Neoplasms

All Conditions

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Immunomodulating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive CA-4948 orally PO BID on days 1-21 and pembrolizumab 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, CT, MRI, or PET throughout the study. Additionally, patients may undergo a tumor biopsy on study.

Biopsy

Biospecimen Collection

Computed Tomography

Emavusertib

Magnetic Resonance Imaging

Positron Emission Tomography

Matthew D Galsky

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.

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.

Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy

Phase 1 Trial of CA-4948 in Combination With Pembrolizumab to Overcome Resistance to PD-1/PD-L1 Blockade in Metastatic Urothelial Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

CBR will be defined as the proportion of patients achieving a CR or PR per RECIST 1.1 criteria at 9 weeks or stable disease at 9 weeks accompanied by a 1.5 or greater reduction in hrCRP. CBR will be reported along with a corresponding two-sided 95% Wilson CI and p-value will be reported from Binomial exact test.

CRP response rate will be defined as achieving a ≥ 1.5 fold reduction in CRP at 9 weeks. The CRP response rate will be reported along with a corresponding two-sided 95% Wilson CI and p-value will be reported from Binomial exact test. Linear mixed models will also be fitted for comparisons between patients achieving and not achieving an objective response and between patients achieving and not achieving clinical benefit. Random effects with autoregressive model of order 1 will be incorporated to describe the correlation of repeated measures. Univariable PH Cox regression models for PFS and OS will also be fitted with hsCRP levels either at baseline or as a time-dependent continuous covariate.

Linear mixed models will also be used for comparisons between patients achieving and not achieving an objective response and between patients achieving and not achieving clinical benefit. Random effects with autoregressive model of order 1 will be incorporated to describe the correlation of repeated measures. Residual plots will be used to check model assumptions. Univariable PH Cox regression models for PFS and OS will also be fitted with cytokine and chemokine levels either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.

A paired t-test will be used to test whether there are a reduction of SPP1+ MoMacs and an increase in intra-tumoral T cells from baseline to on-treatment time points. Univariable logistic regression models will be fitted for ORR and CBR as response variables with either marker levels at baseline or change in marker levels as continuous covariates. PH Cox regression models for PFS and OS will also be fitted with marker levels either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.

Univariable logistic regression models will be fitted for ORR and CBR as response variables with PD-L1 expression as continuous covariate. Univariable PH Cox regression models for PFS and OS will be fitted with PD-L1 expression as continuous covariate. Schoenfeld residuals will be used to check PH assumption.

A paired t-test will be used to test whether there are a decrease in SPP1+ CD68+ cells and an increase in C1QC+ CD68+ cells from baseline to on-treatment time points. Univariable logistic regression models will be fitted for ORR and CBR as response variables with either TME markers at baseline or change in TME marker levels as continuous covariates. PH Cox regression models for PFS and OS will be fitted with TME markers either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.

Adverse events (AEs) will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Occurrence of DLTs along with with count and percentage of subjects experiencing DLTs will be summarized. Safety of the combination regimen will be summarized by the number of adverse events as well as by the number and percentage of subjects experiencing the adverse events in both dose escalation and expansion cohorts. The safety summary will include count and percentage for overall and by AE type, seriousness, severity, attribution, anticipated or not. Furthermore, toxicity index will be calculated as a summary index for each patient to summarize multiple AEs.

The RP2D may be determined to be the highest dose level, the maximum tolerated dose, or it may be a lower dose based on the consensus of the investigators, Cancer Therapy Evaluation Program and pharmaceutical company collaborators.

AEs will be graded using NCI CTCAE v 5.0. Safety will be summarized by the number of AEs as well as by the number and percentage of subjects experiencing the AEs in both the dose escalation and dose expansion phases of the study. The safety summary will include count and percentage for overall and by AE type, seriousness, severity, attribution, anticipated or not. Toxicity will be calculated as a summary index for each patient to summarize multiple AEs.

ORR will be defined as the proportion of patients achieving a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria at 9 weeks. The number of confirmed responses will be reported along with a corresponding two-sided 95% Wilson confidence interval (CI) and p-value will be reported from Binomial exact test.

PFS will be defined as the time from initial treatment to any progression or death from any cause, whichever occurs first. Kaplan-Meier estimates of median PFS time will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. The frequency (number and percentage) of participants with an event (progression or death) and censoring reasons will be presented (alive, withdrawal of consent, lost to follow-up).

OS will be defined as the duration from the first date of study treatment to the date of death. Kaplan-Meyer estimates of median OS will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. the frequency of participants with an event and censoring reasons will be presented.

DOR will be defined as the time from date of the first documentation of response to the first documentation of progression of disease or death due to any cause in the absence of documented progression of disease. Kaplan-Meier estimates of median DOR time will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. The frequency of participants with an event and censoring reasons will be presented.

The 2IR score will be calculated using the mean expression levels of the adaptive immune response and pro-tumorigenic inflammation gene signatures from the baseline and on-treatment transcriptome profile derived for each subject. A paired t-test will be used to test whether there is an increase in 2IR score from baseline to on-treatment time points. Univariable logistic regression models will be fitted for response variables with either 2IR score at baseline and change in 2IR score as continuous covariates. Proportional hazard (PH) Cox regression models for PFS and OS will also be fitted with 2IR score either at baseline or as time-dependent continuous covariates.

National Cancer Institute (NCI)

Digestive System Diseases

Gland and Hormone Related Diseases

Adenocarcinoma

Pancreatic Neoplasms

Carcinoma, Ductal

Carcinoma, Pancreatic Ductal

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Patients receive CA-4948 orally (PO), gemcitabine intravenously (IV), and nab-paclitaxel IV on study. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan, and/or x-ray imaging throughout the trial. Patients also undergo tumor biopsies and blood sample collection during screening and on study.

Gemcitabine Hydrochloride

Nab-paclitaxel

X-Ray Imaging

Site Public Contact

Vincent Chung

Farshid Dayyani

Robert W. Lentz

Patrick Grierson

Mary F. Mulcahy

Reema A. Patel

Ana D. De Jesus Acosta

Jibran Ahmed

Kristen R. Spencer

Gulam A. Manji

Ashwin Somasundaram

Davendra P. Sohal

Shafia Rahman

Susanna V. Ulahannan

Janie Y. Zhang

Monica A. Patel

This phase I trial tests the safety, side effects, and best dose of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in treating patients with pancreatic ductal adenocarcinoma that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). CA-4948 is in a class of medications called kinase inhibitors. It works by blocking the action of abnormal proteins called interleukin-1 receptor-associated kinase 4 (IRAK4) and FMS-like tyrosine kinase 3 (FLT3) that signal cells to multiply. This may help keep cancer cells from growing. The usual approach for patients with pancreatic ductal adenocarcinoma is treatment with chemotherapy drugs gemcitabine and nab-paclitaxel. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. Paclitaxel is in a class of medications called anti-microtubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Giving CA-4948 in combination with gemcitabine and nab-paclitaxel may shrink or stabilize metastatic or unresectable pancreatic ductal adenocarcinoma.

PRIMARY OBJECTIVE:

I. To assess dose limiting toxicities and determine the recommended phase 2 dose of emavusertib (CA--4948) in combination with chemotherapy in patients with pancreatic ductal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of the combination of CA-4948 and chemotherapy.

III. To determine preliminary signals of efficacy, as measured by objective response rate (ORR), CA-4948 response, progression free survival (PFS), and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To evaluate pharmacodynamic effect of CA-4948 in combination with chemotherapy.

II. To evaluate pharmacokinetics of CA-4948 in combination with chemotherapy. III. To explore biomarkers and genomic alterations associated with treatment response.

OUTLINE: This is a dose-escalation study of CA-4948 in combination with fixed-dose gemcitabine and nab-paclitaxel followed by a dose-expansion study.

Patients receive CA-4948 orally (PO), gemcitabine intravenously (IV), and nab-paclitaxel IV on study. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan, and/or x-ray imaging throughout the trial. Patients also undergo tumor biopsies and blood sample collection during screening and on study.

CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer

A Phase I Clinical Trial of CA-4948 in Combination With Gemcitabine and Nab-Paclitaxel in Metastatic or Unresectable Pancreatic Ductal Carcinoma

"NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

Pharmacodynamic indices from biopsies obtained from expansion cohorts will be summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point and the change will be compared by paired t-test or Wilcoxon rank-sum test as appropriate.

Done to confirm whether a clinically relevant drug-drug interaction occurs. Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied in the Phoenix WinNonlin Professional software package. Exposure obtained by noncompartmental methods will also be compared to toxicity and efficacy outcomes using graphical and statistical programs. A formal population PK or exposure-response analyses may be conducted based on these initial findings.

Done to determine the maximum tolerated dose for the combination of CA-4948 and gemcitabine/nab-paclitaxel chemotherapy backbone. Data analysis of the study will be descriptive in nature. Demographic and clinical characteristics of the sample, toxicity by severity, as well as loss to follow-up will be summarized using descriptive statistics. Safety endpoints will be listed for each dose level.

Tabulations of adverse events will be produced by severity and by relationship to study drug.

For efficacy data in the expansion cohort, ORR and its 95% confidence interval will be calculated.

Will be described using Kaplan-Meier product limit methods.

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Hematologic Neoplasms

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Lymphosarcoma

Primary Central Nervous System Lymphoma

Amino Acids

Ibrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Part A1: Dose-level cohorts with up to approximately 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib.

Part A2: Evaluate escalating dose levels of oral emavusertib in combination with 560 mg daily (QD) of oral ibrutinib. The starting dose of emavusertib to be used in combination will be 200 mg twice a day (BID). It is anticipated that 12 to 20 patients at a potential dose level will be required to establish optimal combination dosing.

In two PCNSL Expansion Cohorts (Part B), emavusertib in combination with ibrutinib will be administered in patients with PCNSL. In Cohort 1, emavusertib 100 mg BID will be administered with ibrutinib 560 mg QD consecutively in a 28-day cycle in approximately 6 to 9 patients. In Cohort 2, CA-4948 200 mg BID will be administered with ibrutinib in at least 9 patients.

Emavusertib (formulated for oral administration for BID dosing)

ibrutinib

Reinhard von Roemeling, MD

This is a multi-center, open-label trial to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib (CA-4948) in adult patients with relapsed or refractory (R/R) hematologic malignancies. Part A will evaluate the safety and tolerability of escalating doses of emavusertib as monotherapy (Part A1), and in combination with ibrutinib. In Protocol Version (v) 1.0 through v6.0, patients with Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) were also enrolled at ibrutinib doses of 420 mg (Part A2). Enrollment into Parts A1 and A2 has been closed. Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in patients with primary central nervous system lymphoma (PCNSL).

Part A will evaluate escalating doses of emavusertib (CA-4948) either as monotherapy (Part A1) or in combination with ibrutinib (Part A2). Enrollment is closed for Part A1 and A2. Part B will comprise two expansion cohorts to assess efficacy and safety of emavusertib and ibrutinib in PCNSL.

A Study of CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma

An Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma

The number of patients with a dose-limiting toxicity (DLT) in the first treatment cycle

MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (\<33%) experience a dose limiting toxicity.

RP2D selected based on overall tolerability data from all patients treated at different dose levels and will not exceed the MTD.

Area Under the concentration-time curve (AUC)

Time to maximum plasma concentration (Tmax)

Plasma terminal elimination half-life (T 1/2)

CNS liquor with be sampled from an Ommaya reservoir or with a spinal puncture about 3 hours after oral dosing of emavusertib. At approximately the same timepoint, a peripheral blood sample will be taken to obtain a plasma sample. The respective emavusertib concentrations will be measured in the liquor and in plasma samples. The liquor vs plasma concentration ratio will provide a rough estimate of the blood-brain barrier (BBB) penetration of emavusertib following oral dosing.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy	NCT06439836	Metastatic Urot... Unresectable Ur...	Biopsy Biospecimen Col... Computed Tomogr... Emavusertib Magnetic Resona... Pembrolizumab Positron Emissi...	18 Years -	National Cancer Institute (NCI)
CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer	NCT05685602	Metastatic Panc... Stage III Pancr... Stage IV Pancre... Unresectable Pa...	Biopsy Biospecimen Col... Computed Tomogr... Emavusertib Gemcitabine Hyd... Magnetic Resona... Nab-paclitaxel Positron Emissi... X-Ray Imaging	18 Years -	National Cancer Institute (NCI)
A Study of CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma	NCT03328078	Relapsed Hemato... Refractory Hema... Relapsed Primar... Refractory Prim...	Emavusertib ibrutinib	18 Years -	Curis, Inc.

Spots Global Cancer Trial Database for emavusertib

Every month we try and update this database with for emavusertib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for emavusertib

Every month we try and update this database with for emavusertib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for emavusertib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.