Chemoradiation + Radiation Boost for Rectal Cancer

(Morpheus Trial)

Recruiting at 4 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates two methods of enhancing radiation treatment for rectal cancer following standard chemoradiation. It aims to determine whether an external beam boost or a brachytherapy boost (a type of internal radiation) is more effective for treating rectal cancer that hasn't spread. Suitable candidates for this trial have rectal cancer confined to a specific area and have not received previous pelvic radiation or have tumors larger than 5 cm. As a Phase 2, Phase 3 trial, it evaluates the treatment's effectiveness in a smaller group and represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking cancer treatment advancements.

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.

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

Research has shown that combining chemotherapy and radiation, known as chemoradiation, is generally well-tolerated by patients with rectal cancer. Studies have found that using Xeloda (capecitabine) in these treatments results in relatively low rates of severe side effects. Serious negative reactions are uncommon with Xeloda, making it a simpler and often safer choice for many patients.

For the radiation boosts, both external beam radiation therapy (EBRT) and high-dose-rate brachytherapy (HDRBT) have been studied. Research indicates that the EBRT boost is a safe and practical option, especially for older patients. The HDRBT boost has also shown effective cancer control with only mild side effects when combined with other treatments like EBRT and chemotherapy.

Overall, these treatments are designed to be as safe as possible, with studies supporting their use in patients similar to those in this trial. These findings help ensure that the trial treatments are carefully monitored for safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for rectal cancer because they offer innovative ways to enhance the effects of standard chemoradiation therapy. The Chemoradiation + HDRBT Boost combines standard chemoradiation with high-dose-rate brachytherapy, delivering a targeted radiation boost directly to the tumor, which could potentially improve treatment precision and effectiveness. On the other hand, the Chemoradiation + EBRT Boost uses an external beam radiation boost, aiming to amplify the impact of initial treatment rounds. Both approaches are designed to increase the chances of complete tumor response, which is a promising step forward compared to existing treatments.

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

This trial compares two treatment options for rectal cancer. The first option, Chemoradiation with an EBRT Boost, uses external beam radiation therapy (EBRT) with increased doses up to 55 Gy. This method has improved outcomes and controlled tumors effectively. Participants in this arm may take the chemotherapy drug capecitabine orally during these treatments, which generally causes fewer side effects than the standard intravenous drug, 5-FU, and has shown good long-term results. Alternatively, the Chemoradiation with HDRBT Boost arm combines radiation with internal radiation called brachytherapy (HDRBT), which has demonstrated a 60.6% complete response rate. These findings suggest that both treatment options in this trial can potentially improve survival and slow cancer progression in patients with rectal cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Te Vuong, MD

Principal Investigator

Sir Mortimer Jewish General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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]

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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6831214/

Capecitabine versus 5-fluorouracil in neoadjuvant ... Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12284667/

Radiotherapy boost to the primary tumour in locally ... Primary tumour RT boost is common practice in locally advanced rectal cancer. High variability exists in techniques used for external ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0929664624005461

The impact of radiation dose on chemoradiation outcomes ... This study evaluated whether neoadjuvant radiotherapy with dose escalation to 55 Gy improved the oncological outcomes in rectal cancer.

4. por-journal.com por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2022.1610722/full

Clinical benefits of oral capecitabine over intravenous 5 ... The study confirms advantages of neoadjuvant chemoradiotherapy with oral capecitabine for rectal tumours, such as more favourable side effect profile and ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2786689

Postoperative Chemoradiotherapy With Capecitabine and ... This randomized clinical trial examines the efficacy and toxic effects of postoperative capecitabine vs oxaliplatin plus capecitabine with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02505750

NCT02505750 | Safety of a Boost (CXB or EBRT) in ... Randomised trials have shown that neoadjuvant (chemo)radiotherapy (nCRT) reduces the risk of local recurrence by more than half. At 3 years, it is close to or ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2405630825001065

Review Article Radiotherapy boost to the primary tumour in ... Review Article. Radiotherapy boost to the primary tumour in locally advanced rectal cancer: Systematic review of practices and meta-analysis.

8. withpower.com withpower.com/trial/phase-2-and-3-rectal-neoplasms-3-2017-4ef42

Chemoradiation + Radiation Boost for Rectal Cancer 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, ...

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)43521-7/fulltext

The integration of oral capecitabine into chemoradiation ... Capecitabine chemoradiation is associated with a relatively low rate of grade 3/4 adverse events. Capecitabine simplifies chemoradiation and provides a ...