Trial Title:
Siltuximab for the Prevention of Severe Immune-Related Adverse Events During Immune Checkpoint Inhibitor Rechallenge in Patients With Advanced Cancer, CIRES Trial
NCT ID:
NCT06470971
Condition:
Advanced Malignant Solid Neoplasm
Hematopoietic and Lymphatic System Neoplasm
Conditions: Official terms:
Neoplasms
Antineoplastic Agents, Immunological
Siltuximab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Anti-PD-L1 Monoclonal Antibody
Description:
Receive anti-PD-L1 monoclonal antibody therapy
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Intervention type:
Biological
Intervention name:
Anti-PD1 Monoclonal Antibody
Description:
Receive anti-PD1 monoclonal antibody therapy
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Anti-PD-1 Monoclonal Antibody
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Scan
Description:
Undergo bone scan
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Bone Scintigraphy
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Other
Intervention name:
Quality-of-Life Assessment
Description:
Ancillary studies
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Quality of Life Assessment
Intervention type:
Biological
Intervention name:
Siltuximab
Description:
Given IV
Arm group label:
Treatment (PD1 antibody, PD-L1 antibody, Siltuximab)
Other name:
Anti-IL-6 Chimeric Monoclonal Antibody
Other name:
cCLB8
Other name:
CNTO 328
Other name:
CNTO-328
Other name:
Sylvant
Summary:
This phase II trial studies how well giving siltuximab during the reintroduction
(rechallenge) of immune checkpoint inhibitor (ICI) therapy works in preventing severe
immune-related adverse events (irAEs) in patients with cancer that may have spread from
where it first started to nearby tissue, lymph nodes, or distant parts of the body
(advanced). Immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1 monoclonal
antibodies, may help the body's immune system attack the cancer, and may interfere with
the ability of tumor cells to grow and spread. The use of ICI therapy may lead to severe
irAEs that can affect essentially any organ system in the body. Severe irAEs may lead to
the early stopping of life saving treatment. Most patients that stop ICI therapy early
will eventually progress and require additional treatment. Sometimes the decision is made
to rechallenge with ICI therapy. Many patients who developed severe irAEs during initial
ICI therapy are at risk for developing severe irAEs again during the rechallenge.
Siltuximab is a monoclonal antibody that binds to receptors for a protein called
interleukin-6 (IL-6). This may help lower the body's immune response and reduce
inflammation. Giving siltuximab during ICI rechallenge may help prevent severe irAEs in
patients with advanced cancer.
Detailed description:
PRIMARY OBJECTIVE:
I. To determine whether siltuximab prophylaxis reduces rates of de novo or recurrent
severe irAE within 24 weeks of anti-PD-1/PD-L1 therapy rechallenge.
SECONDARY OBJECTIVE:
I. To assess the preliminary anti-tumor activity of this combination including overall
response rate (ORR), progression-free survival (PFS) and overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To evaluate potential predictive biomarkers such as baseline serum IL-6 level,
C-reactive protein (CRP) suppression level, tissue IL-6 expression, stool microbiome, and
antibody clearance rate.
II. To assess changes in immune cell infiltration of irAE site pre- and post-treatment by
multiomics profiling.
III. To assess patient-reported outcomes by Patient-Reported Outcomes Measurement
Information System (PROMIS) instruments.
IV. To correlate circulating tumor deoxyribonucleic acid (ctDNA) levels with treatment
responses.
OUTLINE:
Patients receive anti-PD1 or anti-PD-L1 monoclonal antibody therapy either every 3 or 6
weeks, or every 2 or 4 weeks per physicians choice. Patients also receive siltuximab
intravenously (IV) over 1 hour on day 1 of each cycle prior to the administration of
anti-PD1 or anti-PD-L1 therapy. Treatment repeats either every 3 weeks for up to 8 doses
or every 4 weeks for up to 6 doses in the absence of disease progression or unacceptable
toxicity. Patients may undergo biopsy and bone scan on study, as well as blood sample
collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout
the study.
After completion of study treatment, patients are followed up at day 28, every 12 weeks
for up to 2 years, and then every 6 months until 5 years following registration.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Males or females aged ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Patients with any advanced cancer types who would benefit from anti-PD1 or
anti-PD-L1 therapy rechallenge at the investigator's discretion
- Patients must have had prior severe irAE while on ICI monotherapy or in combination
with other anticancer treatment. Severe irAE is defined as any grade 2 or higher
irAE requiring treatment discontinuation and prednisone > 0.5 milligrams
(mg)/kilogram (kg)/day (or equivalent) followed by a taper ≥ 4 weeks. Patients with
history of grade 4 severe irAE need to carefully weigh the risks and benefits and
might be eligible on a case-by-case basis after discussion with principal
investigator (PI)
- Recovery from prior irAEs to ≤ grade 1
- Patients who are on prednisone ≤ 10 mg/day (d) or equivalent are allowed
- Hemoglobin > 7 g/dL and < 17 g/dL
- Absolute neutrophil count (ANC) ≥ 1000 per mm^3
- Platelet count ≥ 75 × 10^9/L
- Serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])
≤ 3 × institutional ULN or ≤ 5 × ULN for patients with liver metastases
- Measured or calculated creatinine clearance (CL) ≥ 30 mL/min except patients with
end-stage renal disease on hemodialysis
- Cycle 1 day 1 of the study treatment should be at least 2 weeks since prior systemic
therapy, radiotherapy, or surgery
- Estimated life expectancy, in the judgment of the investigator, of at least 12 weeks
- Subjects of childbearing potential must have a negative serum pregnancy test at
screening
- Subjects of childbearing potential must be willing to completely abstain or agree to
use a highly effective method of contraception (i.e., less than 1% failure rate),
from the time of signing informed consent and for the duration of study
participation through 3 months following the last dose of study drug
- Childbearing potential is defined by the following criteria: 1. Subject has not
undergone a hysterectomy or bilateral oophorectomy; or 2. has not been
naturally postmenopausal for at least 12 consecutive months (i.e., has had
menses at any time in the preceding 12 consecutive months)
- Highly effective birth control methods (less than 1% failure rate per year if
used consistently and correctly) include but are not limited to: 1. Oral,
injected, or implanted hormonal method of contraception; 2. Place of
intrauterine device (IUD) or system (IUS); 3. Tubal ligation (tubes tied) or a
sterile partner (effective bilateral vasectomy)
- Subjects must not breastfeed a child during the study and for 3 months after the
last dose of study drug
- Ability to understand and willingness to sign the written informed consent document
Exclusion Criteria:
- Women who are pregnant or breastfeeding
- Any ≥ grade 3 irAEs in which the risks outweigh the benefits per investigator's
discretion (these may include but are not limited to myocarditis, myasthenia gravis,
Guillain-Barré syndrome, encephalitis, myelitis, or other life-threatening events)
- Has active autoimmune disease or irAE requiring systemic treatment with steroids (>
10 mg daily doses of prednisone or equivalent) or other immunosuppressive agents or
any condition that, in the investigator's judgment, precludes treatment with
anti-PD-1/PD-L1 therapy
- Cycle 1 day 1 of the study treatment must be at least 2 weeks beyond high dose
systemic corticosteroids (prednisone > 0.5 mg/kg/day or equivalent); chronic steroid
use up to 10 mg daily prednisone (or equivalent) is permitted
- Other concurrent anticancer therapy except for palliative radiation and hormone
therapy
- Has a known history of HIV-1/2 with detectable viral load and/or CD4 (cluster of
differentiation 4) count < 300/mL within the previous 3 months
- Has detectable hepatitis B virus (HBV) or hepatitis C virus (HCV) viral load
polymerase chain reaction (PCR) if there is a known history of active hepatitis B or
hepatitis C
- High risk for bowel perforation per the investigator's judgment, such as history of
severe diverticulitis or active ulcers or extensive gastrointestinal (GI)
involvement by the tumor
- Presence of a transplanted solid organ (with the exception of a corneal transplant
more than 3 months prior to screening) or having received an allogeneic bone marrow
transplant or an allogeneic peripheral blood stem cell transplant
- Uncontrolled concomitant illness including, but not limited to, symptomatic
congestive heart failure (New York Heart Association [NYHA] class III or IV),
unstable angina pectoris, myocardial infarction within 1 month prior to enrollment,
uncontrolled cardiac arrhythmias, uncontrolled seizures, or severe noncompensated
hypertension (systolic blood pressure > 180mmHg or diastolic blood pressure >
120mmHg)
- Patients with a current severe infection
- Known unmanageable allergies, hypersensitivity, intolerance to monoclonal
antibodies, to murine, chimeric, human proteins or their excipients
- Prior failure of interleukin-6 or interleukin-6 receptor targeted therapies. Prior
IL-6 or IL-6 receptor-targeted therapies are permitted if the response was favorable
- Received any investigational drug within 30 days
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Status:
Recruiting
Contact:
Last name:
Yuanquan Yang
Phone:
614-366-2485
Email:
Yuanquan.Yang@osumc.edu
Investigator:
Last name:
Yuanquan Yang
Email:
Principal Investigator
Start date:
July 31, 2024
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Yuanquan Yang
Agency class:
Other
Source:
Ohio State University Comprehensive Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06470971
http://cancer.osu.edu
