This is a non-randomized, open label, Phase 1/2, 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-ɑ2 ex­pres­sion, which will be admin­istered to up to 9 patients affected by multiple myeloma in early relapse after intensive front line treat­ment.

Enrollment status: Recruiting.

Countries with trial sites (# of sites): Italy (1).

Type of trial: Interventional.
Phase of trial: Phase 1/2.

Trial IDs: NCT03875495 and TEM-MM-101.

Detailed description

This is a non-randomized, open label, single center, phase I/II, thera­peutic exploratory, dose-escalation, pro­spec­tive­ study, involving a single in­tra­venous infusion of Temferon, an inves­ti­ga­tional ad­vanced ther­apy consisting of au­tol­o­gous CD34+-enriched hema­to­poietic stem and progenitor cells (HSPCs) exposed to transduction with a third-generation, vesicular stomatitis virus-G (VSV-G) pseudo-typed lentiviral vector driving myeloid-specific interferon-ɑ2 (IFN-ɑ2) ex­pres­sion, which will be admin­istered to up to 9 patients affected by multiple myeloma in early relapse after intensive front line treat­ment. The study will recruit, treat and follow-up patients at a specialist hematology and bone marrow trans­plan­ta­tion unit at Ospedale San Raffaele (OSR) in Milan, Italy.

The study will enrol multiple myeloma patients that have ex­peri­enced an early relapse after intensive front line treat­ment, have been treated with an approved second line com­bi­na­tion treat­ment regi­men and obtained at least a very good partial remission (VGPR) according to Inter­na­tional Myeloma Work­ing Group (IMWG) criteria. Once the written informed consent is obtained, and screen­ing procedures have been com­pleted, harvesting of HSPCs will occur. Patients will be offered main­te­nance treat­ment during Temferon pro­duc­tion and release. Upon Temferon release for clin­i­cal use, patients will be admitted to the trans­plan­ta­tion unit for receipt of a reduced-intensity con­di­tioning regi­men consisting of mel­phalan. This will be followed by au­tol­o­gous stem cell trans­plant (ASCT) and admin­istra­tion of Temferon. In-patient monitoring will occur until hema­to­logical re­cov­ery occurs. Thereafter, regular follow-up of patients will occur up to 2 years (+730 days). At the +730 day visit, patients will be invited to par­tic­i­pate in a long term follow-up study which will last for an addi­tional 6 years.

3 cohorts of 3 patients will receive escalating doses of Temferon.

In the event that MM disease pro­gres­sion occurs, patients will be man­aged according to best clin­i­cal practice.

Criteria for participating in the trial:

Inclusion Criteria:

• Multiple myeloma patients with early relapse after intensive front-line treat­ment and disease measurable by serum bio­markers, who have obtained at least a VGPR after second-line salvage treat­ment.
• Able and willing to provide written informed consent.
• Able to comply with study protocol and procedures.
• Performance status scores: Eastern Cooperative Oncology Group (ECOG) < 2 and Karnofsky > 70%.
• Life ex­pec­tancy of ≥ 6 months.
• Adequate cardiac, renal, hepatic and pul­mo­nary functions as evi­denced by (at screen­ing and prior to con­di­tioning):
  • 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 ULN and esti­mated glomerular filtration rate (eGFR) > 30 ml/min/1.73m2;
  • Alkaline phosphatase (ALP), alanine amino­trans­ferase (ALT) and/or aspartate amino­trans­ferase (AST) ≤ 2.5 x ULN, and total bilirubin ≤ 2.0 mg/dl.
• Women of child-bearing poten­tial enrolled in the study must have a negative pregnancy test at screen­ing and agree to use two distinct 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.

Exclusion Criteria:

• Use of other inves­ti­ga­tional agents within 4 weeks prior to experimental treat­ment (within 6 weeks if use of long-acting agents).
• Severe active viral, bacterial, or fungal in­fec­tion at eligibility evaluation.
• Active auto­immune disease or a clin­i­cally relevant auto­immune manifestations, requiring immuno­sup­pres­sive treat­ment, i.e. psoriasis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, immune-mediated periph­eral neuropathies.
• Active sarcoidosis requiring steroid or other immuno­sup­pres­sive treat­ment.
• Primary amyloidosis.
• History of neuropsychiatric illness in­­clud­ing severe depression, schizophrenia, bipolar disorders, im­paired cog­ni­tive function, dementia or suicidal tendency.
• Neuropathy > grade 2.
• History of severe cardiovascular disease such as prior stroke, coronary artery disease requiring intervention, unresolved arrhythmias.
• Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or family history of familial cancer syn­dromes.
• Myelodysplasia, cytogenetic or molecular alterations specifically asso­ci­ated with clonal hemato­poiesis of the myeloid lineage, or other serious hema­to­logical disorder other than the plasma cell dyscrasia.
• Other clin­i­cal con­di­tions judged by the Investigator non-compatible with the study procedures.
• Positivity for HIV-1 or 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.
• Pregnancy or lactation.
• Previous allogeneic bone marrow trans­plan­ta­tion, kidney or liver trans­plant, or gene ther­apy.
• Prior to con­di­tioning: in­abil­ity to meet the target mobilization cell number needed to manu­fac­ture the Drug Product after at least 2 attempts of HSPC collection.

Trial locations:

Italy

Ospedale San Raffaele (Recruiting)
Milan, Italy, 20132

Additional trial in­for­ma­tion at clin­i­caltrials.gov: link.