Clinical TrialsThe James Cancer Center Columbus, OH
open for enrollment
Wild-type Reovirus in Combination with Carfilzomib and Dexamethasone in Treating Patients with Relapsed or Refractory Multiple Myeloma
Pilot trial evaluating viral protein production from the combination of Reolysin and Carfilzomib in Multiple Myeloma
This phase I clinical trial studies the side effects and best dose of wild-type reovirus when combined with carfilzomib and dexamethasone in treating patients with multiple myeloma that has come back following treatment or does not respond to treatment. Drugs used in chemotherapy, such as dexamethasone and carfilzomib, 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. A virus called wild-type reovirus may be able to kill cancer cells without damaging normal cells and seems to work best when given with chemotherapy. Giving wild-type reovirus with chemotherapy may be a more effective treatment than chemotherapy alone.
I. Determine safety and tolerability, and define the maximum tolerated dose of reolysin (wild-type reovirus), carfilzomib and dexamethasone in patients with relapsed multiple myeloma.
II. Obtain evidence of reovirus entry into myeloma cells via localization of reoviral ribonucleic acid (RNA) in multiple myeloma (MM) cells in situ hybridization (ISH), and active viral proliferation/replication via localization of reoviral capsid protein immunohistochemistry (IHC) in MM cells in cycle 1 day 9 bone marrow biopsies in all patients enrolled in dose escalation cohorts.
I. Obtain preliminary data on response as determined by International Myeloma Working Group criteria after protocol therapy.
II. Obtain overall and progression free survival data for all treated patients.
III. Assess cytokine arrays of peripheral blood obtained on days 1, 2, 9, 15 and once during days 22-28 of cycle 1, and day 1 of cycle 2 and each successive cycle to obtain exploratory data regarding inflammatory cytokine concentrations and their correlation with response.
IV. Investigate pretreatment cycle 1 days 1 and 9 bone marrow aspirate interferon (IFN)-beta in MM cells as a potential marker of reolysin resistance.
V. Measure the induction of endoplasmic reticulum (ER) stress and autophagy markers to explore their respective roles in MM cell death following combination reolysin and carfilzomib in patients treated in all dose escalation cohorts.
VI. Evaluate pretreatment cycle 1 days 1 and 9 peripheral blood to explore the antiviral humoral response by measuring the production of neutralizing reoviral antibody (NARA) using a functional killing assay.
VII. Obtain cycle 1 day 1 pretreatment and 1 and 4 hours after treatment, and pretreatment cycle 1 days 2 and 9 peripheral blood, and pretreatment cycle 1 days 1 and 9 bone marrow aspirate samples to investigate the role of carfilzomib in modulating the antiviral immune mediated response.
VIII. Cryopreserve marrow aspirates obtained cycle 1 day 1 and all subsequent marrow aspirates while on trial for future studies.
OUTLINE: This is a dose escalation study of wild-type reovirus.
Patients receive dexamethasone intravenously (IV), carfilzomib IV over 30 minutes, and wild-type reovirus IV over 60 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks and then every 6 months.
Are you eligible?
Patient must have relapsed or refractory myeloma that fits or did fit International Myeloma Working Group (IMWG) diagnostic criteria for symptomatic myeloma (although new or worsening end organ damage is not required to be eligible) as defined below:
Presence of 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 or
- 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
Patients 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 screening 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 been previously treated with an immunomodulatory drug (IMiD) and proteasome inhibitor, must be refractory to carfilzomib defined as progression on or within 2 months of a carfilzomib-containing therapy, and must be progressing
Prior autologous and/or allogeneic transplant is permitted although transplant must have occurred greater than 90 days prior to registration
Both men and women of all races and ethnic groups are eligible for this study
Prior radiation is permitted; however, at least 2 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
Patients with expected carfilzomib sensitive disease, Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) is required for eligibility; those patients with lower performance status based solely on bone pain secondary to multiple myeloma are eligible
Absolute neutrophil count (ANC) >= 1000/uL
Platelet count >= 75,000 and transfusion independent
Total bilirubin < 1.5 mg/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x the institutional upper limit of normal
Ability to understand and the willingness 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 days of reolysin treatment and for two days after
Patients must not have known human immunodeficiency virus (HIV) infection or active hepatitis B or C infections
Systolic cardiac function will be assessed at screening if clinically indicated by history and physical; only patients with left ventricular ejection fraction (LVEF) >= 50% will be eligible for enrollment
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 cycle (if applicable)
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) starting 28 days prior to starting the study until at least 90 days following discontinuation of the trial therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
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, sperm/ova during the course of taking protocol therapy and for at least 4 weeks after stopping treatment
Patients who have had chemotherapy or radiotherapy within 2 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
Patients who are receiving any other therapeutic investigational agents
Patients previously treated on clinical trial with reolysin
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; breastfeeding should be discontinued
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
Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein), and skin changes (POEMS) syndrome
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