Based on preclinical data from the Lim lab (WUSM), the investigators hypothesize that IRAK4 inhibition cripples tumor-intrinsic survival signaling and effectively overcomes the desmoplastic and immune-suppressive tumor microenvironment (TME) to render chemo- and immunotherapies effective in GI malignancy. Therefore, this trial is designed to evaluate the combination of emavusertib (CA-4948) and standard chemoimmunotherapy in untreated advanced or metastatic biliary tract cancer (BTC).
Advanced unresectable or metastatic histologically or cytologically confirmed adenocarcinoma of the biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma. Patients whose tumor have mixed histology but predominantly (>50%) adenocarcinoma are allowed.
Measurable defined by RECIST v1.1.
Neoadjuvant or adjuvant systemic therapy completed > 6 months from planned C1D1.
Up to two prior cycles of gemcitabine/cisplatin/anti-PD1 with no evidence of disease progression is allowed
Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment. Use of medical marijuana is permitted.
A history of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of BTC in the opinion of the investigator
History of allogeneic organ or stem cell transplant.
Currently receiving any other investigational therapeutic agents. Investigational tracers related to imaging studies are allowed with a 7 day-washout.
Sequential
Emavusertib
DrugProvided by Curis.
Gemcitabine
DrugStandard of care.
Cisplatin
DrugStandard of care.
Durvalumab
Biological/VaccineStandard of care.
To determine the safety of emavusertib in combination with gemcitabine, cisplatin, and durvalumab in patients with BTC as measured by incidences and types of adverse events
Graded using CTCAE version 5.0.
Dose escalation only: To determine an expansion dose for emavusertib in combination with gemcitabine, cisplatin, and durvalumab in patients with BTC.
Progression-free rate (PFR)
* Defined as the proportion of evaluable patients who are free of disease progression/recurrence at 6 months from the start of treatment. * Response and progression will be evaluated in this study using the revised international criteria (RECIST version 1.1) proposed by the RECIST committee as well as the modified iRECIST guidelines. Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.
Disease control rate (DCR)
* DCR is the proportion of patients with either complete response (CR), partial response (PR), or stable disease (SD) (with a duration of SD for 6 months). * Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Overall response rate (ORR)
* ORR = number of patients with complete response or partial response * Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Progression-free survival (PFS)
* PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. The alive patients without progression are censored at the last follow-up. * Response and progression will be evaluated in this study using the revised international criteria (RECIST version 1.1) proposed by the RECIST committee as well as the modified iRECIST guidelines. Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.
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Washington University School of Medicine
Lead sponsor
Curis, Inc.
Collaborator
