This is a non-randomized, open label, phase I/IIa, dose-escalation study, involving a single injection of Temferon, an investigational advanced therapy consisting of autologous CD34+-enriched hematopoietic stem and progenitor cells exposed to transduction with a lentiviral vector driving myeloid specific interferon-alpha2 expression, which will be administered to up to 27 patients affected by GBM who have an unmethylated MGMT promoter. Part A will evaluate the safety and tolerability of 5 escalating doses of Temferon and 3 different conditioning regimens in up to 27 patients, following first line treatment.
This is a non-randomized, open label, multicenter, phase I/IIa, therapeutic-exploratory, dose escalation, prospective study, involving a single injection of Temferon, an investigational ATMP consisting of autologous CD34+-enriched HSPCs exposed to transduction with a 3rd generation lentiviral vector driving myeloid-specific IFN-alpha2 expression, which will be administered to up to 27 patients affected by GBM who have an unmethylated MGMT promoter. The study will recruit and follow-up patients at a specialist neurosurgical and neuro-oncology units in Italy. Administration of Temferon and hematological follow up will take place at specialist hematology and bone marrow transplantation units. Potentially eligible patients will be identified immediately after surgical resection of GBM once the MGMT promoter methylator status is known. Once written, informed consent is obtained, and screening procedures have been completed, harvesting of HSPCs will occur. A standard of care regimen lasting approximately 6 weeks, will then take place . During this time, Temferon manufacturing will occur. Following completion of radiotherapy, patients will be admitted for receipt of a conditioning regimen consisting of BCNU and thiotepa (Cohorts 1-6), busulfan and thiotepa (Cohort 5), or busulfan (Cohorts 7 and 8). This will be followed by administration of Temferon. In-patient monitoring will occur until hematological recovery occurs. Thereafter, regular follow-up of patients will occur up to 2 years (+720 days) with the majority of assessments and procedures. At the +720 day visit, patients will be invited to participate in a long term follow-up study which will last for an additional 6 years. In Part A of the study, 8 cohorts of 3 patients will receive 5 escalating doses of Temferon. On completion of dose escalation in Part A, a conditioning regimen and single dose of Temferon will be selected to be studied in up to a further 6 patients. In the event that GBM disease progression occurs, patients will be managed with second line therapies including second surgery, TMZ, BCNU, fotemustine or any other approved therapy for GBM.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Genetically modified HSPCs
Ospedale San Raffaele
Milan, Italy
Fondazione IRCCS Istituto Neurologico "Carlo Besta"
Milan, Italy
Policlinico Universitario Fondazione Agostino Gemelli
Rome, Italy
Tolerability and safety of Temferon over the first 90 days following administration as determined by the incidence of adverse events
Routine clinical and laboratory surveillance
Time frame: 90 days
Long term tolerability and safety of Temferon as determined by the incidence of adverse events
Routine clinical and laboratory surveillance
Time frame: 2 years
Proportion of patients achieving haematologic recovery by Day +30 (defined as the first of at least 3 consecutive days with a neutrophil count >0.5 x 10^9/L and platelet count >20 x 10^9/L)
Hematologic recovery is defined as the first of at least 3 consecutive days with a neutrophil count \>0.5 x 10\^9/L and platelet count \>20 x 10\^9/L.
Time frame: 30 days
Determine the maximum tolerated dose of Temferon
Presence of a CTCAE Grade 3-5 adverse event (AE) that occurs within the first 30 days and is attributed to Temferon.
Time frame: 30 days
Identify presence of transduced myeloid cells in bone marrow as determined by vector copy number
VCN
Time frame: Over 2 years
Incidence of adverse events attributed to the conditioning regimen
Adverse events for BCNU and thiotepa, busulfan and thiotepa, or busulfan monotherapy up to Day +45
Time frame: Day +30
Identify presence of transduced myeloid cells in peripheral blood as determined by vector copy number
VCN
Time frame: Over 2 years
Determine clinical response in patients as determined by iRANO criteria
iRANO criteria
Time frame: Over 2 years
Determine progression free survival in patients
MRI
Time frame: Over 2 years
Determine overall survival in patients
Survival data
Time frame: 2 years
Changes in functional status (Eastern Cooperative Oncology Group)
ECOG assessment: 0 Fully active, able to carry on all pre-disease performance without restriction 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours 3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 5. Dead
Time frame: 2 years
Changes in functional status (Karnofsky)
Karnofsky assessment
Time frame: 2 years
Changes in Quality of Life (European Organisation for Research and Treatment of Cancer EORTC C30)
EORTC C30 questionnaire
Time frame: 2 years
Changes in Quality of Life (BN20)
European Organisation for Research and Treatment of Cancer BN20 questionnaire
Time frame: 2 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.