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Viral Therapy in Treating Patients With Relapsed or Refractory Multiple Myeloma

Primary Purpose

Light Chain Deposition Disease, Refractory Plasma Cell Myeloma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Diagnostic Laboratory Biomarker Analysis
Wild-type Reovirus
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Light Chain Deposition Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient must have relapsed or refractory myeloma that fits or did fit IMWG diagnostic criteria for symptomatic myeloma (although new or worsening end-organ damage is not required to be eligible) as defined below:

    • Presence of ≥ 10% clonal bone marrow plasma cells
    • Presence of serum and/or urinary measurable monoclonal protein or light chains
    • Evidence of any end-organ damage criteria listed below [at any time] attributed to the patient's myeloma:

      • Hypercalcemia: Serum calcium > 11.5 mg/dL
      • Renal insufficiency: Serum creatinine > 2 mg/dL
      • Anemia > 2 g/dL below the lower limit of normal or a hemoglobin value < 10 g/dL
      • Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures
  • Subject must have measurable disease defined as any of the following:

    • Serum monoclonal protein > 500 mg/dL by protein electrophoresis
    • > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
    • Serum immunoglobulin free light chain ≥ 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Patients must have received at least one prior antineoplastic therapy and must have progressed
  • No standard therapy is available or patient declines such options
  • Prior autologous and/or allogeneic transplant is permitted although transplant must have occurred greater than 90 days prior to registration
  • Adverse events from prior therapy must have recovered to no greater than grade 1 with the exception of grade 2 neuropathy
  • Prior radiation is permitted; however, at least 4 weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all radiation-associated toxicities to no greater than grade 1 at the time of registration
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%); patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count (ANC) ≥ 1,000/μL
  • Platelet count ≥ 50,000/μL
  • Hemoglobin > 8 g/dL
  • Total bilirubin < 1.5 mg/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 times the institutional upper limit of normal.
  • Able to understand and willing to sign a written informed consent document
  • Patients must be able to avoid direct contact with pregnant or nursing women, infants, and immunocompromised individuals during the five days of Reolysin treatment and for two days after
  • Patients must not have known immunodeficiency virus (HIV) infection or active hepatitis B or C infections
  • For patients with a history of congestive heart failure, systolic cardiac function must be assessed at screening and left ventricular ejection fraction (LVEF) ≥ 50%
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL prior to starting therapy and prior to beginning another course (if applicable)
  • FCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
  • The patient must be willing to comply with fertility requirements as below:

    • Male patients must agree to use an adequate method of contraception for the duration of the study and for 90 days afterwards
    • Female patients must be either postmenopausal, free from menses ≥ 2 years, surgically sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from heterosexual activity starting with screening and for 90 days afterwards
    • Patients must agree not to donate blood or sperm/ova during the course of taking protocol therapy and for at least 4 weeks after stopping treatment
  • No patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study

    • Patients may be receiving concomitant therapy with bisphosphonates and low-dose corticosteroids (e.g., prednisone up to but no more than 10 mg by mouth daily or its equivalent) for symptom management and comorbid conditions; doses of corticosteroid should be stable for at least 7 days prior to study treatment
  • No patients who are receiving any other investigational agents
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the preceding 6 months, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study
  • No patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to < 1 year, or confound data interpretation
  • No POEMS syndrome
  • No concurrent use of complementary or alternative medicines that, in the opinion of the principal investigator, would confound the interpretation of toxicities and/or antitumor activity of the study drug

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (wild-type reovirus)

Arm Description

Patients receive wild-type reovirus IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Associated adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) criteria and tolerability of wild-type reovirus
The number and severity of toxicity incidents will indicate the level of tolerance for Reolysin in the treatment of relapsed/refractory multiple myeloma. Toxicities will be evaluated using the CTCAE v. 4 standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
Maximum-tolerated dose level
The number and severity of toxicity incidents will indicate the level of tolerance for Reolysin in the treatment of relapsed/refractory multiple myeloma. Toxicities will be evaluated using the CTCAE v. 4 standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Secondary Outcome Measures

Duration of response
Defined as the duration from first observation of partial response to the time of disease progression (taking as a reference for progressive disease the smallest measurements recorded since treatment started), with deaths due to other causes other than progression censored. This includes only patients with confirmed responses, and the date at which the response status was first observed rather than the date of confirmation is used as the start date.
Objective response rate
Will evaluate clinical benefit endpoint described as that portion of patients experiencing CR, VGPR, or PR. The objective response rate will be analyzed by using a 95% confidence interval for the proportion responding at trial closure in the treated population.
Progression-free survival
Time to progression

Full Information

First Posted
February 11, 2012
Last Updated
April 14, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01533194
Brief Title
Viral Therapy in Treating Patients With Relapsed or Refractory Multiple Myeloma
Official Title
A Phase 1 Study of Reolysin Alone in Patients With Relapsed or Refractory Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
December 2014
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
This pilot phase I trial studies the side effects and the best dose of giving viral therapy to patients with relapsed or refractory multiple myeloma. Viral therapy, such as wild-type reovirus, may be able to kill cancer cells without damaging normal cells.
Detailed Description
PRIMARY OBJECTIVES: I. Determine safety and tolerability of Reolysin in patients with relapsed multiple myeloma. II. Obtain evidence of Reovirus replication by immunohistochemical co-localization of Reovirus and tubulin staining in marrow clot sections obtained on cycle 1 day 8. SECONDARY OBJECTIVES: I. Obtain preliminary data on response as determined by International Myeloma Working Group criteria after infusion of Reolysin as a single agent. (Clinical) II. Obtain pilot overall and progression free survival data for all treated patients. (Clinical) III. Assess neutralizing anti-reovirus assay (NARA) results on days 1, 8, 15, and once days 22-28 during cycle 1. (Correlative) IV. Assess feasibility of staining for RAF/MEK/ERK in CD138+ cells using marrow clot sections obtained from pre-treatment specimen. (Correlative) V. Cryopreserve PBMCs for future ancillary studies focused initially on lymphocyte subset(s) and myeloid derived suppressor cell changes after Reolysin infusion during cycle 1. (Correlative) VI. Cryopreserve CD138+-selected cells at screening and after treatment for future ancillary studies of genetic and epigenetic changes focused in part on endoplasmic reticulum (ER) stress. (Correlative) OUTLINE: This is a dose-escalation study. Patients receive wild-type reovirus IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspirate at baseline and periodically during study for RAF/MEK/ERK expression and wild-type reovirus replication analysis by immunohistochemistry. Blood and cryopreserved CD138+ selected cell samples are also collected for future ancillary studies. After completion of study treatment, patients are followed up for 4 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Light Chain Deposition Disease, Refractory Plasma Cell Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (wild-type reovirus)
Arm Type
Experimental
Arm Description
Patients receive wild-type reovirus IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Other
Intervention Name(s)
Diagnostic Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Biological
Intervention Name(s)
Wild-type Reovirus
Other Intervention Name(s)
Reolysin
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Associated adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) criteria and tolerability of wild-type reovirus
Description
The number and severity of toxicity incidents will indicate the level of tolerance for Reolysin in the treatment of relapsed/refractory multiple myeloma. Toxicities will be evaluated using the CTCAE v. 4 standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
Time Frame
Up to 4 weeks post-treatment
Title
Maximum-tolerated dose level
Description
The number and severity of toxicity incidents will indicate the level of tolerance for Reolysin in the treatment of relapsed/refractory multiple myeloma. Toxicities will be evaluated using the CTCAE v. 4 standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Duration of response
Description
Defined as the duration from first observation of partial response to the time of disease progression (taking as a reference for progressive disease the smallest measurements recorded since treatment started), with deaths due to other causes other than progression censored. This includes only patients with confirmed responses, and the date at which the response status was first observed rather than the date of confirmation is used as the start date.
Time Frame
Up to 2 years
Title
Objective response rate
Description
Will evaluate clinical benefit endpoint described as that portion of patients experiencing CR, VGPR, or PR. The objective response rate will be analyzed by using a 95% confidence interval for the proportion responding at trial closure in the treated population.
Time Frame
Up to 4 weeks post-treatment
Title
Progression-free survival
Time Frame
From start of treatment to disease progression or death, regardless of cause of death, whichever comes first, assessed up to 2 years
Title
Time to progression
Time Frame
Time from the start of the treatment until the criteria for disease progression are met, assessed up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient must have relapsed or refractory myeloma that fits or did fit IMWG diagnostic criteria for symptomatic myeloma (although new or worsening end-organ damage is not required to be eligible) as defined below: Presence of ≥ 10% clonal bone marrow plasma cells Presence of serum and/or urinary measurable monoclonal protein or light chains Evidence of any end-organ damage criteria listed below [at any time] attributed to the patient's myeloma: Hypercalcemia: Serum calcium > 11.5 mg/dL Renal insufficiency: Serum creatinine > 2 mg/dL Anemia > 2 g/dL below the lower limit of normal or a hemoglobin value < 10 g/dL Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures Subject must have measurable disease defined as any of the following: Serum monoclonal protein > 500 mg/dL by protein electrophoresis > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis Serum immunoglobulin free light chain ≥ 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio Patients must have received at least one prior antineoplastic therapy and must have progressed No standard therapy is available or patient declines such options Prior autologous and/or allogeneic transplant is permitted although transplant must have occurred greater than 90 days prior to registration Adverse events from prior therapy must have recovered to no greater than grade 1 with the exception of grade 2 neuropathy Prior radiation is permitted; however, at least 4 weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all radiation-associated toxicities to no greater than grade 1 at the time of registration Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%); patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible Life expectancy of greater than 3 months Absolute neutrophil count (ANC) ≥ 1,000/μL Platelet count ≥ 50,000/μL Hemoglobin > 8 g/dL Total bilirubin < 1.5 mg/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 times the institutional upper limit of normal. Able to understand and willing to sign a written informed consent document Patients must be able to avoid direct contact with pregnant or nursing women, infants, and immunocompromised individuals during the five days of Reolysin treatment and for two days after Patients must not have known immunodeficiency virus (HIV) infection or active hepatitis B or C infections For patients with a history of congestive heart failure, systolic cardiac function must be assessed at screening and left ventricular ejection fraction (LVEF) ≥ 50% Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL prior to starting therapy and prior to beginning another course (if applicable) FCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation The patient must be willing to comply with fertility requirements as below: Male patients must agree to use an adequate method of contraception for the duration of the study and for 90 days afterwards Female patients must be either postmenopausal, free from menses ≥ 2 years, surgically sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from heterosexual activity starting with screening and for 90 days afterwards Patients must agree not to donate blood or sperm/ova during the course of taking protocol therapy and for at least 4 weeks after stopping treatment No patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study Patients may be receiving concomitant therapy with bisphosphonates and low-dose corticosteroids (e.g., prednisone up to but no more than 10 mg by mouth daily or its equivalent) for symptom management and comorbid conditions; doses of corticosteroid should be stable for at least 7 days prior to study treatment No patients who are receiving any other investigational agents No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the preceding 6 months, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study No patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to < 1 year, or confound data interpretation No POEMS syndrome No concurrent use of complementary or alternative medicines that, in the opinion of the principal investigator, would confound the interpretation of toxicities and/or antitumor activity of the study drug
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Craig Hofmeister
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Viral Therapy in Treating Patients With Relapsed or Refractory Multiple Myeloma

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