Phase I Trial of Emavusertib (CA-4948) in Combination With Cisplatin, Gemcitabine, and Durvalumab in Patients With Untreated Advanced or Metastatic Biliary Tract Cancer

Plain English Summary

Emavusertib (CA-4948) in Combination With Cisplatin, Gemcitabine, and Durvalumab in Patients With Untreated Advanced or Metastatic Biliary Tract Cancer is a Phase 1 clinical trial sponsored by Washington University School of Medicine studying Metastatic Biliary Tract Cancer, Metastatic Biliary Tract Carcinoma. This trial tests a new drug combination, emavusertib with standard chemotherapy (cisplatin, gemcitabine) and immunotherapy (durvalumab), for advanced or metastatic biliary tract cancer. It is for adults with untreated advanced or metastatic biliary tract cancer, including cholangiocarcinoma and gallbladder cancer. Participation involves receiving the study drugs and regular medical check-ups, including tests and scans. Standard treatment options for advanced biliary tract cancer include chemotherapy and immunotherapy, but this trial explores a novel combination. The trial aims to enroll 48 participants.

Official Summary

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).

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have been diagnosed with advanced or metastatic biliary tract cancer that has not been treated with systemic therapy (with some exceptions). You cannot join if you have active brain metastases, have had certain recent cancer treatments, or have specific pre-existing medical conditions like active autoimmune disease or interstitial lung disease. Good general health, including adequate bone marrow and organ function, is required. Women of childbearing potential must have a negative pregnancy test and agree to use contraception. This trial is studying Metastatic Biliary Tract Cancer, Metastatic Biliary Tract Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcomes measure the safety of the new drug combination by tracking side effects and determining the right dose for further studies. The specific primary outcome measures are: 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 (From consent through 30 days after last dose of study treatment (estimated to be 15 months)); Dose escalation only: To determine an expansion dose for emavusertib in combination with gemcitabine, cisplatin, and durvalumab in patients with BTC. (Completion of cycle 1 (each cycle is 21 days)). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial aims to improve treatment for biliary tract cancer by combining a new drug that targets cancer survival signals with standard therapies, potentially overcoming resistance and improving outc This research targets Metastatic Biliary Tract Cancer, Metastatic Biliary Tract Carcinoma, where improved treatment options are needed.

Investor Insight

This trial targets a rare but aggressive cancer, representing an unmet need and a potential market for novel therapies if successful. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of this specific drug combination, and how it compares to standard treatments. Understand that participation involves regular visits for drug administration, blood tests, imaging scans, and monitoring for side effects. Be prepared for potential side effects and discuss any concerns with your healthcare team promptly. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 48 participants

Interventions

• DRUG: Emavusertib — Provided by Curis.
• DRUG: Gemcitabine — Standard of care.
• DRUG: Cisplatin — Standard of care.
• BIOLOGICAL: Durvalumab — Standard of care.

Primary Outcomes

• 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 (From consent through 30 days after last dose of study treatment (estimated to be 15 months))
• Dose escalation only: To determine an expansion dose for emavusertib in combination with gemcitabine, cisplatin, and durvalumab in patients with BTC. (Completion of cycle 1 (each cycle is 21 days))

Secondary Outcomes

• Progression-free rate (PFR) (At 6 months from start of treatment)
• Disease control rate (DCR) (At 6 months from start of treatment)
• Overall response rate (ORR) (Through completion of treatment (estimated to be 14 months))
• Progression-free survival (PFS) (Through completion of follow-up (estimated to be 38 months))
• Overall survival (OS) (Through completion of follow-up (estimated to be 38 months))

Full Eligibility Criteria

Inclusion Criteria:

* 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.
* No prior systemic treatment for advanced unresectable or metastatic BTC with the following exceptions:

  * 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
* At least 18 years of age.
* ECOG performance status 0, 1, or 2
* Adequate bone marrow and organ function as defined below:

  * Absolute neutrophil count ≥ 1.5 K/cumm
  * Platelets ≥ 100 K/cumm
  * Hemoglobin ≥ 9.0 g/dL
  * Total bilirubin ≤ 1.5 x IULN or ≤ 3 x IULN in patients with documented Gilbert's syndrome
  * AST(SGOT)/ALT(SGPT) ≤ 2 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
  * Creatinine clearance ≥ 35 mL/min by Cockcroft-Gault
  * INR ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤1.5 x IULN
* Creatinine phosphokinase (CPK) elevation at screening \< Grade 2 (CPK \< 2.5 x IULN).
* Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start.
* The effects of emavusertib on the developing human fetus are unknown. For this reason, women of childbearing 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 participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 90 days after completion of the study.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

* 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.
* Clinically active CNS metastasis; treated and asymptomatic metastasis allowed at the discretion of the sponsor/investigator or site PI. Radiotherapy to the brain must be completed \> 10 days prior to planned C1D1.
* Chemoradiation with curative intent within 6 months prior to C1D1 of study therapy.
* Palliative radiation therapy within 10 days prior to C1D1 of study therapy.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to emavusertib, gemcitabine, cisplatin, durvalumab, or other agents used in the study.
* Concomitant use of drugs with a known risk of causing prolonged QTc (with exception of Zofran if needed for supportive care) and/or Torsades de Pointes or a history of risk factors for Torsades de Pointes.
* Presence of interstitial lung disease or pneumonitis ≥ G2 at time of screening.
* Administration of a live attenuated vaccine within 30 days prior to C1D1
* QTc (Fridericia) \>470ms on screening EKG.
* Gastrointestinal condition which could impair absorption of emavusertib or inability to ingest emavusertib in the opinion of the investigator.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia in the opinion of the investigator.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of C1D1.
* Patients with known HIV are eligible unless their CD4+ T-cell counts are \< 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines and in line with contraindicated concomitant medications is recommended.
* Participants with active, known, or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condit

Trial Locations

• Washington University School of Medicine, St Louis, Missouri, United States

Frequently Asked Questions

Related Conditions

• Biliary Tract Cancer
• Cholangiocarcinoma
• Gallbladder Cancer
• Hepatobiliary Neoplasms
• Gastrointestinal Malignancies
• Advanced Cancer
• Metastatic Cancer
• Solid Tumors
• Oncology
• Cancer Immunotherapy

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