A Phase I/II Study Evaluating Temferon in Multiple Myeloma Patients With Early Relapse After Front Line Therapy (TEM-MM)

This is a non-randomized, open label, phase I/II, 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.

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.

Eligibility Criteria:
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.