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

NCT03605719 | Completed Phase 1 DMC FDA Drug

• 4 other identifiers: IRB00104234NCI-2018-01217Winship4398-18P30CA138292
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I trial studies the side effects and best dose of wild-type reovirus (pelareorep) when given together with dexamethasone, carfilzomib, and nivolumab in treating patients with multiple myeloma that has come back (relapsed). 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. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. A virus, called pelareorep, 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 pelareorep may work better in treating patients with multiple myeloma.

Conditions

Recurrent Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (3)

• Dose-limiting toxicity (DLT) of 4-drug regimen evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

  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

  Up to 28 days after cycle 1 start

• Maximum tolerated dose (MTD) of 4-drug regimen

  The Escalation with Overdose Control (EWOC) design will be used to identify the MTD.

  Up to 28 days after cycle 1 start

• DLT of 3-drug regimen evaluated according to NCI CTCAE version 5.0

  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

  Up to 28 days after cycle 1 start

Secondary Outcomes (3)

• Time to progression

  From start of protocol therapy up to 3 years

• Progression-free survival

  From start of protocol therapy up to 3 years

• Overall survival

  From start of protocol therapy up to 3 years

Study Arms (3)

Arm 1

EXPERIMENTAL

Patients 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Carfilzomib; Drug: Dexamethasone; Biological: Nivolumab

Arm 2

EXPERIMENTAL

Patients receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, pelareorep 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Carfilzomib; Drug: Dexamethasone; Biological: Nivolumab; Biological: Pelareorep

Arm 3 (expansion)

EXPERIMENTAL

Patients receive dexamethasone IV on days 1, 2, 8, 9, 15, and 16, pelareorep 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Carfilzomib; Drug: Dexamethasone; Biological: Nivolumab; Biological: Pelareorep

Interventions

Carfilzomib DRUG

Given IV

Also known as: Kyprolis, PR-171

Arm 1; Arm 2; Arm 3 (expansion)

Dexamethasone DRUG

Given IV

Also known as: Decadron, Hexadrol, Ozurdex

Arm 1; Arm 2; Arm 3 (expansion)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Arm 1; Arm 2; Arm 3 (expansion)

Pelareorep BIOLOGICAL

Given IV

Also known as: Reolysin, Wild-type Reovirus

Arm 2; Arm 3 (expansion)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have multiple myeloma that fits or did fit International Myeloma Working Group (IMWG) diagnostic criteria
• In arm 3 but not for arms 1 or 2, 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
• Arm ONE only: Patients must be carfilzomib naive and have received ≥ 2 prior lines of therapy and must have included an IMiD, proteasome inhibitor, and anti-cluster of differentiation 38 (CD38) antibody as defined below
• 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 TWO and THREE only: Patients must have received ≥ 3 prior lines of therapy and must have included an immunomodulatory imide drug (IMiD), proteasome inhibitor, and anti-CD38 antibody as above along with evidence of proteasome inhibitor resistance defined as less than or equal to stable disease with prior treatment with a proteasome inhibitor containing regimen at moderate doses defined as carfilzomib 27+ mg/m²/week (wk), bortezomib 1.3+ mg/m²/wk subcutaneously (SQ) or IV, or ixazomib 3+ mg/wk orally (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 for at least one week prior to screening

You may not qualify if:

• 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 anti-myeloma treatment, 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

Sponsors & Collaborators

• Emory University: lead
• Bristol-Myers Squibb: collaborator
• Oncolytics Biotech: collaborator
• University of Utah: collaborator
• City of Hope Medical Center: collaborator
• Phylogeny: collaborator
• National Cancer Institute (NCI): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (2)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Dexamethasone; Calcium Dobesilate; Nivolumab; reolysin

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Craig Hofmeister, MD, MPH

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 20, 2018
• First Posted: July 30, 2018
• Study Start: October 24, 2018
• Primary Completion: October 10, 2022
• Study Completion: October 10, 2022
• Last Updated: October 6, 2023

Record last verified: 2023-10

Locations

US (2)