VSV-hIFNbeta-NIS in Treating Patients With Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia or Lymphoma

Myelodysplastic Syndrome Clinical Trial

Official title:

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients With Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia, Lymphomas, or Histiocytic/Dendritic Cell Neoplasms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03017820
• Other study ID #: MC1684
• Secondary ID: NCI-2017-00049MC
• Status: Recruiting
• Phase: Phase 1
• Start date: April 4, 2017
• Est. completion date: April 1, 2032

Study information

• Verified date: April 2024
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I trial studies the best dose and side effects of recombinant vesicular stomatitis virus carrying the human NIS and IFN beta genes (VSV-hIFNbeta-sodium iodide symporter [NIS]) with or without cyclophosphamide or ipilimumab and nivolumab or cemiplimab in treating patients with multiple myeloma, acute myeloid leukemia (AML) or lymphoma that has come back or does not respond to treatment. A virus, called VSV-hIFNbeta-NIS, which has been changed in a certain way, may be able to kill cancer cells without damaging normal cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Immunotherapy with ipilmumab and nivolumab or cemiplimab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving VSV-hIFNbeta-NIS and ruxolitinib phosphate may work better at treating multiple myeloma, acute myeloid leukemia and T-cell lymphoma.

Description:

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of VSV-hIFNβ-NIS in different treatment regimens (alone [Group A, F, G] in combination with ruxolitinib [Group B] and in combination with cyclophosphamide [Group C]) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, T and B-cell lymphoma, or histiocytic/dendritic cell neoplasms; in combination with ipilimumab and nivolumab in patients with multiple myeloma [Group D] and in combination with ipilimumab and cemiplimab in patients with T-cell lymphoma [Group E]. SECONDARY OBJECTIVES: I. To determine the safety profile of VSV-hIFNbeta-NIS (alone and in combination). II. To estimate clinical response rate of VSV-hIFNbeta-NIS (alone and in combination) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, T-cell and B-cell lymphoma or histiocytic/dendritic cell neoplasms overall and by disease type. III. To estimate progression-free and overall survival of VSV-hIFNbeta-NIS (alone and in combination) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, T and B-cell lymphoma, or histiocytic/dendritic cell neoplasms overall and by disease type. CORRELATIVE OBJECTIVES: I. To determine the time course of viral gene expression and virus elimination, and the biodistribution of virally infected cells at various times points after infection with VSV-hIFNbeta-NIS using planar and single photon emission computed tomography (SPECT)/computed tomography (CT) imaging. II. To assess virus replication, viremia, viral shedding in urine and respiratory secretions, and virus persistence after systemic administration of VSV-hIFNbeta-NIS. III. To characterize the pharmacodynamics (PD) of VSV-IFNbeta-NIS by way of measuring serum interferon-beta and also vesicular stomatitis virus (VSV)-real time (RT)-polymerase chain reaction (PCR) of VSV-IFNbeta-NIS. IV. Assess CD8+ T cell (both general and VSV-IFNbeta-NIS specific) and natural killer (NK) cell responses. V. Gene expression analysis pre- and post-virotherapy. VI. Assess presence of VSV in tumor and normal tissues subsequent to administration of intravenous (IV) VSV-IFNbeta-NIS. VII. To identify the best dose of VSV-hIFNbeta-NIS in the regimen being evaluated based on activity observed in the correlative measures described above in those dose levels identified as tolerable. OUTLINE: This is a dose escalation study of VSV-IFNbeta-NIS. Patients are assigned to 1 of 3 groups. GROUP A: Patients receive VSV-IFNbeta-NIS intravenously (IV) over 30 minutes on day 1 in the absence of disease progression or unacceptable toxicity. GROUP B: **NO LONGER ENROLLING** Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1 and cyclophosphamide IV over 2 hours on day 2 in the absence of disease progression or unacceptable toxicity. GROUP C: **NO LONGER ENROLLING** Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1, ipilimumab IV over 30 minutes on day -3 and nivolumab IV over 30 minutes on day -3 in the absence of disease progression or unacceptable toxicity. GROUP D: Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1, ipilimumab IV over 30 minutes on day -3 and cemiplimab IV over 30 minutes on day -3 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, position emission tomography (PET) scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed up for 28 days, and then every 3 months for up to 1 year or until progressive disease, then every 6 months for 1 year.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: April 1, 2032
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >= 18 years
• Relapsed or refractory:
• Groups A, B, C or D: Multiple myeloma (MM) previously treated with an immunomodulatory imide drug (IMID), a proteosome inhibitor, and an alkylating agent
• Groups A, B, C only: Relapsed peripheral T-cell lymphoma (PTCL) of the following histologies: peripheral T-cell lymphoma-NOS (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell (ALCL), and mycosis fungoides (MF). Patients should have failed standard therapy and in the case of PTCL-NOS, AITL, and ALCL either have failed or be ineligible for high-dose therapy with autologous stem cell transplant
• Group B and C only: B-cell lymphoma (other than Burkitt's lymphoma), or histiocytic/dendritic cell neoplasms (HCN) at any stage
• Group E only: Relapsed peripheral T-cell lymphoma (PTCL) of the following histologies: peripheral T-cell lymphoma-NOS (PTCL-NOS); anaplastic large cell (ALCL), and mycosis fungoides (MF)
• Group F only: Expansion Cohort for B-cell lymphoma (other than Burkitt's lymphoma) with low tumor burden
• Group G only: Expansion Cohort for peripheral T cell lymphoma (PTCL) with low tumor burden
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (obtained =< 15 days prior to registration)
• Creatinine =< 2.0 mg/dL (obtained =< 15 days prior to registration)
• Direct bilirubin =< 1.5 x ULN (obtained =< 15 days prior to registration)
• International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained =< 15 days prior to registration)
• If baseline liver disease, Child Pugh score not exceeding class A (obtained =< 15 days prior to registration)
• Negative pregnancy test for persons of child-bearing potential (obtained =< 15 days prior to registration)
• FOR MULTIPLE MYELOMA ONLY: Measurable disease of multiple myeloma as defined by at

least ONE of the following:

• Serum monoclonal protein >= 1.0 g/dL by protein electrophoresis
• >= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
• Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
• FOR MULTIPLE MYELOMA ONLY: Absolute neutrophil count (ANC) >= 1000/uL (obtained =< 14 days prior to registration)
• FOR MULTIPLE MYELOMA ONLY: Platelet (PLT) >= 100,000/uL (obtained =< 14 days prior to registration)
• FOR MULTIPLE MYELOMA ONLY: Hemoglobin >= 8.5 g/dl (obtained =< 14 days prior to registration)
• FOR AML ONLY: No ANC restriction (obtained =< 14 days prior to registration)
• FOR AML ONLY: PLT >= 10,000/uL (transfusion to get platelets >= 10,000 is allowed) (obtained =< 14 days prior to registration)
• FOR AML ONLY: Hemoglobin >= 7.5 g/dl (obtained =< 14 days prior to registration)
• FOR AML ONLY: Absence of uncompensated disseminated intravascular coagulation (DIC- as diagnosed by standard International Society on Thrombosis and Hemostasis [ISTH] criteria)
• FOR TCL/BCL ONLY: ANC >= 1,000/uL (obtained =< 14 days prior to registration)
• FOR TCL/BCL ONLY: PLT >= 100,000/uL (obtained =< 14 days prior to registration)
• FOR TCL/BCL ONLY: Hemoglobin >= 8.5 g/dl (obtained =< 14 days prior to registration)
• FOR TCL/BCL ONLY: Measurable disease by CT or magnetic resonance imaging (MRI): must have at least one lesion that has a single diameter of > 2 cm or tumor cells in the blood > 5 x 10^9/L; NOTE: skin lesions can be used if the area is > 2 cm in at least one diameter and photographed with a ruler and the images are available in the medical record
• FOR HCN ONLY: ANC >= 1,000/uL obtained =< 15 days prior to registration
• FOR HCN ONLY: PLT >= 100,000/uL obtained =< 15 days prior to registration
• FOR HCN ONLY: Hemoglobin >= 8.0 g/dl obtained =< 15 days prior to registration
• FOR HCN ONLY: Measurable disease by CT or MRI: Must have at least one lesion that has a single diameter of >= 1.5 cm or tumor cells in the blood >5 x10^9/L. NOTE: Skin lesions can be used if the area is >= 1.5 cm in at least one diameter and photographed with a ruler and the images are available in the medical record
• Absence of active central nervous system (CNS) involvement; NOTE: pre-enrollment lumbar puncture not mandatory
• Ability to provide written informed consent
• Willingness to return to Mayo Clinic for follow-up
• Life expectancy >= 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Willing to provide mandatory biological specimens for research purposes

Exclusion Criteria:

• Availability of and patient acceptance of curative therapy
• Uncontrolled infection
• Active tuberculosis or hepatitis, or chronic hepatitis
• Any of the following prior therapies:
• Chemotherapy (IMIDs, alkylating agents, proteosome inhibitors) =< 2 weeks prior to registration
• Immunotherapy (monoclonal antibodies) =< 4 weeks prior to registration
• Experimental agent in case of AML or TCL within 4 half-lives of the last dose of the agent
• New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia [SVT])
• Active CNS disorder or seizure disorder or known CNS disease or neurologic symptomatology; in case of AML active CNS involvement as detected by lumbar puncture or neuro-imaging (only to be done if clinically indicated)
• Human immunodeficiency virus (HIV) positive test result or other immunodeficiency or immunosuppression
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (used for a non-Food and Drug Administration [FDA] approved indication and in the context of a research investigation);
• NOTE: in AML, the concurrent use of hydroxyurea to help control proliferative counts is allowed throughout the treatment protocol;
• NOTE: in TCL, patients may use topical emollients or corticosteroids, acetic acid soaks, etc. to control pruritis and prevent infection; no topical chemotherapy is allowed (no topical nitrogen mustard)
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are

unknown:

• Pregnant women or women of reproductive ability who are unwilling to use effective contraception
• Nursing women
• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment
• AML ONLY: Current disseminated intravascular coagulopathy (DIC)
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP A (LOW TUMOR BURDEN) ONLY:
• Diagnosis of AML
• Multiple myeloma only: > 25% plasma cells or plasmacytoma > 5cm in largest diameter
• Lymphoma or HCN only: Any mass >5cm
• Diagnosis of Burkitt's lymphoma
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP B (HIGH TUMOR BURDEN) ONLY:
• Diagnosis of AML
• Diagnosis of Burkitt's lymphoma
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP C (COMBINATION WITH CYCLOPHOSPHAMIDE) ONLY:
• Diagnosis of AML
• Diagnosis of Burkitt's lymphoma
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP D AND E (COMBINATION WITH IPILIMUMAB AND

NIVOLUMAB OR CEMIPLIMAB) ONLY:

• Diagnosis of AML
• Diagnosis of AITL
• Hypersensitivity to ipilimumab or its excipients
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP F (BCL EXPANSION COHORT) ONLY:
• Diagnosis of Burkitt's lymphoma
• ADDITIONAL EXCLUSION CRITERIA FOR GROUP G (PTCL EXPANSION COHORT) ONLY:
• Diagnosis of cutaneous TCL

Related Conditions & MeSH terms

• B-Cell Non-Hodgkin Lymphoma
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large-Cell, Anaplastic
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Lymphoma, T-Cell, Peripheral
• Multiple Myeloma
• Mycoses
• Mycosis Fungoides
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Neoplasms
• Neoplasms, Plasma Cell
• Preleukemia
• Previously Treated Myelodysplastic Syndrome
• Recurrence
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Anaplastic Large Cell Lymphoma
• Recurrent Angioimmunoblastic T-Cell Lymphoma
• Recurrent Mycosis Fungoides
• Recurrent Plasma Cell Myeloma
• Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
• Recurrent T-Cell Non-Hodgkin Lymphoma
• Refractory Acute Myeloid Leukemia
• Refractory Anaplastic Large Cell Lymphoma
• Refractory Angioimmunoblastic T-Cell Lymphoma
• Refractory Mycosis Fungoides
• Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified
• Refractory Plasma Cell Myeloma
• Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
• Refractory T-Cell Non-Hodgkin Lymphoma
• Syndrome

Intervention

Procedure:
• Biopsy
Undergo tumor biopsy
• Biospecimen Collection
Undergo blood sample collection
• Bone Marrow Biopsy
Undergo bone marrow biopsy
• Computed Tomography
Undergo SPECT/CT

Drug:
• Cyclophosphamide
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET scan

Biological:
• Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
Given IV

Procedure:
• Single Photon Emission Computed Tomography
Undergo SPECT/CT

Biological:
• Cemiplimab
Given IV

Locations

Country	Name	City	State
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Cook J, Peng KW, Witzig TE, Broski SM, Villasboas JC, Paludo J, Patnaik M, Rajkumar V, Dispenzieri A, Leung N, Buadi F, Bennani N, Ansell SM, Zhang L, Packiriswamy N, Balakrishnan B, Brunton B, Giers M, Ginos B, Dueck AC, Geyer S, Gertz MA, Warsame R, Go — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biodistribution and kinetics of virus spread	Assessed by single photon emission computed tomography (SPECT)/computed tomography (CT) imaging. Descriptive statistics and scatterplots will form the basis of presentation of these variables. Correlations between the laboratory values and other outcome measures will be carried out by standard parametric and non-parametric tests (e.g., Pearson's and Spearman's rho). Will be correlated with tumor distribution.	Up to 2 years
Other	NIS gene expression in tumor samples	Assessed by single photon emission computed tomography (SPECT)/computed tomography (CT) imaging. Descriptive statistics and scatterplots will form the basis of presentation of these variables. Correlations between the laboratory values and other outcome measures will be carried out by standard parametric and non-parametric tests (e.g., Pearson's and Spearman's rho). Will be correlated with tumor distribution.	Up to 2 years
Primary	Incidence of adverse events of grade 3 or higher	Assessed by the Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by cohort and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence.	Up to 2 years
Secondary	Clinical response	The number of responses (complete response [CR], very good partial response, partial response [PR], or minimal response for multiple myeloma; CR, CR with incomplete recovery, cytogenetic complete response, PR for acute myeloid leukemia [AML]; CR or PR for T-cell lymphoma [TCL]) will be summarized by simple descriptive summary statistics.	Up to 2 years
Secondary	Progression-free survival	The distribution of survival time will be estimated using the method of Kaplan-Meier (overall, by dose level, and by disease type).	From registration to disease progression or death due to any cause, assessed up to 2 years
Secondary	Overall survival	The distribution of survival time will be estimated using the method of Kaplan-Meier (overall, by dose level, and by disease type).	From registration to death due to any cause, assessed up to 2 years