FOLFOX Regimen for Rectal Cancer

Overseen By Namrata Vijayvergia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fox Chase Cancer Center

Must be taking: FOLFOX

Must not be taking: Antiretrovirals, Investigational agents

Disqualifiers: Advanced adenocarcinoma, Prior chemotherapy, 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)

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

19 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm phase II study of neoadjuvant chemotherapy followed by local excision and post-operative chemoradiotherapy in patients with early stage, low rectal adenocarcinoma. After completion of pre-treatment tests/procedures (including pelvic MRI/ERUS; MRI is mandatory at baseline and other imaging is encouraged) and confirmation of eligibility, systemic therapy with FOLFOX will be administered for 12 weeks. 2 to 4 weeks after the chemotherapy, restaging of the primary tumor will be done to evaluate response to therapy (Pelvic MRI and /or sigmoidoscopy). Patients with disease progression or inadequate response to chemotherapy to allow local excision will continue with evaluation and treatment per the current standard of care (chemoradiation followed by TME). These patients will be considered failures for the primary endpoint of the study. Patients who respond to the neoadjuvant chemotherapy will proceed with local excision (open, TEMS or TAMIS), 6-12 weeks after the completion of neoadjuvant chemotherapy, followed by 5-FU based chemoradiotherapy 4-12 weeks after local excision. Patients with positive margins at the time of local excision will also be treated as per standard of care and will be considered as failures. Number of patients who can undergo successful local excision with this approach will define the success of the strategy. After chemoradiation therapy post local excision, patients will be followed closely every 3 months for the first 3 years and then every 2 months for the next 2 years (history/physical, CEA and pelvic MRI). Patients who are deemed failures for the primary end-point will be followed as per standard of care, off-study.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on certain medications like antiretroviral therapy for HIV, you may not be eligible to participate. It's best to discuss your current medications with the trial team to get a clear answer.

What data supports the effectiveness of the FOLFOX treatment for rectal cancer?

Research shows that the FOLFOX regimen, which includes drugs like 5-fluorouracil, folinic acid, and oxaliplatin, is effective for colorectal cancer, including rectal cancer. Studies have demonstrated its use in both early-stage and advanced cases, indicating its potential to help patients with rectal cancer. ^{1 2 3 4 5}

Is the FOLFOX regimen generally safe for humans?

The FOLFOX regimen, including its modified versions like mFOLFOX6, has been studied for safety in humans, particularly for colorectal cancer. Common side effects include low blood cell counts, nausea, fatigue, and nerve damage, but it is generally considered tolerable in clinical practice. ^{1 2 6 7 8}

How is the FOLFOX regimen drug unique for rectal cancer?

The FOLFOX regimen is unique for rectal cancer because it combines three drugs—5-fluorouracil, folinic acid, and oxaliplatin—to enhance treatment effectiveness, and it can be used both before and after surgery to shrink tumors and reduce recurrence. This regimen is particularly notable for its use in advanced stages of rectal cancer, where it has shown promising results in improving patient outcomes. ^{1 9 10 11 12}

Eligibility Criteria

This trial is for adults over 18 with early stage, low rectal adenocarcinoma who haven't had treatment for it before. They must be in good health with normal organ and marrow function and not pregnant or breastfeeding. People with certain high-risk tumors, previous malignancies needing systemic therapy within the last 3 years, HIV on antiretroviral therapy, or other serious illnesses are excluded.

Inclusion Criteria

My cancer is in an early stage and hasn't spread to my lymph nodes.

I have not received any treatment for rectal cancer.

I am fully active or can carry out light work.

Exclusion Criteria

I cannot receive FOLFOX chemotherapy and pelvic radiation due to health reasons.

My T1 tumor is larger than 4 cm, has lymphovascular invasion, or is not well differentiated.

My rectal cancer has spread to my lymph nodes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Neoadjuvant Chemotherapy

Systemic therapy with FOLFOX is administered

12 weeks

Regular visits for chemotherapy administration

Restaging and Local Excision

Restaging of the primary tumor and local excision for responders

6-12 weeks after chemotherapy

1-2 visits for restaging and surgery

Post-operative Chemoradiotherapy

5-FU based chemoradiotherapy administered after local excision

4-12 weeks after local excision

Regular visits for chemoradiotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 3 years, then every 2 months for 2 years

Treatment Details

Interventions

• FOLFOX regimen

Trial Overview The study tests a neoadjuvant chemotherapy regimen called FOLFOX followed by local excision and post-operative chemoradiotherapy to see if patients can avoid more invasive surgery. The success of this approach will be measured by the number of patients able to undergo successful local excision without disease progression.

Participant Groups

Group I: Neoadjuvant chemotherapy Experimental Treatment 1 Intervention

FOLFOX regimen is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as FOLFOX for:

• Colorectal cancer

Approved in United States as FOLFOX for:

• Colorectal cancer

Approved in Canada as FOLFOX for:

• Colorectal cancer

Approved in Japan as FOLFOX for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Findings from Research

The modified mFOLFOX-4 regimen combined with radiotherapy showed a 3-year disease-free survival rate of 67.5% and an overall survival rate of 77.3% in 55 patients with stage III rectal adenocarcinoma, indicating its efficacy as an adjuvant treatment.

The treatment was generally well tolerated, with 92.7% of patients completing the planned chemotherapy cycles, although some experienced significant toxicities such as diarrhea (21.8%) and neutropenia (9.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant modified FOLFOX-4 in patients with stage III rectum adenocarcinoma. Cihan, Ş., Uncu, D., Babacan, NA., et al.[2017]

In a study of 40 colorectal cancer patients who underwent potentially curative metastasectomy, those treated with modified FOLFOX6 (mFOLFOX6) showed a trend towards longer relapse-free survival (28.5 months) compared to those treated with oral fluoropyrimidines (14.8 months), although this was not statistically significant (p=0.11).

The overall survival rates were similar between the mFOLFOX6 group (37.9 months) and the fluoropyrimidine group (31.3 months), indicating that while mFOLFOX6 may help delay relapse, it does not significantly improve overall survival compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adjuvant chemotherapy comprising modified FOLFOX6 after curative resection of synchronous or metachronous metastasis from colorectal cancer]. Hatano, S., Ishibashi, K., Amano, K., et al.[2013]

In a phase II study involving 48 patients with unresectable or metastatic colorectal cancer, an alternating regimen of mFOLFOX6 and FOLFIRI resulted in a promising overall response rate of 58.7% and a median overall survival of 28.4 months.

The treatment was well tolerated, with a low incidence of severe neurotoxicity (0%) and manageable adverse events, indicating a favorable safety profile for this chemotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701). Oki, E., Emi, Y., Akagi, Y., et al.[2014]

In a study of 110 Asian patients with metastatic colorectal cancer, those treated with the mFOLFOX6 regimen including a 5-FU bolus had a significantly lower absolute neutrophil count (ANC) compared to those who did not receive the bolus, indicating a potential risk for neutropenia.

The findings suggest that omitting the 5-FU bolus from the mFOLFOX6 regimen may be necessary for patients at high risk of hematological adverse events, particularly neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer. Areepium, N., Sapapsap, B.[2023]

In a study of 124 colorectal cancer patients treated with the mFOLFOX6 regimen, the most common severe adverse events were neutropenia (40%) and leucopenia (16%), indicating that while the treatment can have significant side effects, it is generally tolerable.

The incidence of adverse events in this Japanese cohort was similar or lower than those reported in Western countries, suggesting that the mFOLFOX6 regimen is manageable in clinical practice and that informed consent forms were updated to better inform patients about potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Revision of the informed consent form for patients based on investigation of adverse events of mFOLFOX6 regimen]. Kato, T., Matsunaga, Y., Motokawa, S., et al.[2013]

In a study of 82 patients with locally advanced rectal cancer, the mFOLFOX6 chemotherapy regimen was found to be safe, with low rates of severe adverse reactions such as Grade 4 neutropenia and catheter-related infections (both 2.4%).

Post-chemotherapy, 86.8% of patients showed a partial response, and significant reductions in tumor stages were observed, indicating that mFOLFOX6 is an effective preoperative treatment strategy that can lead to successful surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of preoperative mFOLFOX6 regimen chemotherapy for locally resectable advanced rectal cancer. Liu, L., Jiang, Z.[2021]

References

1. Thailand pubmed.ncbi.nlm.nih.gov

Adjuvant modified FOLFOX-4 in patients with stage III rectum adenocarcinoma. [2017]

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

Multicenter safety study of mFOLFOX6 for unresectable advanced/recurrent colorectal cancer in elderly patients. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

[Adjuvant chemotherapy comprising modified FOLFOX6 after curative resection of synchronous or metachronous metastasis from colorectal cancer]. [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701). [2014]

5. Japan pubmed.ncbi.nlm.nih.gov

Phase II trial of an alternating regimen consisting of first-line mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: FIREFOX plus bevacizumab trial (KSCC0801). [2018]

6. Canada pubmed.ncbi.nlm.nih.gov

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer. [2023]

7. Japan pubmed.ncbi.nlm.nih.gov

[Revision of the informed consent form for patients based on investigation of adverse events of mFOLFOX6 regimen]. [2013]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and efficacy of modified FOLFOX6 for treatment of metastatic or locally advanced colorectal cancer. A single-institution outcome study. [2013]

9. Spain pubmed.ncbi.nlm.nih.gov

[Therapeutic use and profile of toxicity of the FOLFOX4 regimen]. [2013]

10. China pubmed.ncbi.nlm.nih.gov

Safety and efficacy of preoperative mFOLFOX6 regimen chemotherapy for locally resectable advanced rectal cancer. [2021]

11. Japan pubmed.ncbi.nlm.nih.gov

[A case of stage IV AFP producing cecal cancer responding to mFOLFOX6 leading to a partial response]. [2013]

12. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of neoadjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate for T3 or T4 stage II/III rectal cancer: the FACT trial. [2022]