None listed
Conditions
Brief summary
Brief description of the study purpose: This study is investigating a personalised mRNA vaccine for children and young people with high risk central nervous system tumours. The vaccine is made individually for each participant using information from their tumour and is designed, based on laboratory and preclinical research, to help the immune system recognise proteins associated with the tumour. Who is it for? You may be eligible if you are male or female 6 months to 25 years old, have a high-risk central nervous system tumour, and are enrolled in the ZERO Childhood Cancer molecular profiling program, you have measurable disease (with some exceptions for newly diagnosed cases), a Karnofsky/Lansky score equal to or above 50, a life expectancy of at least 12 weeks, have recovered from prior therapy according to required washout periods, and have adequate blood counts, kidney function, liver function, and coagulation. You must not have a known hypersensitivity to mRNA vaccines, not be pregnant or breastfeeding and have no underlying congenital immunodeficiency. You must not be taking corticosteroids other than physiologic replacement doses and have no live vaccines within 3 months of starting protocol therapy. What is involved for participants? Study participants will be required to have periodic physical examinations, sample collections (blood and urine tests), completion of quality of life questionnaires, a heart function check and brain imaging to check the tumour. Study details Participants will receive the recommended Phase II dose (RP2D) of the personalised mRNA vaccine for eight doses, followed by a booster dose at six months. Phase II participants will be enrolled into two strata. Phase II Stratum A will include participants with newly diagnosed DMG and Phase II Stratum B will include participants with other high-risk brain tumours.
Interventions
PTX-108 is a personalised mRNA anti-tumour vaccine designed for the treatment of young patients with brain cancer. The vaccine comprises an individualised mRNA sequence encapsulated in a common lipid nanoparticle. The personalised vaccine is generated from a participant's neoantigens and tumour-associated antigens. This phase II clinical trial will investigate the safety and efficacy of the personalised PTX-108 mRNA cancer vaccine in paediatric and young adult patients with high-risk brain tumo
PTX-108 is a personalised mRNA anti-tumour vaccine designed for the treatment of young patients with brain cancer. The vaccine comprises an individualised mRNA sequence encapsulated in a common lipid nanoparticle. The personalised vaccine is generated from a participant's neoantigens and tumour-associated antigens. This phase II clinical trial will investigate the safety and efficacy of the personalised PTX-108 mRNA cancer vaccine in paediatric and young adult patients with high-risk brain tumours including relapsed or refractory high-grade tumours and patients with newly diagnosed Diffuse Midline Glioma (DMG) following completion of radiation therapy. Phase II will be a stratified expansion phase. Phase II Stratum A will include patients with newly diagnosed DMG, with outcomes compared to matched historical cohorts from the international DIPG Registry (iDIPGR), who were diagnosed after 2010, and have genomic, clinical and survival data available. Phase II Stratum B will include patients with other high-risk or relapsed/refractory brain tumours, with outcomes analysed descriptively. Stratum B is descriptive statistics only. As paediatric brain tumours can have significantly different disease trajectories and timelines to progression, the time-to-event outcomes (progression-free survival and overall survival) will depend on the characteristics of the participants enrolled into Stratum B. As the tumour types and clinical characteristics of the enrolled population cannot be predicted in advance, the appropriate descriptors and analyses will be adapted as the Stratum B population is established and further understood. The vaccine will be given into the muscle, either in the upper arm or the thigh, depending on what is most suitable for the participant. Phase II dose will be determined during phase I of the study. Phase I is described in a separate entry within the registry. The total duration of therapy will be around 26 weeks. Adherence is assessed through directly observed administration of the vaccine by qualified staff during scheduled in-clinic visits, with detailed documentation of attendance and dose administration in study records. The study pharmacist will administer the vaccine. Participants in both strata will receive the same doses and follow the same dose schedule, they will receive 9 doses of personalised mRNA vaccine at the RP2D established in Phase I. In case of dose modifying toxicities DMT, PTX-108 vaccine dose de-escalation will be done as per the following: Dose level 0: 200 micrograms Dose level -1: 100 micrograms Dose level -2: 50 micrograms The dose schedule is described below: Dose 1: Administered on Day 1 Dose 2: Administered on Day 10 Dose 3: Administered on Day 24 Dose 4: Administered on Day 38 Dose 5: Administered on Day 52 Dose 6: Administered on Day 66 Dose 7: Administered on Day 80 Dose 8: Administered on Day 94 Dose 9 (Booster): Administered on Day 180 - 190
Sponsors
Australian and New Zealand Children's Haematology Oncology Group
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
6 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
Each participant (Stratum A or Stratum B) must meet all the following criteria to be enrolled in this trial: Age: Participant must be between 6 months and 25 years at the time of enrolment. Histological confirmation of one of the following high risk central nervous system tumours (either at initial diagnosis or relapsed/refractory disease): - Any relapsed/refractory WHO grade 3 or 4 central nervous system tumour - Newly diagnosed diffuse midline glioma in a patient anticipated to be able to start study therapy within 20 weeks post biopsy - Newly diagnosed high risk medulloblastoma, ependymoma, or other high-risk brain tumour after discussion with the study chairs (includes p53-mutant SHH medulloblastoma, PFA ependymoma with 6q deletion and/or 1q gain or other high risk molecular alterations associated with less than 20% anticipated 5 year survival) who are anticipated to be able to proceed to PTX-108 therapy after completion of institutional standard-of-care treatment. Co-enrolment on the Zero Childhood Cancer (ZERO) molecular profiling platform (repeat tumour sampling in relapsed patients to obtain a current representative sample), with successful tumour WGS +/- RNA-seq analysis with a requirement of at least five potential neoantigens or tumour-associated antigens (TAAs) for vaccine production. Informed consent as demonstrated by a signed and dated informed consent form completed by the participant or a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant’s behalf. For a participant to commence personalised PTX-108 vaccine therapy (Reassessment), participants must be re-screened within 7 days of anticipated treatment start date (28 days for imaging) and the following criteria must be met: - Confirmation of individualised PTX-108 vaccine available at the treating site for the participant. - Measurable disease as per RAPNO/RANO 2.0 criteria (any previously irradiated lesion needs to have progressed since prior radiation therapy except for participants with newly diagnosed DMG and other high-risk brain tumours proceeding to vaccine therapy after completion of standard frontline therapy). Newly diagnosed patients eligible for study otherwise without measurable disease can be enrolled on review with the study team. - Lansky/Karnofsky performance score of greater than 50. Use Karnofsky for patients over 16 years of age and Lansky for patients less than 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. - Life expectancy of at least 12 weeks at the time of re-screening. No clinical or radiological evidence of brain herniation or significant mass effect resulting in risk of imminent neurological deterioration. - Prior therapy: Patients must have fully recovered from prior anti-cancer therapy including ~Myelosuppressive chemotherapy: Greater than 21 days between prior myelosuppressive therapy and PTX-108 commencement (or more than 42 days since last dose of nitrosourea). ~Non-myelosuppressive anticancer agents: greater than 7 days after the last dose. ~Immunotherapy: greater than 42 days after the last dose ~Monoclonal antibodies: greater than 21 days after the last dose. ~Radiation therapy: greater than 4 weeks after completion of radiation including CSI but within 12 weeks of biopsy for those patients with newly diagnosed DMG. - Haematopoietic growth factor: greater than 14 days for long acting (peg-filgrastim) or greater than 7 days for short acting growth factor. - Adequate haematologic function defined as: ~Haemoglobin greater than or equal to 80 g/L (post transfusion permitted) ~Absolute Neutrophil Count (ANC) greater or equal to 1.0 x109/L ~Absolute Lymphocyte Count greater or equal to 1.0 x109/L ~Platelet count greater or equal to 75 x109/L (cannot be post-transfusion) - Adequate renal function defined as: ~Serum creatinine = Less than 1.5x institutional upper limit of normal (ULN) for age and sex - Adequate liver function defined as: ~Total bilirubin = Less than 1.5 x upper limit of normal (ULN) for age ~AST and ALT = Less than 5 x upper limit of normal (ULN) for age ~Adequate coagulation (INR, PT and aPTT = 1.5 times ULN) Investigator confirmation that the participant has no other serious medical conditions which are considered by the investigator to unacceptably increase the risk to the participant
Exclusion criteria
Exclusion Criteria for Study Enrolment: Known hypersensitivity to mRNA vaccines Pregnant and breastfeeding females Underlying congenital immunodeficiency Exclusion Criteria for Vaccine Therapy: Administration of live vaccine within 4 weeks of planned vaccine therapy commencement Pregnant and breastfeeding females No current corticosteroid therapy other than physiologic replacement doses equivalent to hydrocortisone maximum 20mg/m2/day
Outcome results
None listed