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

A Phase I/II Dose Escalation Study Evaluating Safety and Activity of Autologous CD34+-Enriched Hematopoietic Progenitor Cells Genetically Modified With a Lentiviral Vector Encoding for the Human Interferon-ɑ2 Gene in Multiple Myeloma Patients With Early Relapse After Intensive Front Line Therapy

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.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Temferon

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Temferon; Autologous CD34+-enriched hematopoietic progenitor cells exposed ex vivo to a specific lentiviral vector encoding for the human IFN-ɑ2 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 IFN-ɑ2 expression in HSPCs, thereby further increasing the specificity of the delivery strategy for their Tie2 expressing myeloid cell progeny.

Drug: Temferon; Genetically modified autologous HSPCs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability and Safety of Temferon Over the First 90 Days Following Administration as Determined by the Incidence of CTCAEs	0 participants analyzed. All the patients were withdrawn before treatment	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long Term Tolerability and Safety of Temferon as Determined by the Incidence of CTCAEs	0 participants analyzed. All the patients were withdrawn before treatment	2 years
Proportion of Patients Achieving Hematologic 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) in the Absence of Transfusions		30 days
Determine the Maximum Tolerated Dose of Temferon		30 days
Identify Presence of Transduced Myeloid Cells in Bone Marrow as Determined by Vector Copy Number		Up to 2 years
Identify Presence of Transduced Myeloid Cells in Peripheral Blood as Determined by Vector Copy Number		Up to 2 years
Identify Persistence of Transduced Myeloid Cells in Bone Marrow and Peripheral Blood as Determined by Vector Copy Number		At least 12 weeks
Determine Clinical Response in Patients as Determined by IMWG Response Criteria		Up to 2 years
Fraction of Patients Achieving Complete Response With Minimal Residual Disease (MRD) Negativity		Up to 2 years
Determine Progression Free Survival in Patients		Up to 2 years
Determine Overall Survival in Patients		2 years
Changes in Functional Status (Eastern Cooperative Oncology Group, ECOG)		2 years
Changes in Functional Status (Karnofsky)		2 years
Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30		2 years
Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY20		2 years

Collaborators and Investigators

• Sponsor: Genenta Science
• Collaborators: IRCCS San Raffaele
• Investigators: Principal Investigator: Fabio Ciceri, MD, Ospedale San Raffaele, Milan, Italy

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 6, 2019
• Primary Completion (ACTUAL): April 2, 2021
• Study Completion (ACTUAL): April 2, 2021

Study Registration Dates

• First Submitted: March 13, 2019
• First Submitted That Met QC Criteria: March 13, 2019
• First Posted (ACTUAL): March 14, 2019

Study Record Updates

• Last Update Posted (ACTUAL): January 28, 2022
• Last Update Submitted That Met QC Criteria: January 27, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Gene Therapy; Immunotherapy; Temferon; Hematological malignancy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: TEM-MM-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No