AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma

NCT03893903 | Completed Phase 1 DMC

• 3 other identifiers: NCT-2016-04582017-000587-15NOA-21
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 10

Brief 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. 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.

Conditions

Malignant Glioma

Outcome Measures

Primary Outcomes (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.

  Primary treatment phase (week 43)

Secondary Outcomes (9)

• immunogenicity of the IDH1 peptide vaccine

  End of primary treatment phase (week 43)

• Frequency of Treatment-Emergent Adverse Events (Assessment of Tolerability)

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

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

  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

• Overall survival (OS)

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

• Progression-free survival (PFS)

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

Study Arms (3)

IDH1 peptide vaccine

EXPERIMENTAL

IDH1R132H peptide vaccine alone

Drug: IDH1R132H peptide vaccine

combination

EXPERIMENTAL

IDH1R132H peptide vaccine and Avelumab

Drug: IDH1R132H peptide vaccine; Drug: Avelumab

Avelumab

EXPERIMENTAL

Avelumab alone

Drug: Avelumab

Interventions

IDH1R132H peptide vaccine DRUG

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.

IDH1 peptide vaccine; combination

Avelumab DRUG

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.

Avelumab; combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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).
• Abnormal (≥ Grade 2 CTCAE v4.03) laboratory values for thyroid gland: free T4 and TSH
• 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

Sponsors & Collaborators

• German Cancer Research Center: lead

Study Sites (10)

Charité Berlin, Neurosurgery

Berlin, Germany

Location

University Hospital Dresden, Neurosurgery

Dresden, Germany

Location

Essen University Hospital, Neurooncology

Essen, Germany

Location

University Hospital Frankfurt, Neurooncology

Frankfurt am Main, Germany

Location

University Hospital Freiburg, Neurosurgery

Freiburg im Breisgau, Germany

Location

University Hospital Heidelberg, Neurology Clinic

Heidelberg, Germany

Location

Mannheim University Hospital

Mannheim, Germany

Location

LMU, University Hospital Munich

Munich, Germany

Location

Katharinenhospital Stuttgart, Neurosurgery

Stuttgart, Germany

Location

University Hospital Tuebingen, Neurooncology

Tübingen, Germany

Location

Related Publications (1)

• 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.

  PMID: 35599302 DERIVED

MeSH Terms

Conditions

Glioma

Interventions

avelumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Michael Platten, Prof. MD

  German Canecr Research Center, Heidelberg, and Mannheim University Hospital, Neurology, Mannheim

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 16, 2018
• First Posted: March 28, 2019
• Study Start: October 19, 2018
• Primary Completion: September 20, 2024
• Study Completion: September 20, 2024
• Last Updated: March 14, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

DE (10)