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

Study Overview
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Brief Summary
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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 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 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.

Detailed Description
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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 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) while on study. GROUP B: Patients receive VSV-IFNbeta-NIS IV and cyclophosphamide IV while on study. GROUP C: Patients receive VSV-IFNbeta-NIS IV, ipilimumab IV and nivolumab IV while on study. 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.

Official Title
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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

Conditions
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B-Cell Non-Hodgkin Lymphoma, Histiocytic and Dendritic Cell Neoplasm, Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, 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

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Biopsy
* Procedure: Computed Tomography
* Drug: Cyclophosphamide
* Biological: Ipilimumab
* Biological: Nivolumab
* Procedure: Positron Emission Tomography
* Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
* Procedure: Single Photon Emission Computed Tomography


Participation Criteria
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Eligibility Criteria
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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) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (VSV-IFNbeta-NIS)<br>Patients receive VSV-IFNbeta-NIS intravenously (IV) while on study. Patients undergo SPECT, CT scan, PET scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: tomography;Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter<br>* Given IV<br>* Other names: VV1;Procedure: Single Photon Emission Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: Tomography, Emission-Computed, Single-Photon;|
| Experimental: Group B (VSV-IFNbeta-NIS, ruxolitinib)<br>Patients receive VSV-IFNbeta-NIS IV and cyclophosphamide IV while on study. Patients undergo SPECT, CT scan, PET scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter<br>* Given IV<br>* Other names: VV1;Procedure: Single Photon Emission Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: Tomography, Emission-Computed, Single-Photon;|
| Experimental: Group C (VSV-IFNbeta-NIS, ruxolitinib, cyclophosphamide)<br>Patients receive VSV-IFNbeta-NIS IV, ipilimumab IV and nivolumab IV while on study. Patients undergo SPECT, CT scan, PET scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: tomography;Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter<br>* Given IV<br>* Other names: VV1;Procedure: Single Photon Emission Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: Tomography, Emission-Computed, Single-Photon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 |