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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2015 by Mayo Clinic
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00450814
First received: March 20, 2007
Last updated: July 15, 2015
Last verified: July 2015
  Purpose

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 or does not respond to treatment. 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.


Condition Intervention Phase
Recurrent Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Drug: Cyclophosphamide
Other: Laboratory Biomarker Analysis
Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter
Other: Pharmacological Study
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • MTD of oncolytic measles virus encoding thyroidal sodium iodide symporter when administered with or without cyclophosphamide (Phase I) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Defined as the highest safely-tolerated dose level where at most 1 out of six patients experiences dose-limiting toxicity (DLT) or no DLT observed out of 3 patients at the maximum dose level, provided no DLT is observed at any of the previous dose levels.

  • Proportion of confirmed response, defined as a partial response (PR) or better (Phase II) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    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. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the method of Duffy and Santner.


Secondary Outcome Measures:
  • Failure-free survival (Phase II) [ Time Frame: Time from registration to the earliest of progressive disease, alternative treatment for myeloma, or death due to any cause, assessed up to 1 year ] [ Designated as safety issue: No ]
    The distribution of failure-free survival will be estimated using the method of Kaplan-Meier.

  • Incidence of adverse events, graded according to the NCI CTCAE v3.0 (Phase II) [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

  • Incidence of toxicity incidents as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0) (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    The number and severity of toxicity incidents will indicate the level of myeloma. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

  • Number of clinical responses (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    The number of responses (CR, VGPR, PR, or minimal response [MR]) will be summarized by simple descriptive summary statistics across all patients in each group as well as by dose level.

  • Overall survival (Phase II) [ Time Frame: Time from registration to death due to any cause, assessed up to 1 year ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  • Progression-free rate (Phase II) [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • Progression-free rate (Phase II) [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Time to progression (Phase II) [ Time Frame: Time from registration to the earliest date with documentation of disease progression, assessed up to 1 year ] [ Designated as safety issue: No ]
    The distribution of time to progression will be estimated using the method of Kaplan-Meier.

  • Time until any treatment related toxicity (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    Tolerability will be explored in an ancillary manner through time-related variables, including time until any treatment related toxicity. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals. The effect of dose and ancillary dichotomized covariates such as age will be explored using log-rank testing involving one covariate at a time.

  • Time until hematologic nadirs (white blood cells, ANC, platelets) (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Tolerability will be explored in an ancillary manner through time-related variables, including time until hematologic nadirs. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals. The effect of dose and ancillary dichotomized covariates such as age will be explored using log-rank testing involving one covariate at a time.

  • Time until treatment related grade 3+ toxicity (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    Tolerability will be explored in an ancillary manner through time-related variables, including time until treatment related grade 3+ toxicity. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals. The effect of dose and ancillary dichotomized covariates such as age will be explored using log-rank testing involving one covariate at a time.


Other Outcome Measures:
  • Biodistribution and kinetics of virus spread [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Will be correlated with tumor distribution. 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).

  • NIS gene expression in vivo [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Will be correlated with tumor distribution. 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).

  • Radiation dose [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    The radiation dose that could be delivered to the bone marrow as well as critical organs such as the liver, lungs and kidneys if iodine-131 were to be administered using MIRDOSE 3 program will be estimated. Where patterns of correlation are indicated, ordinary and partial correlation coefficients (controlling for dose levels) will be calculated. Inferential testing for significant shifts in the correlative laboratory data results across dose levels will be carried out only as a hypothesis generating exercise.

  • Viral replication [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    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).

  • Viral shedding [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    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).


Estimated Enrollment: 85
Study Start Date: January 2007
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage 1 (MV-NIS alone)
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
Correlative studies
Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter
Given IV
Other Name: MV-NIS
Other: Pharmacological Study
Correlative studies
Experimental: Stage 2 (MV-NIS and cyclophosphamide)
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
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • CYCLOPHOSPHAMIDE
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter
Given IV
Other Name: MV-NIS
Other: Pharmacological Study
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Myeloma relapsed from CR or VGPR

    • 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
      • Extramedullary plasmacytoma >= 2 cm in diameter
    • No prior myeloma directed therapy (other than bisphosphonate) past 12 weeks
  • 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 0.3

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00450814

Locations
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Angela Dispenzieri         
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Angela Dispenzieri Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT00450814     History of Changes
Other Study ID Numbers: MC038C, NCI-2009-01194, Mod06-005263-65, MC038C, P30CA015083, R01CA125614, R01CA168719
Study First Received: March 20, 2007
Last Updated: July 15, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
Cyclophosphamide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on August 03, 2015