Description:
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.
Title
- Brief Title: Dexamethasone, Carfilzomib, & Nivolumab With Pelareorep for Relapsed/Refractory Multiple Myeloma
- Official Title: PD1 Blockade and Oncolytic Virus in Relapsed Multiple Myeloma
Clinical Trial IDs
- ORG STUDY ID:
IRB00104234
- SECONDARY ID:
NCI-2018-01217
- SECONDARY ID:
Winship4398-18
- NCT ID:
NCT03605719
Conditions
- Recurrent Plasma Cell Myeloma
Interventions
Drug | Synonyms | Arms |
---|
Carfilzomib | Kyprolis, PR-171 | Arm 1 |
Dexamethasone | Decadron, Hexadrol, Ozurdex | Arm 1 |
Nivolumab | BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo | Arm 1 |
Pelareorep | Reolysin, Wild-type Reovirus | Arm 2 |
Purpose
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.
Detailed Description
PRIMARY OBJECTIVES:
I. Identify maximum tolerated dose of 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 pelareorep. Patients are assigned to 1 of 3 arms.
ARM 1: Patients 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. Cycles repeat every 28 days in the absence of disease progression
or unacceptable toxicity.
ARM 2: 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.
ARM 3 (expansion cohort): 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.
After completion of study treatment, patients are followed up for a minimum of 4 weeks once
off treatment or at least 100 days after the last nivolumab dose, then every 6 months after.
Trial Arms
Name | Type | Description | Interventions |
---|
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. | - Carfilzomib
- Dexamethasone
- 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. | - Carfilzomib
- Dexamethasone
- Nivolumab
- 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. | - Carfilzomib
- Dexamethasone
- Nivolumab
- Pelareorep
|
Eligibility Criteria
Inclusion Criteria:
- 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
- Platelet count ≥ 70,000 and platelet transfusion independent for one week prior to
screening (platelets allowed to be down to 50,000 if > 50% plasma cells on screening
aspirate or core biopsy)
- 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 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 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 7 months after stopping treatment (for males) and 5 months after
stopping treatment (for females)
- Ability to understand and the willingness to sign a written informed consent document
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
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 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 |
Safety Issue: | |
Description: | 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
Measure: | Time to progression |
Time Frame: | From start of protocol therapy up to 3 years |
Safety Issue: | |
Description: | 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. |
Measure: | Progression-free survival |
Time Frame: | From start of protocol therapy up to 3 years |
Safety Issue: | |
Description: | 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. |
Measure: | Overall survival |
Time Frame: | From start of protocol therapy up to 3 years |
Safety Issue: | |
Description: | Defined as the time from start of protocol therapy to death, censoring patients who are alive at last follow-up. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Emory University |
Last Updated
December 2, 2020