CA-4948 + Chemotherapy for Pancreatic Cancer

Recruiting at 29 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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Emavusertib (CA-4948) for pancreatic cancer?

Research shows that combining gemcitabine with other drugs like bevacizumab and erlotinib has been effective in treating advanced pancreatic cancer, suggesting that combining Emavusertib with chemotherapy might also be beneficial. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Emavusertib (CA-4948) combined with chemotherapy for pancreatic cancer?

The research shows that combining gemcitabine with other drugs like bevacizumab and erlotinib has shown promise in treating advanced pancreatic cancer, suggesting that combining different drugs can be effective. Additionally, targeting specific pathways in cancer cells, as seen with other treatments, has been beneficial, which may support the potential of Emavusertib in combination therapies. ^{1 2 3 4 5}

What makes the drug Emavusertib (CA-4948) unique for treating pancreatic cancer?

Emavusertib (CA-4948) is unique because it is a novel drug that targets specific pathways in cancer cells, potentially offering a new mechanism of action compared to standard treatments like gemcitabine and 5-fluorouracil, which are commonly used for pancreatic cancer. ^{1 6 7 8 9}

What makes the drug Emavusertib (CA-4948) unique for treating pancreatic cancer?

Emavusertib (CA-4948) is unique because it is a novel drug being studied in combination with chemotherapy for pancreatic cancer, potentially offering a new mechanism of action compared to standard treatments like gemcitabine and 5-fluorouracil (5-FU), which are commonly used but have limited effectiveness in improving survival. ^{1 6 7 8 9}

Research Team

Patrick Grierson

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Matuzumab short-term therapy in experimental pancreatic cancer: prolonged antitumor activity in combination with gemcitabine. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Docetaxel plus gemcitabine in combination with capecitabine as treatment for inoperable pancreatic cancer: a phase II study. [2022]

3. United States 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). [2022]

4. England 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. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Treatment of metastatic pancreatic cancer. [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Gemcitabine and Infusional 5-Fluorouracil in Advanced Pancreatic Cancer: A Clinical Benefit Response-Oriented Phase II Study. [2015]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous and intra-arterial delivery in unresectable pancreatic cancer patients. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[The mechanism of resistance to 2', 2'-difluorodeoxycytidine (gemcitabine) in a pancreatic cancer cell line]. [2022]

9. Italy pubmed.ncbi.nlm.nih.gov

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