VSV-hIFNbeta-NIS With or Without Ruxolitinib Phosphate in Treating Patients With Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia, or T-cell Lymphoma
Study Details
Study Description
Brief 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 ruxolitinib phosphate in treating patients with multiple myeloma, acute myeloid leukemia, or T-cell 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. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving VSV-hIFNbeta-NIS and ruxolitinib phosphate may work better at treating multiple myeloma, acute myeloid leukemia and T-cell lymphoma.
Detailed Description
PRIMARY OBJECTIVE:
- To determine the maximum tolerated dose (MTD) of VSV-hIFNbeta-NIS in different treatment regimens (alone [group A] and in combination with ruxolitinib phosphate [ruxolitinib] [group B]) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, or T-cell lymphoma and in combination with ruxolitinib and cyclophosphamide (group C) in relapsed/refractory multiple myeloma patients.
SECONDARY OBJECTIVES:
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To determine the safety profile of VSV-hIFNbeta-NIS (alone and in combination with ruxolitinib).
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To estimate clinical response rate of VSV-hIFNbeta-NIS (alone and in combination with ruxolitinib) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, or T-cell lymphoma overall and by disease type.
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To estimate progression-free and overall survival of VSV-hIFNbeta-NIS (alone and in combination with ruxolitinib) in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia, or T-cell lymphoma overall and by disease type.
CORRELATIVE OBJECTIVES:
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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.
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To assess virus replication, viremia, viral shedding in urine and respiratory secretions, and virus persistence after systemic administration of VSV-hIFNbeta-NIS.
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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.
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Assess CD8+ T cell (both general and VSV-IFNbeta-NIS specific) and natural killer (NK) cell responses.
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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.
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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. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion.
GROUP B: Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1 and ruxolitinib phosphate orally (PO) twice daily (BID) on days -1 to 9. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion.
GROUP C: Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days -1 to 9. Patients also receive cyclophosphamide IV over 2 hours on day 2. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion.
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group A (VSV-IFNbeta-NIS) Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion. |
Procedure: Computed Tomography
Undergo SPECT/CT
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
Given IV
Other Names:
Procedure: Single Photon Emission Computed Tomography
Undergo SPECT/CT
Other Names:
|
| Experimental: Group B (VSV-IFNbeta-NIS, ruxolitinib) Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days -1 to 9. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion. |
Procedure: Computed Tomography
Undergo SPECT/CT
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
Given IV
Other Names:
Drug: Ruxolitinib Phosphate
Given PO
Other Names:
Procedure: Single Photon Emission Computed Tomography
Undergo SPECT/CT
Other Names:
|
| Experimental: Group C (VSV-IFNbeta-NIS, ruxolitinib, cyclophosphamide) Patients receive VSV-IFNbeta-NIS IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days -1 to 9. Patients also receive cyclophosphamide IV over 2 hours on day 2. Patients undergo SPECT/CT scans at baseline, and at days 3 and 8 after VSV-IFNbeta-NIS infusion. |
Procedure: Computed Tomography
Undergo SPECT/CT
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
Given IV
Other Names:
Drug: Ruxolitinib Phosphate
Given PO
Other Names:
Procedure: Single Photon Emission Computed Tomography
Undergo SPECT/CT
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of adverse events of grade 3 or higher [Up to 2 years]
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.
Secondary Outcome Measures
- Clinical response [Up to 2 years]
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.
- Progression-free survival [From registration to disease progression or death due to any cause, assessed up to 2 years]
The distribution of survival time will be estimated using the method of Kaplan-Meier (overall, by dose level, and by disease type).
- Overall survival [From registration to death due to any cause, assessed up to 2 years]
The distribution of survival time will be estimated using the method of Kaplan-Meier (overall, by dose level, and by disease type).
Other Outcome Measures
- Biodistribution and kinetics of virus spread [Up to 2 years]
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.
- NIS gene expression in tumor samples [Up to 2 years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Relapsed or refractory:
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Groups A, B, or C: Multiple myeloma (MM) previously treated with an immunomodulatory drug (IMID), a proteosome inhibitor and an alkylating agent; OR
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Groups A or B: Acute myeloid leukemia (AML), excluding acute promyelocytic leukemia (PML-RARA rearranged- AML-M3); either primary refractory or relapsed/refractory disease after at least two front line chemotherapy regimens (note: induction and consolidation chemotherapy is considered one line of therapy); diagnosis based on 2008 World Health Organization (WHO) criteria; OR
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Groups A, B, or C: Relapsed T-cell lymphoma (TCL) or the following types: peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell (ALCL), and cutaneous TCL (CTCL) of 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
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Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (obtained =< 14 days prior to registration)
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Creatinine =< 2.0 mg/dL (obtained =< 14 days prior to registration)
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Direct bilirubin =< 1.5 x ULN (obtained =< 14 days prior to registration)
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International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained =< 14 days prior to registration)
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If baseline liver disease, Child Pugh score not exceeding class A (obtained =< 14 days prior to registration)
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Negative pregnancy test for persons of child-bearing potential (obtained =< 14 days prior to registration)
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FOR MULTIPLE MYELOMA ONLY: Measurable disease of multiple myeloma as defined by at least ONE of the following:
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Serum monoclonal protein >= 1.0 g/dL by protein electrophoresis
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= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
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Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
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FOR MULTIPLE MYELOMA ONLY: Absolute neutrophil count (ANC) >= 1000/uL (obtained =< 14 days prior to registration)
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FOR MULTIPLE MYELOMA ONLY: Platelet (PLT) >= 100,000/uL (obtained =< 14 days prior to registration)
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FOR MULTIPLE MYELOMA ONLY: Hemoglobin >= 8.5 g/dl (obtained =< 14 days prior to registration)
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FOR AML ONLY: No ANC restriction (obtained =< 14 days prior to registration)
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FOR AML ONLY: PLT >= 10,000/uL (transfusion to get platelets >= 10,000 is allowed) (obtained =< 14 days prior to registration)
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FOR AML ONLY: Hemoglobin >= 7.5 g/dl (obtained =< 14 days prior to registration)
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FOR AML ONLY: Absence of uncompensated disseminated intravascular coagulation (DIC- as diagnosed by standard International Society on Thrombosis and Hemostasis [ISTH] criteria)
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FOR TCL ONLY: ANC >= 1,000/uL (obtained =< 14 days prior to registration)
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FOR TCL ONLY: PLT >= 100,000/uL (obtained =< 14 days prior to registration)
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FOR TCL ONLY: Hemoglobin >= 8.5 g/dl (obtained =< 14 days prior to registration)
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FOR TCL 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
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Absence of active central nervous system (CNS) involvement; NOTE: pre-enrollment lumbar puncture not mandatory
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Ability to provide written informed consent
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Willingness to return to Mayo Clinic for follow-up
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Life expectancy >= 12 weeks
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Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
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Willing to provide mandatory biological specimens for research purposes
Exclusion Criteria:
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Availability of and patient acceptance of curative therapy
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Uncontrolled infection
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Active tuberculosis or hepatitis, or history of hepatitis B or C, or chronic hepatitis
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Any of the following prior therapies:
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Chemotherapy (IMIDs, alkylating agents, proteosome inhibitors) =< 2 weeks prior to registration
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Immunotherapy (monoclonal antibodies) =< 4 weeks prior to registration
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Experimental agent in case of AML or TCL within 4 half-lives of the last dose of the agent
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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])
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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)
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Human immunodeficiency virus (HIV) positive test result or other immunodeficiency or immunosuppression
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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);
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NOTE: in AML, the concurrent use of hydroxyurea to help control proliferative counts is allowed throughout the treatment protocol;
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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)
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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:
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Pregnant women or women of reproductive ability who are unwilling to use effective contraception
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Nursing women
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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
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Prior allogeneic bone marrow transplant
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AML ONLY: Current disseminated intravascular coagulopathy (DIC)
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ADDITION EXCLUSION CRITERIA FOR GROUP A (LOW TUMOR BURDEN) ONLY
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AML ONLY: Acute promyelocytic leukemia (PML-RARA rearranged- AML-M3)
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AML ONLY: AML with > 30% circulating blasts and > 50% bone marrow blasts
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MULTIPLE MYELOMA ONLY: Multiple : >= 15% plasmas cells or plasmacytoma > 5 cm in largest diameter
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TCL ONLY: Any mass >= 5 cm
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ADDITIONAL EXCLUSION CRITERIA FOR GROUP C (COMBINATION WITH CYCLOPHOSPHAMIDE) ONLY:
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Diagnosis of AML
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic in Arizona | Scottsdale | Arizona | United States | 85259 |
| 2 | Mayo Clinic in Florida | Jacksonville | Florida | United States | 32224-9980 |
| 3 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
Sponsors and Collaborators
- Mayo Clinic
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Martha Q Lacy, Mayo Clinic in Rochester
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MC1684
- NCI-2017-00049
- MC1684
- P30CA015083