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

• Sponsor: Genenta Science (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03875495
• Collaborator: IRCCS San Raffaele (Other)
• Enrollment: 9
• Location: 1
• Arm: 1
• Actual Duration (Months): 24.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Temferon	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 6, 2019
• Actual Primary Completion Date: Apr 2, 2021
• Actual Study Completion Date: Apr 2, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Tolerability and Safety of Temferon Over the First 90 Days Following Administration as Determined by the Incidence of CTCAEs [90 days]

   0 participants analyzed. All the patients were withdrawn before treatment

Secondary Outcome Measures

1. Long Term Tolerability and Safety of Temferon as Determined by the Incidence of CTCAEs [2 years]

   0 participants analyzed. All the patients were withdrawn before treatment

2. 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]

3. Determine the Maximum Tolerated Dose of Temferon [30 days]

4. Identify Presence of Transduced Myeloid Cells in Bone Marrow as Determined by Vector Copy Number [Up to 2 years]

5. Identify Presence of Transduced Myeloid Cells in Peripheral Blood as Determined by Vector Copy Number [Up to 2 years]

6. Identify Persistence of Transduced Myeloid Cells in Bone Marrow and Peripheral Blood as Determined by Vector Copy Number [At least 12 weeks]

7. Determine Clinical Response in Patients as Determined by IMWG Response Criteria [Up to 2 years]

8. Fraction of Patients Achieving Complete Response With Minimal Residual Disease (MRD) Negativity [Up to 2 years]

9. Determine Progression Free Survival in Patients [Up to 2 years]

10. Determine Overall Survival in Patients [2 years]

11. Changes in Functional Status (Eastern Cooperative Oncology Group, ECOG) [2 years]

12. Changes in Functional Status (Karnofsky) [2 years]

13. Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 [2 years]

14. Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY20 [2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale San Raffaele	Milan		Italy	20132

Sponsors and Collaborators

• Genenta Science
• IRCCS San Raffaele

Investigators

• Principal Investigator: Fabio Ciceri, MD, Ospedale San Raffaele, Milan, Italy

Study Documents (Full-Text)

• Study Protocol - Nov 26, 2019

More Information

Publications

None provided.

• Responsible Party: Genenta Science
• ClinicalTrials.gov Identifier: NCT03875495
• Other Study ID Numbers: TEM-MM-101
• First Posted: Mar 14, 2019
• Last Update Posted: Jan 28, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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; Hematological malignancy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	3 patients recruited but none received Temferon. Unable to recruit additional patients due to the ongoing COVID-19 pandemic.

Arm/Group Title	Temferon
Arm/Group Description	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. Temferon: Genetically modified autologous HSPCs
Period Title: Overall Study
STARTED	3
COMPLETED	0
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Patient Recruitment
Arm/Group Description	3 patients recruited into the study but no patients received Temferon. Study terminated due to inability to recruit additional patients in view of the ongoing COVID-19 pandemic
Overall Participants	0
Age () []
<=18 years
Between 18 and 65 years
>=65 years
Age () []
Sex: Female, Male () []
Female
Male
Race (NIH/OMB) () []
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Race/Ethnicity, Customized () []
Region of Enrollment (participants) []

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Untreated patients

Arm/Group Title	Untreated Patients
Arm/Group Description	3 Patients were recruited but did not receive Temferon
Measure Participants	0

2. Secondary Outcome

Title	Long Term Tolerability and Safety of Temferon as Determined by the Incidence of CTCAEs
Description	0 participants analyzed. All the patients were withdrawn before treatment
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	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
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Determine the Maximum Tolerated Dose of Temferon
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Identify Presence of Transduced Myeloid Cells in Bone Marrow as Determined by Vector Copy Number
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Identify Presence of Transduced Myeloid Cells in Peripheral Blood as Determined by Vector Copy Number
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Identify Persistence of Transduced Myeloid Cells in Bone Marrow and Peripheral Blood as Determined by Vector Copy Number
Time Frame	At least 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Determine Clinical Response in Patients as Determined by IMWG Response Criteria
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Fraction of Patients Achieving Complete Response With Minimal Residual Disease (MRD) Negativity
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Determine Progression Free Survival in Patients
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Determine Overall Survival in Patients
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Changes in Functional Status (Eastern Cooperative Oncology Group, ECOG)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Changes in Functional Status (Karnofsky)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Changes in Quality of Life: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY20
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	No patients received Temferon
Adverse Event Reporting Description	No treatment related adverse events were reported as Temferon was not adminsitered
Arm/Group Title	Untreated Patients
Arm/Group Description	3 patients recruited but did not receive Temferon
All Cause Mortality
	Untreated Patients
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Serious Adverse Events
	Untreated Patients
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Untreated Patients
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

Although 3 patients were recruited, no patients received Temferon

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.