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Malignant GliomaPhase 1AMPLIFY-NEOVACNCT03893903

AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma

A Phase 1 study testing IDH1R132H peptide vaccine and Avelumab in people with Malignant Glioma, run by German Cancer Research Center at 10 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The trial will address safety and tolerability of the combination of the IDH1R132H-specific vaccine with checkpoint blockade and seeks to explore predictive biomarkers for response to checkpoint blockade in post-treatment tumor tissue. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Glioma
What is being tested?
IDH1R132H peptide vaccine and Avelumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
69 participants
Where
10 sitesGermany
Study dates
19 Oct 2018to 20 Sep 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years, smoking or non-smoking, of any ethnic origin and gender
  • Patients present with unequivocal first, second or third recurrence of a histologically confirmed IDH1R132H-mutated glioma WHO grade II, III or IV progressive after radiotherapy and chemotherapy
  • Absence of chromosomal 1p/19q co-deletion in the primary tumor tissue and/or
  • Loss of nuclear ATRX expression in the primary tumor tissue (partial loss allowed)
  • Availability of tumor tissue for analysis (FFPE bulk tissue)
  • Patients have received radiotherapy (54 - 60 Gy) and at least six months of alkylating chemotherapy
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  • Patients are at least three months off radiotherapy
  • Patients must be candidates for re-resection and the re-resection must be postponable for seven weeks
  • 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)
  • Karnofsky Performance Status ≥ 70
  • Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
  • Ability of patient to understand character and individual consequences of the clinical trial
  • Evidence of informed consent document personally signed and dated by the patient (or a witness in case the patient is unable to write) 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(s) (IMPs).
  • WOCBP must be using an effective method of birth control to avoid pregnancy throughout the study and for 3 months 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 3 months after the last dose of the IMP(s), if their sexual partners are WOCBP (acceptable methods see above).
  • Availability of pre-study MRT (magnetic resonance tomography) of latest tumor recurrence
  • Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Who cannot join

  • Current use of immunosuppressive medication, EXCEPT for the following:
  • intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
  • Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  • Pregnancy or lactation
  • Previous or concurrent experimental treatment for the tumor other than radiotherapy and alkylating chemotherapy. This includes local therapies such as interstitial radiotherapy or local chemotherapy (i.e. BCNU wafers), loco-regional hyperthermia, electric fields, and antiangiogenic therapy (such as Bevacizumab).
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  • Abnormal (≥ Grade 2 CTCAE v4.03) laboratory values for thyroid gland: free T4 and TSH
  • Abnormal (≥ Grade 2 CTCAE v4.03) laboratory values for hematology, liver and renal function (serum creatinine). In detail, the following values apply as exclusion criteria:
  • Hemoglobin < 9 g/dL (5.59 mmol/L)
  • White blood cell count (WBC) decrease (<3.0 x 109/L) or increase (> 10.0 x 109/L)
  • Absolute neutrophil count (ANC) decrease (< 1.5 x 109/L)
  • Platelet count decrease (< 100 x 109/L)
  • Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab´s reference range)
  • ALT > 2,5 x ULN
  • AST > 2,5 x ULN
  • GGT > 2.5 x ULN
  • Serum creatinine increase (> 1.5 x ULN)
  • Patients with history or presence of HIV and/or HBV/HCV positivity (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
  • Patients with history or known presence of tuberculosis (positive QuantiFERON®-TB Gold test (or equivalent) or tuberculin skin test). Patients with an indeterminate result of the QuantiFERON®-TB Gold test (or equivalent) are not eligible unless additional testing demonstrates a negative result (tuberculin skin test or repeated QuantiFERON®-TB Gold test/or equivalent). If a tuberculin skin test is performed, an induration of > 6 mm is "positive" for a patient with history of BCG vaccine, while an induration of > 10 mm is "positive" for a patient without history of BCG vaccine. If necessary, a QuantiFERON®-TB Gold or equivalent test might be complemented by additional specific diagnostic tests as per standard procedures.
  • Patients with severe infection(s) or signs/symptoms of infection within 2 weeks prior to the first administration of the study drug(s)
  • Active infection requiring systemic therapy
  • Patients who have received a live, attenuated vaccine within 4 weeks prior to the first administration of the study drug(s)
  • Patients with a prior solid organ transplantation or haematopoietic stem cell transplantation
  • Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
  • Clinically significant (i.e., active) cardiovascular disease: Cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
  • Persisting toxicity related to prior therapy (NCI CTCAE v.4.03 Grade >1); however, alopecia, sensory neuropathy Grade ≤ 2, or other persisting toxicities Grade ≤ 2 not constituting a safety risk based on investigator´s judgement is acceptable.
  • Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3).
  • Participation in other clinical trials or their observation period during the last 30 days before the first administration of the IMP(s).

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

Germany10 sites

  • Charité Berlin, Neurosurgery

    Berlin

  • University Hospital Dresden, Neurosurgery

    Dresden

  • Essen University Hospital, Neurooncology

    Essen

  • University Hospital Frankfurt, Neurooncology

    Frankfurt am Main

  • University Hospital Freiburg, Neurosurgery

    Freiburg im Breisgau

  • University Hospital Heidelberg, Neurology Clinic

    Heidelberg

  • Mannheim University Hospital

    Mannheim

  • LMU, University Hospital Munich

    Munich

  • Katharinenhospital Stuttgart, Neurosurgery

    Stuttgart

  • University Hospital Tuebingen, Neurooncology

    Tübingen

Other trials in Germany

About this study

Official title: AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma - a Randomized, Open Label, 3 Arm Multicenter Phase I Trial to Assess Safety, Tolerability and Immunogenicity of IDH1R132H-specific Peptide Vaccine in Combination with Checkpoint Inhibitor Avelumab

The trial will address safety and tolerability of the combination of the IDH1R132H-specific vaccine with checkpoint blockade and seeks to explore predictive biomarkers for response to checkpoint blockade in post-treatment tumor tissue. The study will enroll 48 evaluable patients (presumably, 60 in total) with IDH1R132H-mutated gliomas with an unfavorable molecular profile (no 1p/19q co-deletion, nuclear ATRX- loss) progressive after radiotherapy and alkylating chemotherapy eligible for re-resection. After diagnosis of recurrent disease on imaging patients will be randomized assigned in a 1:1:2 ratio into three arms. Arm 1 (12 patients) will receive three IDH1R132H peptide vaccines alone in two week intervals. Arm 2 (12 patients) will receive three IDH1R132H peptide vaccines in combination with three doses of Avelumab in two week intervals. Arm 3 (24 patients) will receive three doses of Avelumab in two week intervals. After 6 weeks of treatment patients (Arms 1-3) will undergo planned re-resection. Four weeks after the operation treatment will be resumed consisting of five additional vaccines (Arm 1+2) in 4 week intervals, followed by maintenance vaccines until progression in three months' intervals after a pause of 16 weeks. Avelumab will be administered in monthly intervals in Arms 2 and 3 starting four weeks after the operation until progression.

Key outcome parameters will be safety and immunogenicity (Arms 1 and 2) based on peripheral and intratumoral immune analyses assessed 9 months after re-resection.

Read the detailed description

The standard of care (SOC) treatment of patients with malignant gliomas is - independent of molecular markers - still confined to surgery, irradiation and alkylating chemotherapy as targeted therapies to date have failed to prove superiority over standard of care in controlled trials. At the same time, novel concepts in immunotherapy have evolved with the identification of potential (neo)epitopes and phase III clinical trials investigating the efficacy of checkpoint inhibitors. Despite patients frequently undergoing resection of recurrent tumor, patient selection criteria for innovative immunotherapy in glioma have been hampered by the lack of availability of post-treatment tumor tissue. Neoepitope-specific vaccines have gained considerable interest also in a challenging disease such as glioma. IDH1R132H, a frequent driver mutation in gliomas, was previously identified to contain a neoepitope. A peptide vaccine targeting this epitope is currently tested in a phase I first-in-man multicenter clinical trial. The clinical phase of this trial was completed in Q3 2017 with 32 patients treated. The primary endpoints were met by demonstrating safety and immunogenicity. Checkpoint inhibitors are tested in unselected populations of glioma patients despite evidence that response is associated with high mutational load, which is infrequent in untreated gliomas, but may occur particularly after long periods of exposure to alkylating chemotherapy.

The trial will address safety and tolerability of the combination of the IDH1R132H-specific vaccine with checkpoint blockade and seeks to explore predictive biomarkers for response to checkpoint blockade in post-treatment tumor tissue. The study will enroll 48 evaluable patients (presumably, 60 in total) with IDH1R132H-mutated gliomas with an unfavorable molecular profile (no 1p/19q co-deletion, nuclear ATRX loss) progressive after radiotherapy and alkylating chemotherapy eligible for re-resection. After diagnosis of recurrent disease on imaging patients will be randomized assigned in a 1:1:2 ratio into three arms. Arm 1 (12 patients) will receive three IDH1R132H peptide vaccines alone in two week intervals. Arm 2 (12 patients) will receive three IDH1R132H peptide vaccines in combination with three doses of Avelumab, a humanized anti-PD-L1 antibody approved for patients with Merkel cell carcinoma and urothelial cancer, in two week intervals. Arm 3 (24 patients) will receive three doses of Avelumab in two week intervals. After 6 weeks of treatment patients (Arms 1-3) will undergo planned re-resection. A safety MRI will be performed three weeks after initiation of the experimental treatment. Four weeks after the operation treatment will be resumed consisting of five additional vaccines (Arm 1+2) in 4 week intervals, followed by maintenance vaccines until progression in three months' intervals after a pause of 16 weeks. Avelumab will be administered in monthly intervals in Arms 2 and 3 starting four weeks after the operation until progression.

Key outcome parameters will be safety and immunogenicity (Arms 1 and 2) based on peripheral and intratumoral immune analyses assessed 9 months after re-resection. Additional exploratory analyses will determine efficacy (all Arms), dependent on predictive molecular immune and imaging biomarkers, such as increased mutational load (Arm 3). Based on the experience in the NOA-04 and CATNON trials the expected time to second progression is 9-12 months.

The trial is supported by the German Cancer Consortium (DKTK) and the Neurooncology Working Group of the German Cancer Society (NOA).

Being tested
IDH1R132H peptide vaccine, Avelumab
Medical subject headings
Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IDH1R132H peptide vaccineDrug

    The vaccine is applied by s.c. injection with 300 μg IDH1R132H peptide emulsified in 0.5 ml 33% DMSO / 0.5 ml Montanide® per dose.

    Patients receive 3 doses in two week intervals for 6 weeks, followed by re-resection. 4 weeks after surgery, treatment will be resumed consisting of 5 additional vaccinations in 4 week intervals, followed by maintenance vaccines until progression in three months intervals after a pause of 16 weeks.

  • AvelumabDrug

    Avelumab is a humanized anti-PD-L1 antibody approved for patients with Merkel cell carcinoma and urothelial cancer. It is applied by i.v. infusion with 10 mg/kg per dose.

    Patients receive 3 doses of Avelumab in 2week intervals for 6 weeks, followed by re-resection. Avelumab will be administered in monthly intervals starting 4 weeks after the surgery until progression.

Study groups in NCT03893903
Study groupRoleWhat they receive
IDH1 peptide vaccineExperimentalIDH1R132H peptide vaccine alone
Receives: Drug: IDH1R132H peptide vaccine
combinationExperimentalIDH1R132H peptide vaccine and Avelumab
Receives: Drug: IDH1R132H peptide vaccine; Drug: Avelumab
AvelumabExperimentalAvelumab alone
Receives: Drug: Avelumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. safety and tolerability: Regime Limiting Toxicity

    To determine safety and tolerability of repeated fixed dose vaccinations of the IDH1 peptide vaccine administered with topical imiquimod (Aldara®) alone (Arm 1) or in combination with Avelumab (Arm 2), or Avelumab alone (Arm 3).

    Primary endpoint is the Regime Limiting Toxicity (RLT) until End of Primary Treatment Phase.

    Measured: Primary treatment phase (week 43)

Secondary outcomes (9)

  1. immunogenicity of the IDH1 peptide vaccine

    To assess immunogenicity of the IDH1 peptide vaccine alone or in combination with Avelumab. The main immunogenicity endpoint is the presence of IDH1R132H-specific T-cells and/or antibody responses in the peripheral circulation and/or the presence of IDH1R132H-specific T-cells in the tumor tissue

    Measured: End of primary treatment phase (week 43)

  2. Frequency of Treatment-Emergent Adverse Events (Assessment of Tolerability)

    This endpoint includes all AEs (adverse event), their severity, SAEs (serious adverse event), the relation of AEs to the study treatment, dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic effects will be graded according to CTCAE, current version.

    Measured: Time from baseline until EOS (end of study) (12 weeks after last treatment administration); up to 38 months

  3. Objective response rate (ORR) to assess the efficacy of Avelumab in association with the number of non-synonymous mutations in the tumor tissue.

    The ORR, defined as the proportion of patients with a treatment-induced hypermutator phenotype compared with a non-hypermutator phenotype showing complete response (CR), partial response (PR) or stable disease (SD) at end of the Primary Treatment Phase and at EOS compared to the baseline value (MRI at visit 7). ORR analysis will be based on the central disease assessment according to the iRANO criteria

    Measured: Time from baseline until end of the primary treatment phase (week 43) and at EOS (12 weeks after last treatment administration); up to 38 months

  4. Overall survival (OS)

    OS, defined as the time from the first study treatment date until death. For patients who do not die, time to death will be censored at the time of the end of observation. The end of observation is defined as the date of study termination as indicated by the corresponding entry of the CRF (case report form). If this date is not documented, the end of observation is defined as the last documented date.

    Measured: Time from the first study treatment date until death or end of observation (up to 38 months)

  5. Progression-free survival (PFS)

    The PFS, defined as time from the day of first study treatment date to the day of tumor progression or the day of death of any cause (whichever occurs first), censored by the end of the observation. The end of observation is defined as the date of study termination as indicated by the corresponding entry of the CRF. If this date is not documented, the end of observation is defined as the last documented date.

    Measured: Time from the day of first study treatment date, censored by the end of the observation (up to 38 months)

  6. Objective response rate (ORR)

    The ORR, defined as the proportion of patients showing complete response (CR), partial response (PR) or stable disease (SD) at end of the Primary Treatment Phase and at EOS compared to the baseline value (MRI at visit 7). ORR analysis will be based on the central disease assessment according to the iRANO criteria

    Measured: Time from baseline until end of the primary treatment phase (week 43) and at EOS (12 weeks after last treatment administration); up to 38 months

  7. Association between immunogenicity and Objective response rate (ORR)

    To analyse the association between immunogenicity and the clinical outcome parameter. The clinical outcome will be evaluated by assessing the ORR. Logistic regression models will be used to explore the relationship between the relative changes in the immunologic parameters and ORR.

    Measured: Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months

  8. Association between immunogenicity and Progression-free Survival (PFS)

    To analyse the association between immunogenicity and the clinical outcome parameter. The clinical outcome will be evaluated by assessing the PFS. Proportional Hazards models will be used to analyze the prognostic influence of relative changes in the immunologic parameters, for the PFS.

    Measured: Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months

  9. Association between immunogenicity and Overall survival (OS)

    To analyse the association between immunogenicity and the clinical outcome parameters. The clinical outcome will be evaluated by assessing the OS. Proportional Hazards models will be used to analyze the prognostic influence of relative changes in the immunologic parameters, for the OS.

    Measured: Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Mar 2019
  2. Study start19 Oct 2018
  3. Primary completion20 Sep 2024
  4. Study completion20 Sep 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
69 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03893903
Sponsor's protocol ID
NCT-2016-0458
Other IDs
2017-000587-15, NOA-21, 2017
Acronym
AMPLIFY-NEOVAC
Status last verified
Mar 2025
First submitted
16 Aug 2018
Last updated
14 Mar 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Bunse L, Rupp AK, Poschke I, Bunse T, Lindner K, Wick A, Blobner J, Misch M, Tabatabai G, Glas M, Schnell O, Gempt J, Denk M, Reifenberger G, Bendszus M, Wuchter P, Steinbach JP, Wick W, Platten M. AMPLIFY-NEOVAC: a randomized, 3-arm multicenter phase I trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with an immune checkpoint inhibitor targeting programmed death-ligand 1 in isocitrate dehydrogenase 1 mutant gliomas. Neurol Res Pract. 2022 May 23;4(1):20. doi: 10.1186/s42466-022-00184-x.

    PubMed 35599302

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing IDH1R132H peptide vaccine and Avelumab in people with Malignant Glioma, run by German Cancer Research Center at 10 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

safety and tolerability: Regime Limiting Toxicity (time frame: Primary treatment phase (week 43)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03893903, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Mar 2025.

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