Perioperative Chemotherapy for Pancreatic Cancer

Recruiting at 393 trial locations

Overseen By Tatjana Kolevska, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, Prior pancreatic cancer treatment, others

Stay on Your Current Meds You can continue your current medications while participating

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 13

352 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal timing for chemotherapy in individuals with pancreatic cancer that can be surgically removed. It compares chemotherapy administered both before and after surgery to chemotherapy given only after surgery. The goal is to determine which approach more effectively stops cancer growth and spread. This trial is suitable for individuals diagnosed with pancreatic cancer that has not spread to other organs. The chemotherapy treatments under study include Fluorouracil (5-FU), Irinotecan Hydrochloride, Leucovorin Calcium, and Oxaliplatin. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong inhibitors or inducers of CYP3A4 (a liver enzyme that affects drug metabolism) before joining. If you're on these medications, you'll need to discontinue them prior to registration.

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

Research has shown that the combination of chemotherapy drugs used in this trial—fluorouracil, irinotecan, leucovorin, and oxaliplatin—is generally well-tolerated. One study found that patients who received these treatments before and after surgery experienced manageable side effects. The most common issues included fatigue, nausea, and a drop in blood cells, which can increase tiredness or the risk of infections.

Another study highlighted that while these side effects can occur, they are usually expected and manageable with proper care. These drugs are already used to treat other types of cancer, supporting their safety. It is important for patients to discuss these findings with healthcare providers to understand their implications for individual health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pancreatic cancer because they explore the timing of chemotherapy in relation to surgery, which could significantly impact patient outcomes. Unlike the traditional approach where chemotherapy follows surgery, one arm of this trial administers chemotherapy both before and after surgery, which could shrink tumors and make them easier to remove. This perioperative approach is different from the standard care, aiming to enhance the effectiveness of surgery and potentially improve survival rates. By comparing these strategies directly, researchers hope to find out if the timing of chemotherapy can lead to better results for patients with pancreatic cancer.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research has shown that perioperative chemotherapy, which involves administering chemotherapy before and after surgery, can extend the lives of pancreatic cancer patients. In this trial, participants in Arm I will receive perioperative chemotherapy, including a combination of drugs such as fluorouracil, irinotecan, leucovorin, and oxaliplatin. One study found that 66.7% of patients who received this treatment were still alive after 18 months, outperforming some other treatments. Another study demonstrated that using this drug combination in a perioperative setting was safe and effective, leading to better survival rates compared to past data. This approach aims to halt tumor growth more effectively by applying chemotherapy at different stages. Meanwhile, participants in Arm II will undergo surgery followed by adjuvant chemotherapy with the same drug combination. ^{6 7 8 9 10}

Who Is on the Research Team?

Cristina R. Ferrone, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults with removable pancreatic cancer who have not had prior treatments. They must have normal bilirubin and creatinine levels or adequate kidney function, no severe liver conditions like Gilbert's Syndrome, and be fit for surgery. Pregnant or nursing women can't join, nor those on certain drugs affecting the liver enzyme CYP3A4. Participants need to be in good physical condition (ECOG 0-1) with minimal nerve damage from neuropathy.

Inclusion Criteria

My tumor partially touches the blood vessels near my liver or intestine but hasn't blocked them.

My cancer has not spread to distant parts of my body.

My surgeon has approved me for a surgery aimed at curing my pancreatic cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Patients receive mFOLFIRINOX chemotherapy before surgery for 8 cycles

16 weeks

8 visits (in-person)

Surgery

Patients undergo surgical resection of the pancreatic tumor

1 week

1 visit (in-person)

Adjuvant Chemotherapy

Patients receive mFOLFIRINOX chemotherapy after surgery for 4 cycles

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 years

What Are the Treatments Tested in This Trial?

Interventions

• Fluorouracil
• Irinotecan Hydrochloride
• Leucovorin Calcium
• Oxaliplatin
• Resection

Trial Overview The study compares two approaches using chemotherapy drugs fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin: one where patients receive chemo before and after surgery (perioperative), versus only after surgery (adjuvant). The goal is to see which method is more effective at treating pancreatic cancer that can be surgically removed.

How Is the Trial Designed?

Group I: Arm I (perioperative chemotherapy, surgery) Experimental Treatment 6 Interventions

Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Within 2-8 weeks of completing neoadjuvant chemotherapy, patients undergo surgical resection. Patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (surgery, adjuvant chemotherapy) Active Control 6 Interventions

Patients undergo surgical resection. Beginning 3-12 weeks after surgery, patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Fluorouracil is already approved in United States, European Union, Canada for the following indications:

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 107 patients with resectable pancreatic ductal adenocarcinoma (rPDAC), the perioperative treatment with NALIRIFOX resulted in a 65.3% rate of R0 resection, indicating successful removal of cancer with no residual disease.

The median overall survival for patients treated with NALIRIFOX was 32.3 months, suggesting that this treatment approach may improve outcomes compared to traditional methods, although further randomized trials are needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial. Melisi, D., Zecchetto, C., Merz, V., et al.[2023]

In a study of 485 patients with localized pancreatic cancer, those treated with FOLFIRINOX showed higher rates of partial response according to RECIST criteria compared to those treated with gemcitabine plus nab-paclitaxel (GA), indicating better initial tumor response.

Despite the higher response rates and more frequent surgeries (pancreatectomy) in the FOLFIRINOX group, overall survival rates were similar between the two treatment regimens, suggesting that while FOLFIRINOX may be more effective in shrinking tumors, it does not necessarily lead to longer survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response and Survival Associated With First-line FOLFIRINOX vs Gemcitabine and nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma. Perri, G., Prakash, L., Qiao, W., et al.[2022]

Neoadjuvant chemotherapy using S-1 and gemcitabine significantly improves survival rates for patients with resectable pancreatic cancer compared to immediate surgery, while maintaining similar perioperative outcomes.

Japanese guidelines now recommend neoadjuvant chemotherapy for resectable pancreatic cancer due to its ability to increase R0 resection rates, although identifying predictive markers for chemotherapy response is crucial to avoid missing surgical opportunities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present status and perspective of perioperative chemotherapy for patients with resectable pancreatic cancer in Japan. Yamada, Y.[2022]

The modified FOLFIRINOX (mFOLFIRINOX) regimen showed a tolerable safety profile with lower hematological toxicity compared to the full-dose FOLFIRINOX, while still maintaining comparable efficacy in treating advanced pancreatic ductal adenocarcinoma (PDAC).

In a study of 18 patients, 80% achieved at least stable disease, with a median overall survival of 9.3 months and progression-free survival of 7.2 months, indicating that mFOLFIRINOX can be an effective treatment option for fit patients with advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. Ghorani, E., Wong, HH., Hewitt, C., et al.[2023]

The NEONAX trial is a large, phase II study involving 166 patients with resectable pancreatic ductal adenocarcinoma, comparing the efficacy of perioperative chemotherapy (nab-paclitaxel and gemcitabine) against standard adjuvant therapy to improve disease-free survival (DFS) at 18 months.

Preliminary evidence suggests that nab-paclitaxel/gemcitabine has a favorable toxicity profile compared to FOLFIRINOX, making it a promising option for patients undergoing surgery for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. Ettrich, TJ., Berger, AW., Perkhofer, L., et al.[2022]

In a study of 196 patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant FOLFIRINOX, alterations in the SMAD4 gene were linked to a significantly lower rate of surgical resection (27.8% vs 59.4%) and a higher risk of developing metastatic disease during treatment.

While common alterations in KRAS and TP53 were observed, no specific somatic alterations were associated with major pathologic response, highlighting the potential role of SMAD4 as a biomarker for treatment response and the need for alternative therapies for patients with these alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma. Ecker, BL., Court, CM., Janssen, QP., et al.[2023]

In a study of 520 patients with resectable pancreatic cancer who underwent neoadjuvant FOLFIRINOX treatment, adjuvant chemotherapy did not show a significant overall survival benefit for the entire group, with a median overall survival of 29 months for both those who received adjuvant therapy and those who did not.

However, in patients with node-positive disease, adjuvant chemotherapy was associated with improved survival, showing a median overall survival of 26 months compared to 13 months for those who did not receive it, indicating that the effectiveness of adjuvant therapy may depend on the lymph node status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment. van Roessel, S., van Veldhuisen, E., Klompmaker, S., et al.[2022]

The modified FOLFIRINOX regimen is effective and well-tolerated for patients with advanced nonmetastatic pancreatic cancer, showing a high rate of surgical resection (72% attempted, 51.1% accomplished) with manageable toxicity, primarily diarrhea in 14% of patients.

Patients who underwent surgical resection after treatment with mFOLFIRINOX experienced a median progression-free survival of 18 months, significantly longer than the 8 months for those who did not have surgery, indicating a potential survival benefit from this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas. Blazer, M., Wu, C., Goldberg, RM., et al.[2022]

Liver perfusion chemotherapy (LPC) combined with gemcitabine was feasible and well-tolerated in 27 patients after pancreatic surgery, with 89% of patients completing the treatment without life-threatening complications.

The treatment showed promising results, with a median survival time of 27.5 months and a 2-year survival rate of 68.7% in patients without paraaortic node involvement, indicating potential benefits for specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver perfusion chemotherapy with 5-Fluorouracil followed by systemic gemcitabine administration for resected pancreatic cancer: preliminary results of a prospective phase 2 study. Kurosaki, I., Kawachi, Y., Nihei, K., et al.[2022]

Adjuvant chemotherapy significantly improves 5-year survival rates and delays tumor recurrence in patients with resected pancreatic adenocarcinoma, with gemcitabine being the standard treatment due to its favorable toxicity profile.

The study established that both 5-fluorouracil plus leucovorin and gemcitabine are effective options for treatment, providing validated alternatives for patients, which could lead to better outcomes as new therapies are integrated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for pancreas adenocarcinoma: where are we going? O'Reilly, EM.[2020]

The study investigates the NALIRIFOX regimen, which substitutes liposomal irinotecan for nonliposomal irinotecan in the FOLFIRINOX chemotherapy combination, aiming to enhance drug delivery and reduce toxicity for patients with localized pancreatic cancer.

By potentially minimizing adverse effects associated with traditional chemotherapy, NALIRIFOX could improve the safety and effectiveness of treatment in the preoperative setting, making patients more suitable for surgical resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in pancreatic adenocarcinoma. Singhal, R., Rogers, SC., Lee, JH., et al.[2023]

The intensified postoperative adjuvant regimen combining chemotherapy and radiotherapy showed manageable acute toxicity, with no severe nonhematologic toxicities and a 47% incidence of short-duration Grade 3 or 4 hematologic toxicities among 45 patients treated for periampullary adenocarcinoma.

The regimen resulted in a significant improvement in disease-free survival, with 66% of patients remaining disease-free at 12 months, compared to only 25% in a previous study, indicating a potential benefit of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival. Chakravarthy, A., Abrams, RA., Yeo, CJ., et al.[2022]

Neoadjuvant chemotherapy using the FOLFIRINOX regimen significantly improves the chances of surgical resection in patients with borderline resectable or unresectable pancreatic cancer, with a resection rate of 43% based on a meta-analysis of 13 studies involving 253 patients.

The study found that the radical (R0) resection rate was 39.4% overall, with particularly high rates of 63.5% for borderline resectable cases, indicating that FOLFIRINOX can effectively down-stage tumors to make them operable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. Petrelli, F., Coinu, A., Borgonovo, K., et al.[2022]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2820217

Perioperative Modified FOLFIRINOX for Resectable ... In this study, perioperative modified FOLFIRINOX was safe and effective, with a clinically meaningful improvement in survival compared with historical controls.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39847363/

Adjuvant Chemotherapy After Resection of Localized ... In this cohort study, adjuvant (m)FOLFIRINOX and other multiagent chemotherapy regimens were associated with improved OS following resection of localized ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.01118

Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 ... The ESPAC4 study showed improved overall survival (OS) with the combination of gemcitabine with the oral fluorouracil prodrug capecitabine ( ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04617457

NCT04617457 | Chemotherapy and Surgical Resection in ... NAPOX chemotherapy in 14-day cycles with the four IMPs given intravenously in the following order: nal-irinotecan, oxaliplatin, folinic acid and 5-fluouracil.

5. mdanderson.org mdanderson.org/newsroom/preoperative-combination-chemotherapy-improved-survival-in-patients-with-pancreatic-cancer.h00-159541323.html

Preoperative combination chemotherapy improved ... The patients receiving neoadjuvant modified FOLFIRINOX had an 18-month overall survival (OS) rate of 66.7%, exceeding both the preselected ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11190830/

Perioperative Modified FOLFIRINOX for Resectable ... This nonrandomized controlled trial assesses whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06210360

Perioperative Treatment in High-risk Resectable ... This multicentric randomized trial will compare the efficacy and safety of neoadjuvant chemotherapy + surgery + adjuvant chemotherapy or surgery + adjuvant ...

8. asco.org asco.org/abstracts-presentations/ABSTRACT402624

Open-label, single arm phase II trial investigating ... Open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined ...

9. clinicaltrials.eu clinicaltrials.eu/trial/study-comparing-perioperative-and-adjuvant-mfolfirinox-treatment-for-patients-with-resectable-pancreatic-cancer-using-irinotecan-oxaliplatin-folinic-acid-and-fluorouracil/

Study of perioperative versus post-surgery FOLFIRINOX ... This clinical trial investigates the efficacy of the chemotherapy drugs Irinotecan, Oxaliplatin, Folinic Acid, and Fluorouracil, ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7745557/

A phase II study of liposomal irinotecan with 5-fluorouracil ... In a recent phase I/II trial has been assessed the safety, tolerability, and dose-limiting toxicities of nal-IRI+5-FU/LV + oxaliplatin for the first-line ...