CA-4948 + Chemotherapy for Pancreatic Cancer

Recruiting at 32 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Chemotherapy, Radiotherapy, Transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: Up to 1 year

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for pancreatic cancer that has spread or cannot be surgically removed. The goal is to determine the safest dose of a new drug, emavusertib (CA-4948), when combined with standard chemotherapy drugs gemcitabine and nab-paclitaxel. Researchers aim for this combination to shrink or stabilize the cancer by inhibiting cancer cell growth. Individuals with pancreatic cancer that has progressed after certain treatments might be suitable for this study. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take medications that affect CYP3A4 enzymes. You should discuss your current medications with the trial team to ensure there are no interactions.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take medications that affect CYP3A4 enzymes. You should discuss your current medications with the trial team to ensure there are no interactions.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that emavusertib (CA-4948) is being tested for safety and side effects when combined with common chemotherapy drugs like gemcitabine and nab-paclitaxel. Emavusertib, a kinase inhibitor, works by stopping proteins that help cancer cells grow.

In studies with patients who have different types of cancer, emavusertib has generally been well-tolerated. Reported side effects include tiredness, nausea, and changes in blood tests, typically mild to moderate.

This information comes from early trials, which aim to determine the safety and optimal dose of the treatment. Since emavusertib is still in the early stages of testing for pancreatic cancer, ongoing trials will provide more detailed safety information. Patients should discuss potential risks and benefits with healthcare providers when considering participation in a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pancreatic cancer?

Researchers are excited about Emavusertib (CA-4948) for pancreatic cancer because it brings something new to the table by targeting the IRAK4 pathway, which is not addressed by standard treatments like gemcitabine and nab-paclitaxel alone. This unique mechanism of action may enhance the effectiveness of existing chemotherapy options and offer a new line of attack against cancer cells. By combining it with traditional chemotherapy, there's potential for a more comprehensive approach, possibly improving outcomes for patients who have limited options.

What evidence suggests that this treatment might be an effective treatment for pancreatic cancer?

Research has shown that emavusertib (CA-4948) can enhance the effectiveness of chemotherapy drugs like gemcitabine and nab-paclitaxel. Animal studies found that emavusertib aids these drugs by blocking proteins that promote cancer cell growth. These proteins, IRAK4 and FLT3, are often overactive in cancer cells, leading to increased growth. By inhibiting these proteins, emavusertib may help slow or stop cancer spread. This trial will examine the combination of emavusertib with gemcitabine and nab-paclitaxel to determine its potential benefits for patients with difficult-to-treat pancreatic cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Patrick Grierson

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with pancreatic ductal adenocarcinoma that's spread or can't be surgically removed, who've had disease progression after fluorouracil-based therapy. Must have proper kidney function, no recent statin dose changes, controlled HIV or hepatitis C if present, and agree to contraception. Excludes pregnant women, those with certain heart diseases or other cancers that could affect the trial outcome.

Inclusion Criteria

My brain scans show no cancer growth after treatment for brain metastases.

I have been on the same dose of cholesterol medication for at least 3 weeks.

My kidney function, measured by GFR, is 60 mL/min or higher.

Exclusion Criteria

I am not taking drugs that affect CYP3A4 due to my treatment.

You have had allergic reactions to drugs similar to CA-4948 or other drugs used in the study.

I am using or plan to use natural remedies for my cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive CA-4948 orally, gemcitabine intravenously, and nab-paclitaxel intravenously. Imaging and biopsies are conducted throughout the trial.

Up to 1 year

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Emavusertib (CA-4948)

Trial Overview The safety and optimal dosage of emavusertib (CA-4948) combined with standard chemotherapy drugs gemcitabine and nab-paclitaxel are being tested. This study aims to see if adding CA-4948—a kinase inhibitor targeting specific cancer cell proteins—to usual chemotherapy can better control metastatic or unresectable pancreatic cancer.

How Is the Trial Designed?

Group I: Treatment (CA-4948, gemcitabine, nab-paclitaxel) Experimental Treatment 9 Interventions

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Intra-arterial delivery of gemcitabine resulted in significantly lower plasma concentrations compared to intravenous delivery, suggesting a targeted approach that may reduce systemic exposure and toxicity.

Despite the small sample size of seven patients, intra-arterial administration showed promising clinical outcomes, with one patient achieving a partial response and six maintaining stable disease, indicating potential efficacy in treating advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous and intra-arterial delivery in unresectable pancreatic cancer patients. Shamseddine, AI., Khalifeh, MJ., Mourad, FH., et al.[2022]

In a phase III trial involving 602 patients with advanced pancreatic cancer, the combination of gemcitabine and bevacizumab did not significantly improve overall survival compared to gemcitabine alone, with median survival times of 5.8 months and 5.9 months, respectively.

While the combination treatment did show a slightly higher rate of severe side effects like hypertension and proteinuria, the overall response rates were similar, indicating that adding bevacizumab does not provide a meaningful benefit in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). Kindler, HL., Niedzwiecki, D., Hollis, D., et al.[2022]

In a phase II study involving 20 patients with advanced pancreatic cancer, the combination of gemcitabine and 5-fluorouracil (5-FU) demonstrated modest antitumor activity, with a 25% overall response rate and a clinical benefit response in 41.7% of assessable patients.

The treatment was generally well tolerated, with manageable side effects, including neutropenia and thrombocytopenia occurring in 9.3% and 5.3% of patients, respectively, and a median survival of 8.0 months for participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and Infusional 5-Fluorouracil in Advanced Pancreatic Cancer: A Clinical Benefit Response-Oriented Phase II Study. Choi, JH., Ahn, MJ., Im, SA., et al.[2015]

In a study of 40 previously untreated patients with advanced pancreatic cancer, the combination of gemcitabine, docetaxel, and capecitabine resulted in a 40% overall response rate and an 80% disease control rate, indicating significant efficacy.

The treatment was generally well-tolerated, with major toxicities including neutropenia (17.5%) and diarrhea (10%), but no treatment-related deaths were reported, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel plus gemcitabine in combination with capecitabine as treatment for inoperable pancreatic cancer: a phase II study. Xenidis, N., Chelis, L., Amarantidis, K., et al.[2022]

Recent studies indicate that gemcitabine, either alone or in combination with 5-fluorouracil and radiation, plays a significant role in the treatment of resected and locally advanced pancreatic cancer, although survival rates remain low.

Combination therapies involving gemcitabine with other agents like oxaliplatin or capecitabine have shown improved response rates in clinical trials, but they have not significantly enhanced overall survival according to phase III trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic cancer: are we moving forward yet? Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 20th, 2007. Saif, MW.[2018]

In a phase II study involving 44 patients with advanced pancreatic cancer, the combination of gemcitabine, capecitabine, erlotinib, and bevacizumab showed a confirmed radiological response rate of 23%, indicating potential efficacy in this difficult-to-treat cancer.

The treatment regimen was found to be feasible with manageable side effects, including neutropenia and lethargy, and resulted in a median overall survival of 12.6 months for all patients, and 10.1 months for those with metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of a chemotherapy doublet (gemcitabine and capecitabine) with a biological doublet (bevacizumab and erlotinib) in patients with advanced pancreatic adenocarcinoma. The results of a phase I/II study. Watkins, DJ., Starling, N., Cunningham, D., et al.[2022]

Matuzumab, a fully humanized monoclonal antibody targeting the ErbB-1 receptor, significantly reduced tumor growth and metastasis in pancreatic cancer models, demonstrating strong antiproliferative and proapoptotic effects.

When combined with gemcitabine, matuzumab enhanced its therapeutic efficacy, showing prolonged antitumor activity even with short-term treatment, indicating a promising strategy for pancreatic cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matuzumab short-term therapy in experimental pancreatic cancer: prolonged antitumor activity in combination with gemcitabine. Kleespies, A., Ischenko, I., Eichhorn, ME., et al.[2022]

Pancreatic adenocarcinoma is a leading cause of cancer-related deaths, with most patients diagnosed at advanced stages where surgery isn't an option, making systemic therapy crucial.

Optimizing gemcitabine delivery through fixed-dose rate infusion, combining it with synergistic agents like platinum compounds, and integrating targeted therapies such as bevacizumab and erlotinib may improve patient outcomes in metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of metastatic pancreatic cancer. Ko, AH., Tempero, MA.[2022]

The pancreatic cancer cell line SW1990-GEM exhibits resistance to gemcitabine due to decreased levels of deoxycytidine kinase (dCK) and increased levels of ribonucleotide reductase (RR) and mdr-1, which are associated with drug resistance mechanisms.

Salvicine (SAL) can reverse this resistance in a dose-dependent manner by down-regulating mdr-1 expression, leading to increased accumulation of gemcitabine in the cells, although it requires higher, potentially toxic concentrations to be effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The mechanism of resistance to 2', 2'-difluorodeoxycytidine (gemcitabine) in a pancreatic cancer cell line]. Yao, J., Feng, FY., Lin, C., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05685602

Study Details | NCT05685602 | CA-4948 Added to ... 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 ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-08984

CA-4948 Added to Standard Chemotherapy to Treat ... 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 ...

3. aacrjournals.org aacrjournals.org/cancerres/article/85/18_Supplement_3/A069/765790/Abstract-A069-A-phase-I-trial-of-emavusertib-CA

Abstract A069: A phase I trial of emavusertib (CA-4948) in ... In preclinical animal models, the oral IRAK4 inhibitor emavusertib (CA-4948) augments the efficacy of cytotoxic chemotherapy by suppressing cell ...

4. letswinpc.org letswinpc.org/research/kinase-inhibitor-plus-chemotherapy/

Enhancing Standard Chemotherapy in Metastatic ... Early studies in mice have shown it may also have a broader application in treating solid tumors such as pancreatic cancer. Joining the Trial.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS4168

Phase I trial of CA-4948, an IRAK4 inhibitor, in combination ... Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple ...