Perioperative Chemotherapy for Pancreatic Cancer

Recruiting at 375 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

Trial Summary

What is the purpose of this trial?

This phase III trial compares perioperative chemotherapy (given before and after surgery) versus adjuvant chemotherapy (given after surgery) for the treatment of pancreatic cancer that can be removed by surgery (removable/resectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before and after surgery (perioperatively) may work better in treating patients with pancreatic cancer compared to giving chemotherapy after surgery (adjuvantly).

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.

What data supports the effectiveness of the drug FOLFIRINOX for pancreatic cancer?

Research shows that FOLFIRINOX, which includes fluorouracil, leucovorin, irinotecan, and oxaliplatin, has improved survival rates for patients with metastatic pancreatic cancer compared to standard treatments, although it can have significant side effects. ^{1 2 3 4 5}

Is perioperative chemotherapy for pancreatic cancer safe for humans?

The combination of drugs used in perioperative chemotherapy for pancreatic cancer, such as 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin, has been studied for safety. While these treatments can be effective, they are known to have significant side effects, which can sometimes lead to stopping the treatment or making surgery unsuitable for some patients. ^{5 6 7 8 9}

How does the perioperative chemotherapy treatment for pancreatic cancer differ from other treatments?

This treatment uses a combination of drugs known as mFOLFIRINOX, which includes 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, and is preferred worldwide for its reduced toxicity and better tolerance compared to other regimens. It is unique because it is used both before and after surgery (perioperative), which can help shrink the tumor before surgery and kill remaining cancer cells after surgery. ^{2 10 11 12 13}

Research Team

Cristina R. Ferrone, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment. [2022]

2. England 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. [2022]

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

Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas. [2022]

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

Response and Survival Associated With First-line FOLFIRINOX vs Gemcitabine and nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma. [2022]

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

Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for pancreas adenocarcinoma: where are we going? [2020]

8. England pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in pancreatic adenocarcinoma. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

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

11. United States 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. [2022]

12. United States 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. [2022]

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

FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. [2022]