Glioma
Conditions
Keywords
IDH1R132H, peptide vaccine, immunotherapy, IDH1R132H-mutated glioma
Brief summary
The NOA-16 trial is the first-in-man trial of the IDH1 (isocitrate dehydrogenase type 1) peptide vaccine targeting the IDH1R132H mutation (amino acid exchange from arginine to glutamine at position 132 of IDH1). The aim of this trial is to evaluate the safety and tolerability of and immune response to the IDH1 peptide vaccine in patients with IDH1R132H-mutated, WHO grade III-IV gliomas.
Detailed description
The patient population will be molecularly defined and include IDH1R132H mutant grade III and IV gliomas without co-deletion of 1p/19q and with loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression. Within this trial, the IDH1 peptide vaccine will be administered to 39 patients. In treatment group 1 vaccination treatment will be done alone starting 4-6 weeks post radiotherapy. In treatment groups 2 and 3 vaccination treatment will be done in parallel with temozolomide (TMZ) chemotherapy starting at day 10 of the 4th TMZ cycle (treatment group 2) or at day 10 of the 1st TMZ cycle post concomitant radiochemotherapy (treatment group 3).
Interventions
DRUGIDH1 peptide vaccine
Sponsors
University Hospital Heidelberg
German Cancer Research Center
Neuro-Oncology Working Group of the German Cancer Society
National Center for Tumor Diseases, Heidelberg
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients present with histologically confirmed diagnosis of an IDH1R132H-mutated glioma (with or without measurable residual tumor after tumor resection or biopsy) * Histology may be astrocytoma, oligodendroglioma, or oligoastrocytoma WHO grade III or IV * Absence of chromosomal 1p/19q co-deletion in the tumor tissue * Loss of nuclear ATRX expression in the tumor tissue (partial loss allowed) * Availability of tumor tissue for molecular screening (FFPE bulk tissue or biopsy) * Patients have received radiotherapy (54 - 60 Gy) alone, 3 cycles of chemotherapy with TMZ (150-200 mg/m2, 5/28 days) or standard combined radiochemotherapy with TMZ prior to enrollment. * Patients should be immunocompetent (i.e. no concomitant treatment with dexamethasone (or equivalent), or receive stable/decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent) during the last 3 days prior to clinical screening; no severe lymphopenia) * ≥18 years old, smoking or non-smoking, of any ethnic origin and gender * Karnofsky Performance Status ≥ 70 * Ability of patient to understand character and individual consequences of the clinical trial * Evidence of two informed consent documents personally signed and dated by the patient (or a witness in case the patient is unable to write) covering the molecular screening procedure (short IC) and the remaining trial-related procedures (extended IC) and indicating that the patient has been informed of all pertinent aspects of the study and that the patient consents to participate in the trial. * Women of child-bearing potential (WOCBP; i.e., those who have not undergone a hysterectomy, bilateral salpingectomy and bilateral oophorectomy or who have not been post-menopausal for at least 24 consecutive months) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of the investigational medicinal product (IMP). * WOCBP must be using an effective method of birth control to avoid pregnancy throughout the study and for 24 weeks after the last dose of the IMP. This includes two different forms of effective contraception (e.g., hormonal contraceptive and condom, IUD/IUS and condom) or sterilization, resulting in a failure rate less than 1% per year. * Men must be willing and able to use an effective method of birth control throughout the study for up to 24 weeks after the last dose of the IMP, if their sexual partners are WOCBP (acceptable methods see above). * Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
Exclusion criteria
* Progressive (incl. pseudoprogression) or recurrent disease after radiation therapy, chemotherapy or radiochemotherapy based on local MRI assessment * Previous or concurrent experimental treatment for the tumor. This includes local therapies such as interstitial radiotherapy or local chemotherapy (i.e. BCNU wafers), loco-regional hyperthermia, and antiangiogenic therapy (such as bevacizumab) * Antitumor treatment other than standard radiotherapy and/or standard TMZ chemotherapy. Daily metronomic TMZ or intensified dosing scheduled as a substitute for maintenance TMZ cycles are not allowed. (Dose reductions of standard TMZ chemotherapy are allowed.) * Abnormal (≥ Grade 2 CTCAE v4.0) laboratory values for hematology, liver and renal function (serum creatinine). In detail the following values apply as
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| safety and tolerability of repeated fixed dose vaccinations of the IDH1 peptide vaccine administered with topical imiquimod (Aldara®) assessed by Regime Limiting Toxicity (RLT). | 15 months | Primary safety endpoint is the Regime Limiting Toxicity (RLT). |
| immunogenicity of the IDH1 peptide vaccine | 15 months | The primary immunogenicity endpoint is the presence of an IDH1R132H-specific T-cell and/or antibody response at any time point during the trial measured by IFN-gamma ELISpot and ELISA, respectively (response Yes/No). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| immunogenicity by assessing the IDH1R132H-specific T-cell and antibody response | 15 months | — |
| progression-free survival (PFS) | 15 months | — |
| overall response rate (ORR) | 15 months | — |
| association between immunogenicity (IDH1R132H-specific T-cell and antibody response) and the clinical outcome parameters (ORR, PFS) | 15 months | assessed by Logistic regression and Proportional Hazard models |
Countries
Germany
Outcome results
None listed