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A Phase I/IIa Study Evaluating Temferon in Patients With Glioblastoma & Unmethylated MGMT (TEM-GBM)

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ClinicalTrials.gov Identifier: NCT03866109
Recruitment Status : Recruiting
First Posted : March 7, 2019
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Genenta Science

Brief Summary:
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 21 patients affected by GBM who have an unmethylated MGMT promoter. Part A will evaluate the safety and tolerability of 3 escalating doses of Temferon in up to 9 patients, following first line treatment. In Part B, a further 12 patients will receive a single dose of Temferon, as idenitifed from Part A.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Drug: Temferon Phase 1 Phase 2

Detailed Description:

This is a non-randomized, open label, two center, 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 21 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 unit (Istituto Neurologico Carlo Besta, INCB) in Milan, Italy. Administration of Temferon and hematological follow up will take place at a specialist hematology and bone marrow transplantation unit at Ospedale San Raffaele (OSR) in Milan, Italy.

Potentially eligible patients will be identified at INCB 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 at OSR. A standard of care regimen lasting approximately 6 weeks, will then take place at INCB. During this time, Temferon manufacturing will occur. Following completion of radiotherapy, patients will be admitted to OSR for receipt of a conditioning regimen consisting of BCNU and thiotepa. This will be followed by administration of Temferon. In-patient monitoring at OSR 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 performed at INCB and some assessments/procedures at OSR. 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, 3 cohorts of 3 patients will receive escalating doses of Temferon. On completion of Part A, a single dose of Temferon will be selected to be studied in up to a further 12 patients in Part B. Criteria for study eligibility are the same for both Part A and Part B.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/IIa Dose Escalation Study Evaluating the Safety and Efficacy of Autologous CD34+-Enriched HSPCs Genetically Modified With Human Interferon-α2 in Patients With Glioblastoma Multiforme and Unmethylated MGMT Gene Promoter
Actual Study Start Date : March 5, 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Temferon
Autologous CD34+-enriched hematopoietic progenitor cells exposed in vitro to specific lentiviral vector encoding for the human interferon-alpha 2 gene. Its expression is tightly controlled by the human TIE2 enhancer/promoter sequence and by a post-transcriptional regulation layer represented by target miRNA sequences. This enables suppression of interferon-alpha2 expression in HSPCs, thereby further increasing the specificity of the delivery strategy for their Tie2 expressing myeloid cell progeny.
Drug: Temferon
Genetically modified HSPCs




Primary Outcome Measures :
  1. Tolerability and safety of Temferon over the first 90 days following administration as determined by the incidence of CTCAEs [ Time Frame: 90 days ]

Secondary Outcome Measures :
  1. Long term tolerability and safety of Temferon as determined by the incidence of CTCAEs [ Time Frame: 2 years ]
  2. 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) [ Time Frame: 30 days ]
  3. Determine the maximum tolerated dose of Temferon [ Time Frame: 30 days ]
  4. Identify presence of transduced myeloid cells in bone marrow as determined by vector copy number [ Time Frame: Over 2 years ]
  5. Identify presence of transduced myeloid cells in peripheral blood as determined by vector copy number [ Time Frame: Over 2 years ]
  6. Identify persistence of transduced myeloid cells in peripheral blood as determined by vector copy number [ Time Frame: At least 12 weeks ]
  7. Determine clinical response in patients as determined by iRANO criteria [ Time Frame: Over 2 years ]
  8. Determine progression free survival in patients [ Time Frame: Over 2 years ]
  9. Determine overall survival in patients [ Time Frame: 2 years ]
  10. Changes in functional status (ECOG) [ Time Frame: 2 years ]
  11. Changes in functional status (Karnofsky) [ Time Frame: 2 years ]
  12. Changes in Quality of Life (EORTC C30) [ Time Frame: 2 years ]
  13. Changes in Quality of Life (BN20) [ Time Frame: 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed, newly diagnosed supratentorial glioblastoma with unmethylated MGMT gene promoter.
  • Patients have undergone complete or partial tumor resection.
  • Able and willing to provide written informed consent and comply with the study protocol and procedures.
  • Eligible for radiotherapy.
  • Life expectancy of 6 months or more at Screening.
  • Women of child-bearing potential enrolled in the study must have a negative pregnancy test at screening and agree to use acceptable methods of contraception during the trial.
  • Men enrolled in the study with partners who are women of child-bearing potential, must be willing to use an acceptable barrier contraceptive method during the trial or have undergone successful vasectomy at least 6 months prior to entry into the study. Successful vasectomy needs to have been confirmed by semen analysis.
  • Karnofsky performance score (KPS)≥70.

Additional inclusion criteria to be assessed within 20 days of Temferon administration:

  • Adequate cardiac, renal, hepatic and pulmonary function as evidenced by:
  • Left ventricular ejection fraction (LVEF) ≥ 45% by echo and normal electrocardiogram (ECG) or presence of abnormalities not significant for cardiac disease.
  • Absence of severe pulmonary hypertension;
  • Diffusing capacity of the lung for carbon monoxide (DLCO) >50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) > 60% predicted (if non cooperative: pulse oximetry > 95% in room air);
  • Serum creatinine < 2x upper limit normal and estimated glomerular filtration rate (eGFR) ≥ 30ml/min/1.73m^2;
  • Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 2.0 mg/dl.
  • Hemoglobin ≥10 g/dL, platelet count ≥100000/mm^3, absolute neutrophil count >1500/mm^3.

Exclusion Criteria:

  • Use of other investigational agents or procedures within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents) or participation in a previous gene therapy study.
  • Known hypersensitivity to carmustine (or any other nitrosurea), thiotepa, lenograstim, plerixafor, or any excipients used in these products.
  • Receipt of any oral or parenteral chemotherapy or immunotherapy within 2 years of Screening.
  • Previous allogeneic bone marrow transplantation, kidney or liver transplant.
  • Clinical evidence of persistent raised intracranial pressure following surgical resection.
  • Clinically relevant active viral, bacterial, or fungal infection at eligibility evaluation.
  • Active autoimmune disease or a relevant history of important autoimmune manifestations, in particular psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis, immunemediated peripheral neuropathies.
  • History of sarcoidosis.
  • History or current evidence of neuropsychiatric illness including depression, schizophrenia, bipolar disorders, impaired cognitive function, dementia or suicidal tendency.
  • History of severe cardiovascular disease such as prior stroke, coronary artery disease requiring intervention or unresolved arrhythmias in the past 6 months.
  • Evidence of any hematological neoplasm.
  • Positivity for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2) (serology or RNA), and/or Hepatitis B Virus Surface Antigen (HbsAg) and/or Hepatitis B Virus (HBV) DNA and/or Hepatitis C virus (HCV) RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection.
  • Active alcohol or substance abuse within 6 months of the study.
  • Current pregnancy or lactation.
  • Known bleeding diathesis or history of abnormal bleeding, or any other known coagulation abnormalities that would contraindicate lumbar puncture for CSF or future surgery.
  • Use of immunosuppressants with the exception of steroids. The maximum permitted dexamethasone (or equivalent) dose is 4 mg per day.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03866109


Contacts
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Contact: Carlo Russo, MD +39 02 2643 3982 info-trial@genenta.com
Contact: Andrew Zambanini, MD +39 02 2643 3982 info-trial@genenta.com

Locations
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Italy
Ospedale San Raffaele Enrolling by invitation
Milan, Italy, 20132
Fondazione IRCCS Istituto Neurologico "Carlo Besta" Recruiting
Milan, Italy, 20133
Contact: Gaetano Finocchiaro, MD         
Sponsors and Collaborators
Genenta Science
Investigators
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Principal Investigator: Gaetano Finocchiaro, MD Fondazione IRCCS Istituto Neurologico "Carlo Besta"

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Responsible Party: Genenta Science
ClinicalTrials.gov Identifier: NCT03866109     History of Changes
Other Study ID Numbers: TEM-GBM_001
2018-001404-11 ( EudraCT Number )
First Posted: March 7, 2019    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Genenta Science:
Temferon
Gene Therapy
Immunotherapy
Solid tumor

Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Interferons
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents