Chemoradiation for Rectal Cancer

(SMART TNT Trial)

Overseen By Zuzel Rodriguez

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Miami

Must not be taking: Anti-anxiety agents

Disqualifiers: Metastatic disease, Synchronous cancer, others

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

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining chemotherapy with higher-dose radiation can effectively treat locally advanced rectal cancer without surgery. Participants will first receive chemotherapy, including drugs like 5-fluorouracil (5-FU or Fluorouracil), Capecitabine (Xeloda), Leucovorin, and Oxaliplatin. They will then proceed to radiation therapy, with doses guided by MRI scans. If the cancer responds well, surgery might be unnecessary. The trial seeks individuals with recently diagnosed rectal cancer who have a tumor close to the anus (within 18 cm) and have been cleared for intensive treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that the treatments in this trial have been studied before, providing important safety information.

5-fluorouracil (5-FU), a widely used chemotherapy drug, is generally safe according to studies, though some may experience rare severe side effects like heart issues. Capecitabine, a similar drug approved by the FDA for other cancers, is usually well-tolerated but can cause side effects such as hand-foot syndrome (red, swollen hands and feet) and diarrhea. Oxaliplatin, another drug in this trial, may cause nerve damage, leading to numbness or tingling in fingers and toes, but these effects are usually manageable. Leucovorin, often used to boost the effects of 5-FU, is generally safe, though allergic reactions can occur.

The trial also includes intensity-modulated radiation therapy (IMRT), a precise form of radiation treatment. Research shows it is usually safe, with mild side effects like diarrhea, while severe reactions are uncommon.

This trial is in its early stages, focusing on safety and determining the right dose, so unknown risks may exist. However, the treatments have a history of safe use in other cancer treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial for chemoradiation in rectal cancer because it explores using MRI-guided radiation therapy, which allows for more precise targeting of the tumor. This precision could mean fewer side effects compared to traditional radiation therapy. Additionally, the trial tests different combinations of chemotherapy drugs, including FOLFIRINOX and CAPOX regimens, which may offer a more effective treatment plan by customizing therapy based on patient response. This approach aims to improve outcomes by potentially avoiding surgery if a complete clinical response is achieved, making it a promising development for rectal cancer treatment.

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

In this trial, participants will receive different treatment regimens to evaluate their effectiveness in treating rectal cancer. Research has shown that treatments using 5-fluorouracil (5-FU) work well for colorectal cancer, though responses vary. Some participants will receive 5-FU, especially when combined with other drugs like leucovorin. Capecitabine, similar to 5-FU, is another option in this trial, particularly when paired with oxaliplatin for more advanced cancer stages. Oxaliplatin enhances the effectiveness of these treatments, helping to control tumors better. Intensity-modulated radiation therapy (IMRT) is also included in the trial, as it can reduce side effects and the need to pause treatment, making it a promising choice for rectal cancer. These combined treatments aim to shrink tumors effectively and may help avoid surgery. ^{6 7 8 9 10}

Who Is on the Research Team?

Benjamin Spieler, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed rectal cancer that hasn't spread beyond the pelvis. Participants must have a certain level of physical fitness (ECOG 0-2), acceptable liver function, and no severe heart conditions or immune deficiencies. Pregnant women and those with metal implants incompatible with MRI are excluded.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

My tumor is within 18 cm of the anal verge.

Serum liver function tests values within the range of 1.5 x Upper Limit of Normal (within 6 weeks of enrollment)

Exclusion Criteria

Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity

I have had radiation therapy in the pelvic area before.

I do not have severe infections needing IV antibiotics or active TB.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Participants receive neoadjuvant chemotherapy with either FOLFOX, mFOLFIRINOX, or CAPOX

12-16 weeks

Chemo-radiation Therapy (Plan I)

Participants receive MRI-guided pelvic IMRT and concurrent chemotherapy

5 weeks

Radiation Therapy Boost (Plan II)

Participants not achieving complete Clinical Response receive an accelerated radiation therapy boost

1 week

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes after treatment

Up to 30 months

What Are the Treatments Tested in This Trial?

Interventions

• 5-fluorouracil
• Accelerated Radiation Therapy
• Capecitabine
• Intensity-modulated radiation therapy
• Leucovorin
• Oxaliplatin

Trial Overview

The study tests if starting with chemotherapy followed by higher-than-usual doses of radiation can help patients avoid surgery while effectively treating locally advanced rectal cancer. The chemo drugs used include 5-fluorouracil, Leucovorin, Oxaliplatin, and Capecitabine.

How Is the Trial Designed?

Group I: SMART TNT Plan II Experimental Treatment 1 Intervention

Plan II boost RT (1 week): For participants not achieving cCR after chemo-radiation. Participants will receive MRI-guided accelerated radiation therapy (ART) boost to the primary tumor. Participants achieving a cCR will continue to follow-up. Participants still showing residual tumor will undergo standard of care treatment including surgery and adjuvant chemotherapy per institutional guidelines during follow-up.

Group II: SMART TNT Plan I Experimental Treatment 6 Interventions

Participants will initiate therapy with neoadjuvant chemotherapy of either six (6) 14-day cycles of 5-fluorouracil + leucovorin + oxaliplatin (FOLFOX), six (6) 14-day cycles of 5-fluorouracil + leucovorin + irinotecan + oxaliplatin (mFOLFIRINOX), or four (4) 21-day cycles of capecitabine+oxaliplatin (CAPOX). Participants will then receive chemo-radiation therapy according to Plan I as follows: Plan I (5 weeks): * MRI-guided pelvic IMRT to the Planning Tumor Volume (PTV) at a dose of 50 Grays (gy) delivered in 25 fractions (fx) over 5 weeks. * Concurrent chemotherapy beginning on Day 1 of RT either: * 5-FU delivered 5 or 7 days per week. * Capecitabine (Xeloda) delivered 5 days per week. After completing Plan I, participants achieving complete Clinical Response (cCR) after completing Plan I chemo-radiation will forgo the Plan II boost and continue to follow-up. Participants not achieving cCR will begin Plan II, one week after completing Plan I.

5-fluorouracil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in European Union as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Canada as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Japan as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Published Research Related to This Trial

In a study of 41 patients with lower rectal cancer, four courses of mFOLFOX6 chemotherapy before surgery resulted in a 3-year recurrence-free survival rate of 72.8% and a local recurrence rate of 8.5%, indicating a promising long-term oncological benefit.

Patients with clinical Stage III cancer who received adjuvant chemotherapy after the initial mFOLFOX6 treatment had a significantly higher 3-year recurrence-free survival rate (76.6%) compared to those who did not receive adjuvant therapy (40.0%), suggesting the importance of additional treatment for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study. Ichikawa, N., Homma, S., Funakoshi, T., et al.[2022]

Neoadjuvant chemoradiation, particularly with fluorouracil (5-FU) plus radiation, is now the preferred treatment for stage II/III rectal cancer, showing lower local relapse rates and better safety compared to postoperative treatments.

Capecitabine (Xeloda) plus radiation has been found to be as effective as 5-FU plus radiation, making it a viable alternative, while combinations with oxaliplatin or irinotecan show promise for improved outcomes and warrant further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? Patel, A., Puthillath, A., Yang, G., et al.[2018]

In a study involving 67 patients with stage II and III rectal adenocarcinoma, capecitabine was found to be at least as effective as 5-Fluorouracil in adjuvant chemoradiotherapy, with no significant differences in toxicity or overall survival rates.

There was a notable trend towards improved loco-regional recurrence-free survival in patients treated with capecitabine, suggesting it may work better in combination with radiotherapy compared to 5-Fluorouracil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of protracted infusion 5-fluorouracil and capecitabine in adjuvant chemoradiotherapy for rectal cancer. Kurt, M., Ozkan, L., Kurt, E., et al.[2015]

In a study of 50 patients with nonmetastatic colorectal cancer, adverse reactions were more frequent with the XELOX regimen (capecitabine combined with oxaliplatin), particularly neurotoxicity, thrombocytopenia, and neutropenia, compared to capecitabine monotherapy.

The type of capecitabine formulation (innovative vs. generic) did not significantly affect the safety profile; instead, the chemotherapy scheme used was the main factor influencing the occurrence of adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. Sánchez-Gundín, J., Torres-Suárez, AI., Fernández-Carballido, AM., et al.[2020]

Oral doxifluridine combined with leucovorin is as effective as intravenous 5-fluorouracil (5-FU) in treating rectal cancer post-surgery, with similar rates of recurrence (6.5% for oral vs. 12.1% for IV).

Patients receiving oral doxifluridine reported a significantly better quality of life compared to those on intravenous 5-FU, with more patients scoring 'good' quality of life at 1 and 2 months after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. Min, JS., Kim, NK., Park, JK., et al.[2022]

5-fluorouracil (5-FU) combined with leukovorin is commonly used for treating metastatic colorectal cancer, but it can cause severe gastrointestinal side effects, including stomatitis and diarrhea, which can be life-threatening in up to 30% of patients.

This case report highlights therapy-induced enteritis as a serious complication of 5-FU treatment, emphasizing the need for early recognition and intervention to prevent significant morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features. Zamani, R., Heldmann, M.[2022]

In a study of 86 patients with locally advanced rectal cancer, both neoadjuvant chemotherapy regimens (mFOLFOXIRI and XELOX/SOX) showed similar pathological response rates, with 36.7% for mFOLFOXIRI and 40.5% for XELOX/SOX.

However, mFOLFOXIRI was associated with significantly higher toxicity, as 45% of patients experienced severe neutropenia compared to only 8% in the XELOX/SOX group, indicating that while both regimens are effective, XELOX/SOX may be a safer option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Comparison of mFOLFOXIRI With XELOX/SOX as Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer. Kodama, H., Terazawa, T., Ishizuka, Y., et al.[2021]

In a study of 11 patients with locally advanced rectal cancer, the combination of oral 5-doxifluridine (5-dFUR) and l-leucovorin with pelvic radiotherapy resulted in two patients achieving pathologically complete remission after treatment, indicating potential effectiveness in improving tumor response.

The treatment was generally well-tolerated, with manageable side effects such as grade 3 diarrhea in one patient and mild nausea and vomiting in three, while no significant hematological toxicity was observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated treatment with doxifluridine and radiotherapy in recurrent or primary unresectable rectal cancer. A feasibility study. Di Bartolomeo, M., Bajetta, E., Buzzoni, R., et al.[2022]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

In a Phase II trial involving 23 patients with unresectable primary rectal cancer, the combination of oral doxifluridine and leucovorin with pelvic radiation showed promising efficacy, with 23.8% achieving a complete response and 61.9% a partial response.

The treatment was associated with low toxicity levels, primarily Grade 1/2 side effects, with diarrhea being the only Grade 3 toxicity observed in 33.3% of patients, indicating that doxifluridine may be a safer alternative to traditional intravenous chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer. Seong, J., Cho, JH., Kim, NK., et al.[2019]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3141199/

5-Fluorouracil-based chemotherapy for colorectal cancer ...

The overall response rate to 5-FU in advanced colorectal cancer is limited to 10–15%. Although survival is reported to improve after the addition of irinotecan ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10344727/

Review of 5-FU resistance mechanisms in colorectal cancer

5-FU remains central to the management of colorectal cancer and it is widely used both in the adjuvant setting to treat CRC patients with ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2303269

Preoperative Treatment of Locally Advanced Rectal Cancer

In this trial, neoadjuvant FOLFOX was an effective treatment option for patients with T2 node-positive, T3 node-negative, or T3 node-positive ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.59

Analysis of the impact of eliminating bolus 5-fluorouracil in ...

Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also ...

5.

coloproctol.org

coloproctol.org/journal/view.php?number=1461

Effectiveness of Adjuvant Chemotherapy with 5-FU/ ...

The five-year overall survival (OS) rate was 90.1%, and the five-year disease-free survival (DFS) rate was 84.7%. Among high-risk patients, the ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39010662/

Adverse drug events associated with fluorouracil use in ...

Our study provides a comprehensive analysis of 5-FU's safety profile in mCRC patients, helping healthcare professionals mitigate risks in clinical practice.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3126013/

Safety and efficacy of weekly 5-fluorouracil/folinic acid ...

Therefore, FUFOXIRI is a promising backbone for future studies incorporating biologic 'targeted' agents for the treatment of gastrointestinal cancers. Keywords: ...

8.

tandfonline.com

tandfonline.com/doi/abs/10.1080/14740338.2024.2380513

Adverse drug events associated with fluorouracil use in ...

Fluorouracil (5-FU) is widely used to treat metastatic colorectal cancer (mCRC), but real-world safety data is limited. Our study aimed to evaluate 5-FU's ...

9.

cardiooncologyjournal.biomedcentral.com

cardiooncologyjournal.biomedcentral.com/articles/10.1186/s40959-024-00294-2

Cardiovascular safety of 5-fluorouracil and capecitabine in ...

Fluoropyrimidine use in patients with colorectal carcinoma did not increase the risk of MACE, cardiovascular death, or other specific cardiovascular conditions.

10.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0163725819301998

5-fluorouracil and other fluoropyrimidines in colorectal cancer

Although 5-FU ranks among the safest chemotherapy agents, severe side and toxic effects still occur in a proportion of CRC patients. The clinical manifestation ...