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