Chemoradiation + Radiation Boost for Rectal Cancer

(Morpheus Trial)

Recruiting at 2 trial locations

Overseen By Stephan Bukera, BSc, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Sir Mortimer B. Davis - Jewish General Hospital

Must be taking: 5-FU, Xeloda

Disqualifiers: Previous pelvic radiation, Metastasis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

131 Participants Needed

Trial Summary

What is the purpose of this trial?

A randomized study of 131 patients. Patients with a clinical T2-3 N0 rectal cancer will be randomized to two arms (arm A: standard chemoradiation (45 Gy in 25 with concomitant 5-FU or Xeloda chemotherapy) and an external beam boost of 9 Gy compared to arm B: standard chemoradiation (45 Gy in 25 with concomitant 5-FU or Xeloda chemotherapy) and followed by a brachytherapy boost of 30 Gy in 3 fractions).

Do I need to stop my current medications for the trial?

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.

What data supports the effectiveness of the drug Xeloda (capecitabine) for rectal cancer?

Research shows that Xeloda, an oral form of 5-FU, is at least as effective as the standard intravenous 5-FU treatment for colorectal cancer, with similar progression-free and overall survival rates, and it is associated with less toxicity. ^{1 2 3 4 5}

Is the treatment of chemoradiation with 5-FU or capecitabine generally safe for humans?

5-Fluorouracil (5-FU) and capecitabine (Xeloda) are commonly used in chemotherapy and have been studied for their safety. Some patients may experience heart-related side effects, but these are infrequent. Overall, these drugs have been used safely in many cancer treatments. ^{2 4 5 6 7}

What makes the Chemoradiation + Radiation Boost treatment for rectal cancer unique?

This treatment combines chemoradiation with a radiation boost and uses capecitabine (Xeloda) as an oral alternative to the traditional infusion of 5-FU, offering a more convenient administration while potentially enhancing the concentration of the active drug in tumor tissues. ^{2 4 8 9 10}

Research Team

Te Vuong, MD

Principal Investigator

Sir Mortimer Jewish General Hospital

Eligibility Criteria

This trial is for adults over 18 with early-stage rectal cancer that hasn't spread, can be seen via colonoscopy, and is within 10 cm of the anal verge. The tumor must be less than 5 cm, occupy less than half the circumference of the rectum, and not have penetrated deeply into surrounding fat. Participants need to use effective birth control if applicable.

Inclusion Criteria

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

Adequate birth control measures in women of childbearing potential

Written informed consent

Exclusion Criteria

My cancer has spread to distant parts of my body.

My cancer has spread to the anal canal.

My cancer is at a stage where it has grown very large or spread to nearby tissues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard chemoradiation (45 Gy in 25 with concomitant 5-FU or Xeloda chemotherapy) followed by either an external beam boost of 9 Gy or a brachytherapy boost of 30 Gy in 3 fractions

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for local recurrence and overall survival

5 years

Treatment Details

Interventions

• 5-FU
• Chemoradiation + EBRT Boost
• Chemoradiation + HDRBT Boost
• HDRBT Boost
• Xeloda

Trial Overview The study compares two treatments after standard chemoradiation for rectal cancer: one group receives an external beam radiation boost (EBRT), while another gets a high-dose-rate brachytherapy boost (HDRBT). Patients are randomly assigned to either treatment arm.

Participant Groups

Group I: Chemoradiation + HDRBT Boost Experimental Treatment 2 Interventions

standard chemoradiation (45 Gy in 25 with concomitant 5-FU or Xeloda chemotherapy) and followed by a brachytherapy boost of 30 Gy in 3 fractions; Complete responders and Non-complete responders

Group II: Chemoradiation + EBRT Boost Experimental Treatment 2 Interventions

standard chemoradiation (45 Gy in 25 with concomitant 5-FU or Xeloda chemotherapy) and an external beam boost of 9 Gy in 5; Complete responders and Non-complete responders

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

Approved in United States as Fluorouracil for:

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

Approved in European Union as Fluorouracil for:

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

Approved in Canada as Fluorouracil for:

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

Approved in Japan as Fluorouracil for:

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

Who Is Running the Clinical Trial?

Sir Mortimer B. Davis - Jewish General Hospital

Lead Sponsor

Trials

61

Recruited

25,800+

Findings from Research

In a study of 45 patients with locally advanced rectal cancer, preoperative chemoradiation using capecitabine resulted in significant tumor downstaging, with 63% of primary tumors and 90% of lymph nodes showing downstaging, and a pathologic complete response in 31% of patients.

The treatment was found to be safe and well-tolerated, with no severe hematologic toxicities and manageable Grade 3 side effects, suggesting that capecitabine can effectively enhance surgical options, including sphincter-preserving surgeries for tumors near the anal verge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Kim, JS., Kim, JS., Cho, MJ., et al.[2022]

5-fluorouracil (5-FU) remains a key chemotherapy drug for colorectal cancer, but its oral form was previously abandoned due to inconsistent absorption; however, Xeloda (capecitabine) offers a solution by being an orally administered drug that is selectively activated in tumors, leading to higher local concentrations of 5-FU.

In phase II clinical trials for colorectal cancer, Xeloda demonstrated response rates of 21-24% and a median time to disease progression of 127-230 days, indicating its efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. Brito, RA., Medgyesy, D., Zukowski, TH., et al.[2017]

Xeloda (capecitabine) is an oral pro-drug that is effectively converted to 5-fluorouracil in the body, particularly in colorectal cancer, where the enzyme needed for activation is more active.

In large phase III trials, capecitabine demonstrated at least equal efficacy to the standard intravenous treatment of 5-FU and leucovorin, with better response rates and significantly lower toxicity, suggesting it may become the preferred treatment for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xeloda in colorectal cancer. Cassidy, J.[2015]

In a study of 452 patients with locally advanced rectal cancer, the rate of pathological complete response (pCR) was lower in those treated with oral capecitabine (9.5%) compared to intravenous 5-fluorouracil (20%), although this difference was not statistically significant (P = 0.082).

Despite the lower pCR rate with capecitabine, achieving pCR was found to be a strong independent predictor of survival, highlighting the importance of effective neoadjuvant chemotherapy in improving clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment. Jootun, N., Evans, T., Mak, J., et al.[2018]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

In a study of 19 colorectal cancer patients, capecitabine was shown to preferentially convert to 5-fluorouracil (5-FU) in tumor tissues, with 5-FU concentrations in tumors being 3.2 times higher than in adjacent healthy tissues, indicating effective targeting of the drug.

The enzyme thymidine phosphorylase (TP) plays a crucial role in this preferential activation, being significantly more active in colorectal tumors compared to healthy tissue, which helps explain the enhanced efficacy of capecitabine in treating colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Schüller, J., Cassidy, J., Dumont, E., et al.[2022]

In a study of 644 patients undergoing chemotherapy with 5-Fluorouracil (5FU) and oral capecitabine, 4.03% experienced cardiac-related symptoms, with a higher incidence (6.7%) observed in those receiving continuous 5FU infusion compared to other administration methods.

The study highlights that 5FU has a significant cardiotoxic effect that is schedule-dependent, while oral capecitabine also poses a low risk of cardiac events, indicating the need for careful monitoring during treatment with these drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. Kosmas, C., Kallistratos, MS., Kopterides, P., et al.[2022]

In a phase 1 study involving 18 patients with locally advanced anal cancer, the combination of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with capecitabine and mitomycin C resulted in a high complete response rate of 83%, indicating strong efficacy in treating this type of cancer.

The maximum tolerated dose of capecitabine was established at 825 mg/m² twice daily, with manageable side effects such as radiation dermatitis and fatigue, suggesting that this treatment regimen is both tolerable and effective for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study. Deenen, MJ., Dewit, L., Boot, H., 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]

Combining capecitabine (an oral fluoropyrimidine) with radiation therapy shows promise as a more convenient and effective approach for treating gastrointestinal cancers, with ongoing studies examining its efficacy compared to infusional fluorouracil (5-FU).

Capecitabine's activation to 5-FU is enhanced by thymidine phosphorylase, which is more active in tumor tissues, potentially leading to better drug accumulation in tumors and improved outcomes in radiation therapy, as indicated by ongoing and planned clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and radiation therapy for advanced gastrointestinal malignancies. Rich, T.[2015]

References

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

Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. [2017]

3. India pubmed.ncbi.nlm.nih.gov

Xeloda in colorectal cancer. [2015]

4. Australia pubmed.ncbi.nlm.nih.gov

Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment. [2018]

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

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. [2022]

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

Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study. [2018]

9. Greece pubmed.ncbi.nlm.nih.gov

Comparison of protracted infusion 5-fluorouracil and capecitabine in adjuvant chemoradiotherapy for rectal cancer. [2015]

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

Capecitabine and radiation therapy for advanced gastrointestinal malignancies. [2015]