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Dexamethasone, Carfilzomib, & Nivolumab With Reovirus for Relapsed/Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03605719
Recruitment Status : Recruiting
First Posted : July 30, 2018
Last Update Posted : November 5, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
Oncolytics Biotech
University of Utah
City of Hope Medical Center
Phylogeny
Information provided by (Responsible Party):
Craig Hofmeister, Emory University

Brief Summary:
This phase I trial studies the side effects and best dose of wild-type reovirus when given together with dexamethasone, carfilzomib, and nivolumab in treating participants with multiple myeloma that has come back. Drugs used in chemotherapy, such as dexamethasone, 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. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. A virus, called wild-type reovirus, which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells. Giving dexamethasone, carfilzomib, and nivolumab with wild-type reovirus may work better in treating participants with multiple myeloma.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Drug: Carfilzomib Drug: Dexamethasone Biological: Nivolumab Biological: Wild-type Reovirus Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Identify maximum tolerated dose of wild-type reovirus (pelareorep) in combination with other antineoplastic agents.

II. Identify whether the combination of carfilzomib and nivolumab lead to a safety profile different than what has been reported with either agent independently.

SECONDARY OBJECTIVES:

I. Assess the relative roles of immune-mediated and direct cytotoxic myeloma cell killing.

II. Understand the clinical benefit of nivolumab in programmed death-ligand 1 (PD-L1) positive multiple myeloma (MM) cells.

OUTLINE: This is a dose-escalation study of wild-type reovirus. Participants are assigned to 1 of 3 arms.

ARM I: Participants receive dexamethasone intravenously (IV) on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, wild-type reovirus IV on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III (expansion): Participants receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, wild-type reovirus IV on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 4 weeks, then every 6 months after.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PD1 Blockade and Oncolytic Virus in Relapsed Multiple Myeloma
Actual Study Start Date : October 24, 2018
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : October 31, 2024


Arm Intervention/treatment
Experimental: Arm I
Participants receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171

Drug: Dexamethasone
Given IV
Other Names:
  • Decadron
  • Hexadrol
  • Ozurdex

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm II
Participants receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, wild-type reovirus IV on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171

Drug: Dexamethasone
Given IV
Other Names:
  • Decadron
  • Hexadrol
  • Ozurdex

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Biological: Wild-type Reovirus
Given IV
Other Names:
  • Reolysin
  • Pelareorep

Experimental: Arm III (expansion)
Participants receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, wild-type reovirus IV on days 1, 2, 8, 9, 15, and 16, carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171

Drug: Dexamethasone
Given IV
Other Names:
  • Decadron
  • Hexadrol
  • Ozurdex

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Biological: Wild-type Reovirus
Given IV
Other Names:
  • Reolysin
  • Pelareorep




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) of 4-drug regimen evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Up to 28 days after cycle 1 start ]

    A DLT is defined as one of the following toxicities:

    • Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/µL) lasting 5 days or more.
    • Grade 3 to 4 thrombocytopenia associated with bleeding requiring platelet transfusion
    • Cardiac dysfunction: Grade > 3 left ventricular systolic dysfunction or grade > 2 myocarditis
    • Any grade 3-4 treatment-emergent non-hematologic adverse event (AE) clearly unrelated to the underlying disease and considered to be at least possibly related to protocol therapy

  2. Maximum tolerated dose (MTD) of 4-drug regimen [ Time Frame: Up to 28 days after cycle 1 start ]
    The Escalation with Overdose Control (EWOC) design will be used to identify the MTD.

  3. DLT of 3-drug regimen evaluated according to NCI CTCAE version 5.0 [ Time Frame: Up to 28 days after cycle 1 start ]

    A DLT is defined as one of the following toxicities:

    • Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/µL) lasting 5 days or more.
    • Grade 3 to 4 thrombocytopenia associated with bleeding requiring platelet transfusion
    • Cardiac dysfunction: Grade > 3 left ventricular systolic dysfunction or grade > 2 myocarditis
    • Any grade 3-4 treatment-emergent non-hematologic adverse event (AE) clearly unrelated to the underlying disease and considered to be at least possibly related to protocol therapy


Secondary Outcome Measures :
  1. Time to progression [ Time Frame: From start of protocol therapy up to 3 years ]
    Defined as the time from start of protocol therapy until the criteria for disease progression are met. Patients who are either lost to follow-up, die or who begin alternative treatments prior to progression, will have their data censored as of the date considered to be lost to follow-up, date of death, or the first day of alternative therapy.

  2. Progression-free survival [ Time Frame: From start of protocol therapy up to 3 years ]
    Defined as the time from start of protocol therapy to disease progression or death from any cause, censoring patients without an event at time of last clinical assessment.

  3. Overall survival [ Time Frame: From start of protocol therapy up to 3 years ]
    Defined as the time from start of protocol therapy to death, censoring patients who are alive at last follow-up.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient must have multiple myeloma that fits or did fit International Myeloma Working Group (IMWG) diagnostic criteria
  • Patients must have measurable disease defined as any of the following:

    • Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis
    • ≥ 200 mg of monoclonal protein in the urine on screening 24-hour electrophoresis
    • If no m-spike is present, involved serum immunoglobulin free light chain ≥ 100 mg/L AND an abnormal serum light chain ratio (< 0.26 or > 1.65)
  • Progressive disease or clinical relapse at the time of study entry as defined by IMWG
  • ≥ 3 prior lines of therapy and must have included an immunomodulatory drug (IMiD), proteasome inhibitor, and anti-cluster of differentiation 38 (CD38) antibody

    • IMiD exposure: At least 1 cycle of prior treatment unless stopped due to intolerance
    • CD38 antibody exposure: At least 4 doses unless stopped due to intolerance
    • Proteasome inhibitor exposed: At least 1 cycle of prior treatment unless stopped due to intolerance
  • Arm 1 only: Patients must be carfilzomib naive
  • Arm 2 and 3 only: Patients must have evidence of proteasome inhibitor resistance as defined below

    * Proteasome inhibitor moderate resistance: Less than or equal to stable disease with prior treatment with proteasome inhibitor containing regimen at moderate doses defined as carfilzomib 27+ mg/m²/wk, bortezomib 1.3+ mg/m²/wk subcutaneously (SQ) or IV, or ixazomib 3+ mg/wk PO

  • Both men and women of all races and ethnic groups are eligible for this study
  • 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
  • Prior autologous and/or allogeneic transplant is permitted although transplant must have occurred greater than 90 days prior to registration
  • Absolute neutrophil count (ANC) > 1000/µL
  • Platelet count ≥ 70,000 and platelet transfusion independent for 1 week prior to screening
  • Estimated creatinine clearance ≥ 30 mL/min as defined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) or Cockcroft-Gault
  • Total bilirubin < 1.5 mg/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3x the institutional upper limit of normal
  • Left ventricular ejection fraction ≥ 40%
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy. The effects of pelareorep and nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential 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. 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. Female of childbearing potential (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 7 months afterwards
    • Female patients must be either postmenopausal, free from menses ≥ 2 yrs, 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 5 months after last treatment in all patients
    • Patients must agree not to donate blood, sperm/ova while taking protocol therapy and for at least 4 weeks after stopping treatment
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Known human immunodeficiency virus (HIV) infection or active hepatitis B or C due to risk of viral infectivity of pelareorep
  • Known pulmonary hypertension
  • Patients who are receiving any other anti-myeloma investigational agents
  • Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome, primary amyloidosis (AL amyloidosis), and Waldenstrom macroglobulinemia
  • Patients who have had chemotherapy, radiotherapy, plasmapheresis, or major surgery (as defined by the investigator) within 2 weeks prior to cycle 1 day 1 of 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
  • Uncontrolled 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 because protocol therapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to protocol treatment of the mother, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03605719


Contacts
Contact: Craig Hofmeister, MD, MPH 404-778-4191 craig.hofmeister@emory.edu

Locations
United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jennifer Shipp    404-778-4191    jennifer.shipp@emory.edu   
Contact: Eduardo Sanabria    404-778-2164    esanab2@emory.edu   
Sponsors and Collaborators
Emory University
Bristol-Myers Squibb
Oncolytics Biotech
University of Utah
City of Hope Medical Center
Phylogeny
Investigators
Principal Investigator: Craig Hofmeister, MD, MPH Emory University

Responsible Party: Craig Hofmeister, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT03605719     History of Changes
Other Study ID Numbers: IRB00104234
NCI-2018-01217 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Winship4398-18 ( Other Identifier: Winship Cancer Institute )
First Posted: July 30, 2018    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Nivolumab
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents