Trial Title:
Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy
NCT ID:
NCT06439836
Condition:
Metastatic Urothelial Carcinoma
Unresectable Urothelial Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Transitional Cell
Pembrolizumab
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tumor biopsy
Arm group label:
Treatment (CA-4948, pembrolizumab)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (CA-4948, pembrolizumab)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (CA-4948, pembrolizumab)
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:
Biological
Intervention name:
Emavusertib
Description:
Given PO
Arm group label:
Treatment (CA-4948, pembrolizumab)
Other name:
AU 4948
Other name:
AU-4948
Other name:
CA 4948
Other name:
CA-4948
Other name:
CA4948
Other name:
Interleukin-1 Receptor-associated Kinase 4 Inhibitor CA-4948
Other name:
IRAK4 Inhibitor CA-4948
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (CA-4948, pembrolizumab)
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:
Biological
Intervention name:
Pembrolizumab
Description:
Given IV
Arm group label:
Treatment (CA-4948, pembrolizumab)
Other name:
BCD-201
Other name:
GME 751
Other name:
GME751
Other name:
Keytruda
Other name:
Lambrolizumab
Other name:
MK 3475
Other name:
MK-3475
Other name:
MK3475
Other name:
Pembrolizumab Biosimilar BCD-201
Other name:
Pembrolizumab Biosimilar GME751
Other name:
Pembrolizumab Biosimilar QL2107
Other name:
QL2107
Other name:
SCH 900475
Other name:
SCH-900475
Other name:
SCH900475
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET
Arm group label:
Treatment (CA-4948, pembrolizumab)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Summary:
This phase I trial tests the safety, side effects, best dose, and effectiveness of
emavusertib (CA-4948) in combination with pembrolizumab in treating patients with
urothelial cancer that has spread from where it first started to other places in the body
(metastatic) and that has a resistance to PD-1/PD-L1 immune checkpoint inhibitors.
CA-4948, a kinase inhibitor, may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
pembrolizumab, may help the body's immune system attack the tumor, and may interfere with
the ability of tumor cells to grow and spread. Giving CA-4948 in combination with
pembrolizumab may be safe, tolerable and/or effective in treating patients with
metastatic urothelial cancer that is resistant to PD-1/PD-L1 immune checkpoint
inhibitors.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose of the combination of CA-4948 plus
pembrolizumab in patients with immune checkpoint blockade (ICB)-resistant metastatic
urothelial cancer (Dose Escalation Cohort).
II. To determine the safety of the combination of CA-4948 plus pembrolizumab in patients
with ICB-resistant metastatic urothelial cancer (Dose Escalation Cohort and Dose
Expansion Cohort).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To measure the objective response
(complete response [CR] or partial response [PR]) as defined by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 at 9 weeks and the best overall response (CR or PR)
as defined by RECIST 1.1 at any time while on study.
III. To determine progression-free survival, overall survival, and duration of response.
IV. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in 2IR
scores (as defined by ribonucleic acid [RNA] sequencing) in paired tumor biopsies.
EXPLORATORY OBJECTIVES:
I. To assess the clinical benefit rate with pembrolizumab plus CA-4948 therapy. II. To
assess the "C-reactive protein (CRP) response rate" as defined by the proportion of
patients achieving a ≥ 1.5 fold reduction in CRP at 9 weeks.
III. To explore the association between the 2IR score as defined by bulk-ribonucleic acid
(RNA) sequencing of pre-treatment tumor tissue and objective response rate, clinical
benefit rate, progression-free survival, and/or overall survival.
IV. To explore whether CA-4948 plus pembrolizumab leads to on-treatment changes in the
cellular and/or molecular composition of the tumor microenvironment (TME).
V. To explore the association between the quantity and spatial localization of SPP1+
monocytes-macrophages (MoMacs) defined by multiplex immunohistochemistry on pre-treatment
tumor tissue and objective response rate, clinical benefit rate, progression-free
survival, and/or overall survival.
VI. To explore the association between the cellular and molecular composition of the TME
defined by spatial RNA sequencing on pre-treatment tumor tissue and objective response
rate, clinical benefit rate, progression-free survival, and/or overall survival.
VII. To explore on-treatment changes in high-sensitivity (hs) CRP and cytokines and
chemokines in peripheral blood and their association with objective response rate,
clinical benefit rate, progression-free survival, and/or overall survival.
VIII. To explore the association between PD-L1 expression on pre-treatment tumor tissue
and objective response rate, clinical benefit rate, progression-free survival, and/or
overall survival.
IX. To explore the association between the CXCL9:SPP1 ratio as defined by bulk-RNA
sequencing of pre-treatment tumor tissue and objective response rate, clinical benefit
rate, progression-free survival, and/or overall survival.
X. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in the
CXCL9:SPP1 ratio (as defined by RNA sequencing) in paired tumor biopsies.
OUTLINE: This is a dose-escalation study of CA-4948 in combination with pembrolizumab
followed by a dose-expansion study.
Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 and pembrolizumab
intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days
for up to 2 years in the absence of disease progression or unacceptable toxicity.
Patients undergo blood sample collection, computed tomography (CT), magnetic resonance
imaging (MRI), or positron emission tomography (PET) throughout the study. Additionally,
patients may undergo a tumor biopsy on study.
After completion of study treatment, patients are followed up every 3 months for 2 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically confirmed urothelial cancer that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective
- Age ≥ 18 years
- Because no dosing or adverse event data are currently available on the use of
CA-4948 in combination with pembrolizumab in patients < 18 years of age,
children are excluded from this study, but will be eligible for future
pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
within 28 days prior to registration
- Leukocytes ≥ 3,000/mcL
- Absolute neutrophil count (ANC) ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
- Criteria must be met without packed red blood cell (pRBC) transfusion within
the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥
approximately 3 months)
- Creatine phosphokinase (CPK) < grade (Gr) 2 ( grade 1) Note: Patients with grade ≤ 2 neuropathy
or grade ≤ 2 alopecia are an exception to this criterion and may qualify for the
study. Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy
- Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study drug
- Grade ≥ 3 immune related adverse event with prior PD-1/PD-L1 blockade
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to CA-4948 and/or pembrolizumab
- Patients with uncontrolled intercurrent illness, including but not limited to
interstitial lung disease or active, non-infectious pneumonitis, symptomatic
congestive heart failure, unstable angina pectoris, or cardiac arrhythmia that would
limit compliance with study requirements
- Patients who are receiving any other investigational agents
- Patients with carcinomatous meningitis
- Patients with malabsorption syndrome or other conditions that would interfere with
intestinal absorption
- Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
patient's participation for the full duration of the trial, or is not in the best
interest of the patient to participate, in the opinion of the treating investigator
- Has received a live vaccine within 30 days of planned treatment start. Seasonal flu
vaccines that do not contain live virus are permitted
- Pregnant women are excluded from this study because pembrolizumab is a monoclonal
antibody with the potential for teratogenic or abortifacient effects. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with pembrolizumab, breastfeeding should be discontinued if
the mother is treated with pembrolizumab. These potential risks may also apply to
other agents used in this study
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] RNA [qualitative] is detected)
- Has a known history of active tuberculosis (TB)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
December 16, 2024
Completion date:
October 1, 2025
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06439836
