Onvansertib + NALIRIFOX for Pancreatic Cancer

(PANCONVA Trial)

Overseen By KUCC Navigation

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Kansas Medical Center

Must not be taking: QT prolonging, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Brain metastasis, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 2 years

21 Participants Needed

Trial Summary

What is the purpose of this trial?

Pancreatic cancer is a deadly disease and will be the second leading cause of cancer related death behind lung cancer by 2030. Over 62,000 people are diagnosed each year in the United States with about 90% succumbing to the disease within 5 years. In the metastatic setting, NALIRIFOX, FOLFIRINOX and nab-paclitaxel-gemcitabine are standard treatment options in patients with good performance status (Eastern Cooperative Oncology Group \[ECOG\] 0/1). All three combinations have shown a survival advantage over previously standard gemcitabine-based therapy, with 11.1 months overall survival (OS) for NALIRIFOX/FOLFIRINOX and 8.7 months for nab-paclitaxel-gemcitabine versus 6.7 months for gemcitabine alone. There is an urgent need to improve treatment of patients with current and emerging therapeutic strategies. KRAS is the most common oncogene mutated in pancreatic adenocarcinoma, and it is mutated in nearly all tumors. Mutant KRAS is essential for PDAC growth, where the constitutive activated RAS proteins contribute to tumorigenesis, treatment resistance, and metastases. Despite research and drug development efforts focused on KRAS, no effective RAS inhibitors have been approved for the treatment of pancreatic cancer with KRAS mutation. The poor prognosis of KRAS-mutated PDAC patients and the absence of KRAS-targeted therapies, highlight the urgency to develop novel therapies aimed at KRAS. This study will investigate onvansertib (also known as PCM-075 and NMS-1286937) as the first PLK1-specific adenosine triphosphate competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models.

Will I have to stop taking my current medications?

The trial requires stopping certain medications that affect heart rhythm or interact with the study drug. If you're on these, you may need to switch to alternatives or stop them 1-2 weeks before starting the trial. Check with the trial team for specific guidance.

What data supports the effectiveness of the drug combination Onvansertib + NALIRIFOX for pancreatic cancer?

The combination of drugs similar to NALIRIFOX, like FOLFIRINOX, has shown to improve survival in patients with advanced pancreatic cancer compared to single-agent treatments. This suggests that drug combinations can be more effective than using one drug alone. ^{1 2 3 4 5}

How is the drug Onvansertib + NALIRIFOX unique for treating pancreatic cancer?

Onvansertib + NALIRIFOX is unique because it combines Onvansertib, a novel drug, with NALIRIFOX, a regimen that includes irinotecan, oxaliplatin, leucovorin, and fluorouracil, offering a new approach for treating pancreatic cancer, which has limited treatment options. ^{1 3 6 7 8}

Research Team

Anup Kasi, MD, MPH

Principal Investigator

The University of Kansas Cancer Center

Eligibility Criteria

This trial is for adults (18+) with advanced pancreatic cancer that hasn't spread and who haven't had treatment yet. They need to be able to understand the study, agree in writing, and have measurable disease by RECIST 1.1 standards. Participants must also provide tissue samples and have a good performance status (ECOG 0/1), along with specific blood cell count levels.

Inclusion Criteria

My cancer can be measured using standard imaging techniques.

I understand the study and agree to sign the consent form.

I am 18 years old or older.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Onvansertib orally daily on D1-5 of each 14-day cycle and NALIRIFOX intravenously on D1 of each 14-day cycle

Approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• NALIRIFOX
• Onvansertib

Trial Overview The trial tests Onvansertib, an oral drug targeting PLK1 proteins involved in tumor growth, combined with NALIRIFOX therapy. It aims to improve survival rates for patients with KRAS-mutated pancreatic cancer where current treatments are limited.

Participant Groups

Group I: Treatment Experimental Treatment 2 Interventions

Study Drug: Onvansertib: Orally daily on D1 - 5 of each 14-day cycle NALIRIFOX Intravenous D1 of each 14-day cycle

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Cardiff Oncology

Industry Sponsor

Trials

12

Recruited

650+

Findings from Research

In a phase II trial involving 17 patients with advanced pancreatic cancer, the combination of sorafenib and gemcitabine showed no objective responses, with only 18% of patients achieving stable disease.

The treatment resulted in a median overall survival of 4.0 months and was associated with significant toxicities, including thrombosis in 18% of patients, indicating that this combination is not effective for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Kindler, HL., Wroblewski, K., Wallace, JA., et al.[2022]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

The introduction of newer chemotherapy regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, led to a significant improvement in overall survival for patients with metastatic pancreatic cancer, with median survival increasing from 8.97 months to 9.95 months between the years 2006-2010 and 2011-2015.

Despite the overall improvement in survival rates, African American patients experienced worse outcomes, indicating a disparity in treatment effectiveness, with a hazard ratio of 1.63 for death compared to Caucasian patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma With the Introduction of New Chemotherapeutic Drugs: 10-Year Experience of a Single NCI-designated Comprehensive Cancer Center. Zhang, KJ., Dyson, G., Gatz, JL., et al.[2019]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

The combination of APX005M (sotigalimab) with gemcitabine and nab-paclitaxel, with or without nivolumab, was found to be tolerable in patients with metastatic pancreatic adenocarcinoma, with a recommended phase 2 dose of 0.3 mg/kg for APX005M established during the study.

Clinical activity was observed, with 58% of patients showing responses, suggesting that this treatment regimen could potentially replace the current chemotherapy-only standard of care for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. O'Hara, MH., O'Reilly, EM., Varadhachary, G., et al.[2022]

In the NAPOLI 3 study involving 770 patients with metastatic pancreatic ductal adenocarcinoma, the NALIRIFOX treatment regimen resulted in a median overall survival of 11.1 months, which was significantly longer than the 9.2 months observed with the nab-paclitaxel and gemcitabine combination.

Both treatment groups experienced a high rate of grade 3 or higher adverse events (87% for NALIRIFOX and 86% for nab-paclitaxel-gemcitabine), indicating that while NALIRIFOX may improve survival, it does not significantly increase the risk of severe side effects compared to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Wainberg, ZA., Melisi, D., Macarulla, T., et al.[2023]

In a study of 76 patients with metastatic pancreatic cancer, mFOLFIRINOX treatment resulted in significantly better objective response rates (20.0% vs 0%) and progression-free survival (3.7 months vs 2.1 months) compared to the oral fluoropyrimidine S-1.

While mFOLFIRINOX showed promising treatment outcomes, it also led to more frequent severe side effects, such as grade 3-4 neutropenia and peripheral sensory neuropathy, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer. Ikezawa, K., Kiyota, R., Takada, R., et al.[2022]

A combination of gemcitabine and erlotinib has been shown to provide a survival advantage in patients with locally advanced and metastatic pancreatic cancer compared to gemcitabine alone, highlighting its efficacy in a disease known for poor outcomes.

Erlotinib, a tyrosine kinase inhibitor targeting the epidermal growth factor receptor, demonstrates anti-tumor activity when used alongside gemcitabine, suggesting a promising mechanism of action in treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of erlotinib in the management of pancreatic cancer. Starling, N., Neoptolemos, J., Cunningham, D.[2021]

References

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

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]

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

Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma With the Introduction of New Chemotherapeutic Drugs: 10-Year Experience of a Single NCI-designated Comprehensive Cancer Center. [2019]

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

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. [2023]

5. England pubmed.ncbi.nlm.nih.gov

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Role of erlotinib in the management of pancreatic cancer. [2021]