Vaccine Therapy With or Without Cyclophosphamide in Treating Patients With Recurrent or Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects and best dose of vaccine therapy when given with or without cyclophosphamide and to see how well they work in treating patients with multiple myeloma that has come back (recurrent) or has not responded to previous treatment (refractory). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vaccine therapy together with cyclophosphamide may be a better treatment for multiple myeloma.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) when administered with or without cyclophosphamide in patients with relapsed or refractory multiple myeloma. (Phase I) II. To evaluate the confirmed response rate of MV-NIS alone in patients with relapsed or refractory multiple myeloma who have exhausted all therapeutic options. (Phase II, Cohort A) III. To evaluate the confirmed response rate of MV-NIS alone in patients who are relapsing from very good partial response (VGPR) or complete response (CR) and have not received myeloma directed therapy for at least 12 weeks. (Phase II, Cohort B) SECONDARY OBJECTIVES: I. To determine the safety and toxicity of the intravenous administration of an Edmonston vaccine strain measles virus engineered to express the thyroidal sodium iodide symporter (MV-NIS) when administered with or without cyclophosphamide in patients with relapsed or refractory multiple myeloma. (Phase I) II. To evaluate the confirmed response rate of MV-NIS in patients with relapsed or refractory multiple myeloma. (Phase I) III. To further evaluate the adverse event profile of MV-NIS in patients with relapsed or refractory multiple myeloma. (Phase II) IV. To evaluate overall survival, failure-free survival and progression-free survival. (Phase II) TERTIARY 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 MV-NIS (when administered with or without cyclophosphamide) using 99m-technetium (Tc) gamma camera imaging. (Phase I and II) II. To assess virus replication, viremia, viral shedding in urine and respiratory secretions, and virus persistence after systemic administration of MV-NIS (when administered with or without cyclophosphamide). (Phase I and II) III. To monitor humoral responses to the injected virus. (Phase I and II) IV. To explore the anti-myeloma efficacy (i.e. clinical response rate, time to progression, progression free survival, duration of response) of the virus using standard myeloma response criteria as well as immunoglobulin free light chain measurements. (Phase I and II) OUTLINE: This is a phase I, dose-escalation study of MV-NIS followed by a phase II study. Patients are assigned to 1 of 2 treatment arms (Stage 1 or Stage 2) in phase I and assigned to Stage 1 in phase II. STAGE 1 (MV-NIS ALONE, closed to accrual on 12/17/2009 and reopened 10/13/2011): Patients receive MV-NIS intravenously (IV) over 1 hour on day 1. STAGE 2 (MV-NIS AND CYCLOPHOSPHAMIDE, temporarily closed to accrual on 10/13/11): Patients receive cyclophosphamide IV over 30 minutes and then MV-NIS IV over 1 hour 2 days later. After completion of study treatment, patients are followed up at 6 weeks, 12 weeks, and then every 3 months for 1 year.

Official Title
-----------------
Phase I/II Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, With or Without Cyclophosphamide, in Patients With Recurrent or Refractory Multiple Myeloma

Conditions
-----------------
Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Other: Laboratory Biomarker Analysis
* Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter
* Other: Pharmacological Study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Myeloma relapsing from partial response or better Patients relapsing > 18 months from transplant if not on maintenance, or If off maintenance, discontinued at least 6 months ago, or If relapsing on maintenance, at least 3 years from transplant, or Off prior myeloma therapy at least 6 months ago Sufficient tumor burden that is assessable for response Serum M-spike >= 0.5 g/dL, or If immunoglobulin A (IgA) myeloma, IgA > 1000 mg/dL, or Difference between involved and uninvolved free light chain (dFLC) > 10 mg/dL, or Urine M-spike >= 200 mg/24 hours, or Bone marrow plasmacytosis >= 10%, or Plasmacytoma >= 2 cm in diameter Absolute neutrophil count (ANC) >= 1000/uL Platelets (PLT) >= 50,000/uL Hemoglobin >= 8.5 g/dl Aspartate aminotransferase (AST) =< 2 times upper limit of normal Creatinine < 2 times upper limit of normal Total bilirubin =< 1.5 x upper limit of normal International normalized ratio (INR) =< 1.4 x ULN at the time of registration Ability to provide informed consent Willingness to return to Mayo Clinic Rochester for follow-up Life expectancy >= 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Willingness to provide all biological specimens as required by the protocol Negative serum pregnancy test done =< 7 days prior to registration for women of childbearing potential only Measles antibody titer on the BioRad Multiplex assay less than or equal to 1.0 Exclusion Criteria: Uncontrolled infection Active tuberculosis Any myeloma directed therapy within 12 weeks of registration including plasmapheresis or transfusion New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review Active central nervous system (CNS) disorder or seizure disorder Human immunodeficiency virus (HIV) positive test result 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) Previous exposure to heat inactivated measles virus vaccine (this vaccine was given to some individuals between the years of 1963-1967) Any of the following: 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 Evidence of chronic or acute graft versus host disease or on-going treatment for graft versus host disease from prior allogeneic stem cell transplantation Exposure to household contacts =< 15 months old or household contact with known immunodeficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 (MV-NIS alone)<br>Patients receive MV-NIS IV over 1 hour on day 1. (Closed to accrual on 12/17/2009 and reopened 10/13/2011) | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter<br>* Given IV<br>* Other names: MV-NIS;Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Stage 2 (MV-NIS and cyclophosphamide)<br>Patients receive cyclophosphamide IV over 30 minutes and then MV-NIS IV over 1 hour 2 days later. (Temporarily closed to accrual on 10/13/11) | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter<br>* Given IV<br>* Other names: MV-NIS;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. The number of patients reporting a dose-limiting event are reported. | 6 weeks | 
| Maximum Tolerated Dose (MTD) (Phase I) | The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. The MTD is reported below. | 6 weeks | 
| Proportion of Confirmed Response, Defined as a Partial Response (PR) or Better (Phase II) | Confirmed response will be evaluated using all cycles. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Toxicity Rate, Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) (Phase I) | The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below by stage for Phase I patients. | Up to 1 year | 
| Number of Patients With Clinical Responses (Phase I) | The number of patients with clinical responses (CR, VGPR, PR, or minimal response [MR]) will be summarized by stage. | Up to 1 year | 
| Overall Survival (Phase II) | Time from registration to death due to any cause, assessed up to 1 year. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause, assessed up to 1 year | 
| Time to Progression (TTP) (Phase II) | Time from registration to the earliest date with documentation of disease progression, assessed up to 1 year. The distribution of time to progression will be estimated using the method of Kaplan-Meier. | Time from registration to the earliest date with documentation of disease progression, assessed up to 1 year | 
| Progression-free Survival (Phase II) | 1-year progression-free survival (PFS1). Evidence of local recurrence, distant metastasis, or death from any cause within 1 year counted as events in the time-to-event Kaplan-Meier analysis of progression-free survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | At 1 year | 
| Progression-free Survival (Phase II) | 2-year progression-free survival (PFS2). Evidence of local recurrence, distant metastasis, or death from any cause within 2 years counted as events in the time-to-event Kaplan-Meier analysis of progression-free survival. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | At 2 years | 
| Progression-free Survival (Phase II) | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Up to 5 years | 
| Failure-free Survival (Phase II) | Time from registration to the earliest of progressive disease, alternative treatment for myeloma, or death due to any cause, assessed up to 1 year. The distribution of failure-free survival will be estimated using the method of Kaplan-Meier. | Time from registration to the earliest of progressive disease, alternative treatment for myeloma, or death due to any cause, assessed up to 1 year | 
| Overall Toxicity Rate, Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) (Phase II) | The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below for Phase II patients. | Up to 1 year |