
• Patients must have adequate bone marrow function prior to each leukapheresis procedure (hemoglobin >10 g/dl or >100g/L, white blood count ≥ 3.6x10E3/mm3 or ≥ 3.6x10E9/L, absolute granulocyte count ≥1.5x10E3/mm3 or ≥1.5x10E9/L, absolute lymphocyte count ≥0.5x10E3/mm3 or ≥0.5x10E9/L, and platelet count ≥100x10E3/mm3 or ≥100x10E9/L). Patients for whom a transfusion is clinically indicated may be considered eligible based on post-transfusion Hgb levels. These values are determined by a central laboratory.
• Adequate liver function (SGPT, SGOT, and alkaline phosphatase ≤4.0 times upper limits of normal (ULN) and total bilirubin ≤1.5 mg/dl or <25.7 µmol/L), and adequate renal function (BUN or creatinine ≤1.5 times ULN) prior to starting therapy. These values are determined by a central laboratory.
Determined at baseline visit
• Patients must have a KPS rating of ≥70 at the Baseline Visit (Visit 5)
• Patients may have received steroid therapy as part of their primary treatment. Steroid treatment should preferably be stopped; or if continued steroid use is clinically indicated, be tapered down to no more than 4 mg dexamethasone per day (or equivalent) at least 7 days prior to the first immunization.
• Patients must be willing to forego cytotoxic anti-tumor therapies except temozolomide while being treated with study drug/placebo. DCVax-L and placebo must be given as described and temozolomide must be given essentially according to the Stupp Protocol guidelines. Administration of adjuvant temozolomide is minimally modified from the guidelines to allow for vaccine dose window adherence.
• A minimum of 5 immunizations must be available for treatment as determined by the contracted manufacturer.
E.4 Principal exclusion criteria: Determined at pre-screening
• History of prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or other cancers that were deemed fully resolved 5 or more years prior to Visit 1 (surgery) of the study. Prior lower grade gliomas are acceptable unless treated with chemotherapy, and provided that all other eligibility criteria are met.
• History of immunodeficiency disease or unresolved autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, scleroderma, polymyositis-dermatomyositis, juvenile onset insulin dependent diabetes, or vasculitis.
• Known HIV-1,2, HTLV-1,2 or Hepatitis B, C infection
• Pregnancy
• Inability to obtain informed consent because of psychiatric or complicating medical problems.
• Any known genetic cancer-susceptibility syndromes.
Determined at or around surgery
• Bilateral or metastatic disease detected at diagnosis, during surgery or at post-surgical magnetic resonance imaging (MRI). Tumors may cross into, but not beyond the corpus callosum.
• Positive test(s) for infectious agents (HIV 1 and 2, Anti-HIV-1,2, Hepatitis B, HBsAg, Anti HBc, Hepatitis C, Anti-HCV-Ab, Syphilis) that would preclude eligibility for tumor procurement and processing per applicable manufacturing guidelines (e.g. German manufacturing vendors).
• Post operative MRI scan evidence of biopsy only without significant tumor resection.
• Implantation of Gliadel® wafers (polifeprosan 20 with carmustine implant) at surgery.
Determined at pre-leukapheresis visit
• Positive HIV-1, HIV-2, HTLV-1, 2, hepatitis B surface antigen, or hepatitis C antibody.
• Patients with organ allografts.
• Allergies to reagents used in this study.
• Patients who are unable to stop or taper steroid treatment to no more than 4mg of dexamethasone per day (or equivalent) prior to leukapheresis are excluded from the trial; steroid use should be stopped or tapered down to the lowest clinically acceptable dose approximately 7 days prior to leukapheresis. The Leukapheresis Visit must occur a minimum of 45 days before the projected Baseline Visit.
• Inability or unwillingness to return for required visits and follow-up exams.
• Any previous cytotoxic drug therapies within the last 5 years.
Determined at or prior to baseline visit
• Patients who have evidence of disease progression (including possible pseudoprogression) as determined by central review
• Patients may not be taking medications that might affect immune function and that have documented anti-tumor activity: The following are exceptions: nonprescription strength doses of NSAIDS, acetaminophen (paracetamol) or acetylsalicylic acid (aspirin).
Determined at baseline visit:
• Acute infection: any active viral, bacterial, or fungal infection that requires specific therapy. Antibiotic therapy must be completed at least 7 days prior to the first immunization.
• Active uncontrolled infection. Examples are a sexually transmitted disease (STD), herpes, uncontrolled tuberculosis, malaria, etc.
• Fever ≥101.5°F (38.6 °C). If considered possibly transient, retesting is allowed.
• Unstable or severe intercurrent medical conditions such as unstable angina, uncontrolled arrhythmias, ulcerative colitis etc.
• Females of child-bearing potential who are pregnant or lactating or who are not using adequate contraception (abstinence, surgical, hormonal or double barrier, i.e. condom and diaphragm).
E.5 End points
E.5.1 Primary end point(s): Time to objective demonstration of disease progression or death,
measured from time of randomization (progression free survival, PFS),
in patients with no evidence of disease progression after external beam
radiation therapy with concurrent temozolomide chemotherapy.
E.5.1.1 Timepoint(s) of evaluation of this end point: The primary endpoint will be evaluated when 248 events of progression or death have occurred. in addition, two interim analyses will evaluate the endpoint when approximately 60% and 80% of the events have occurred.
E.5.2 Secondary end point(s): Overall survival: In patients with no evidence of disease progression after external beam radiation therapy with concurrent temozolomide chemotherapy.
E.5.2.1 Timepoint(s) of evaluation of this end point: Overall survival will be assessed when 233 deaths have occurred.
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: No
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: Yes
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: Yes
E.8.2.3 Other: No
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: 20
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 28
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:
Canada
Germany
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: LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 4
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 4
F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 298
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 50
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 87
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 132
F.4.2.2 In the whole clinical trial: 348
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Current standard of care of that condition by their physcians.
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2013-07-30
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2012-06-04
P. End of Trial
P. End of Trial Status: Temporarily Halted
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