Chemotherapy + Immunotherapy for Rectal Cancer

Overseen By John Cho, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Autoimmune disorders, Active infection, 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

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat rectal cancer by combining chemotherapy and immunotherapy. It compares two treatment plans: one uses radiation alone, and the other combines radiation with a low dose of the chemotherapy drug cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan) before surgery. After surgery, both groups receive additional immunotherapy. The trial seeks participants with rectal cancer who haven't been treated yet and have tumors that can be surgically removed. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking advancements in rectal cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take any other chemotherapy, investigational products, or biologic or hormonal therapy for cancer treatment while participating in this trial.

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

Research has shown that low-dose cyclophosphamide is generally safe for patients. In a study involving individuals with advanced colorectal cancer, these low doses were well-tolerated and caused only minor side effects, suggesting it can be a safe option for similar conditions.

The combination of tremelimumab and durvalumab, treatments that help the immune system fight cancer, also appears safe for most people. Past research found that only a small number of patients experienced severe side effects, with most side effects being mild. This combination has been tested in various types of cancer, indicating that while some patients experience significant side effects, many tolerate it well.

Both treatments have been studied extensively, providing a good understanding of their safety. However, individual reactions can vary. Always consult a healthcare professional to understand personal risks and benefits. ^{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 combine traditional radiation with innovative approaches. In one arm, sub-ablative radiation is paired with low-dose cyclophosphamide, a drug that enhances the immune response, offering a potential boost over standard treatment by activating the body's natural defenses against cancer. The other arm uses radiation alone, followed by surgery and immunotherapy, providing a more focused treatment that could limit side effects while still tackling the cancer effectively. These approaches aim to improve outcomes by integrating immunotherapy, which is not typically part of standard treatment, potentially leading to more effective and less invasive options for patients.

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

Research has shown that low-dose cyclophosphamide, which participants in the Radiation+Drug arm of this trial may receive, can enhance the immune system's ability to fight cancer by boosting T cell activity in patients with advanced colorectal cancer. It achieves this by reducing Treg cells, which typically suppress the immune response, thus allowing the immune system to more effectively attack cancer cells. Additionally, combining tremelimumab and durvalumab, part of the adjuvant immunotherapy in this trial, has increased the response rate in some cancer patients, with certain studies showing a response rate as high as 64.5%. This combination can potentially strengthen the body's immune response against tumors. Together, these treatments offer promising ways to help the immune system target and destroy cancer cells. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

The SMARTEST trial is for adults over 18 with previously untreated mesothelioma, stages I-III. Participants must be fit for surgery, have good organ function, weigh more than 30 kg, and have a life expectancy of at least 12 weeks. They should not have had recent cancer treatments or other clinical trials that could interfere.

Inclusion Criteria

My doctor thinks I can undergo surgery and combined treatment.

I have mesothelioma and have not received any treatment for it.

I weigh more than 30 kilograms.

Exclusion Criteria

I have had radiation therapy to the chest area before.

I have not had major surgery within the last 28 days.

You have participated in a study involving durvalumab or tremelimumab before, no matter which treatment you received.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive sub-ablative radiation, with Arm A also receiving low dose cyclophosphamide

4-6 weeks

Surgery

Participants undergo surgery following radiation treatment

1 week

Adjuvant Immunotherapy

Participants receive consolidation tremelimumab-durvalumab after surgery

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Tremelimumab, Durvalumab

Trial Overview This phase II trial tests low dose cyclophosphamide with radiation before surgery (Arm A) against radiation alone (Arm B). After surgery, eligible patients from both arms receive tremelimumab-durvalumab to assess safety and effectiveness.

How Is the Trial Designed?

Group I: Radiation+Drug (Arm A) Experimental Treatment 3 Interventions

sub-ablative radiation plus low dose cyclophosphamide followed by surgery and adjuvant immunotherapy

Group II: Radiation alone (Arm B) Experimental Treatment 2 Interventions

sub-ablative radiation alone followed by surgery and adjuvant immunotherapy

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Ontario Institute for Cancer Research

Collaborator

Trials

24

Recruited

9,200+

OICR

Collaborator

Trials

4

Recruited

300+

Published Research Related to This Trial

In a study of 24 patients with locally advanced rectal cancer, the combination of PD-1 antibody and total neoadjuvant chemoradiotherapy showed good safety, with only 25% experiencing mild treatment-related adverse events, including some immune-related effects.

The treatment resulted in a 30% pathological complete response rate, particularly benefiting patients with wild-type Ras/Raf mutations, indicating that genetic testing can help identify those who may respond best to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors]. Li, YJ., Zhang, L., Dong, QS., et al.[2022]

For clinically resectable rectal cancer, two main treatment approaches exist: surgery followed by postoperative therapy for certain tumor stages, or preoperative therapy followed by surgery and additional postoperative therapy for more advanced tumors.

New chemotherapeutic agents are being tested in combination with pelvic radiation, particularly in preoperative settings, showing promising early results with higher complete response rates compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy of resectable rectal cancer: current approaches. Minsky, BD.[2005]

Neoadjuvant chemotherapy, specifically regimens like FOLFIRINOX followed by chemoradiotherapy, has shown positive results in patients with locally advanced rectal cancer, establishing new therapeutic standards.

These treatment approaches aim to improve outcomes by reducing the risk of locoregional recurrence, although they have not yet demonstrated a reduction in metastatic recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Contribution of neoadjuvant chemotherapy in rectal cancer]. Bachet, JB.[2022]

In a study of 3096 patients with locally advanced rectal cancer, elderly patients (over 75 years) had a significantly lower 3-year overall survival rate (77.2%) compared to younger patients (88.9%), indicating age is a critical factor in treatment outcomes.

Despite the age difference, elderly patients in good health can achieve similar cancer-specific survival and disease-free survival rates as younger patients when treated with neoadjuvant chemotherapy combined with chemoradiotherapy and total mesorectal excision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision. He, F., Chen, M., Xiao, WW., et al.[2021]

The mFOLFOXIRI regimen, a combination of 5-fluorouracil, oxaliplatin, and irinotecan, was found to be safe for patients with advanced colorectal cancer, with no treatment-related deaths reported despite some serious adverse events like intestinal perforation and neutropenia.

In terms of efficacy, the regimen showed a promising overall response rate of 63.8% in patients with metastatic colorectal cancer, with significantly better outcomes for those who completed more than four cycles of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis on safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (FOLFOXIRI) in advanced colorectal cancer]. Cai, Y., Deng, R., Hu, H., et al.[2018]

Adjuvant therapy has evolved to include Stage II colon cancer patients, with the combination of 5-fluorouracil plus leucovorin showing a slight survival benefit over the standard 5-fluorouracil plus levamisole regimen.

For Stage II and III rectal cancer, the most effective postoperative treatment is systemic 5-fluorouracil combined with radiation therapy, while preoperative radiation or chemoradiation may enhance surgical outcomes and reduce complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for colorectal cancer: present and future perspectives. Casillas, S., Pelley, RJ., Milsom, JW.[2019]

Adjuvant chemotherapy, particularly using the MOF protocol, has shown a survival advantage in stage II-III rectal cancers, supported by multiple meta-analyses and randomized trials that highlight its efficacy when combined with radiation therapy.

Neoadjuvant chemotherapy combined with radiotherapy is a reasonable approach for locally advanced rectal cancer, facilitating surgical resection in about two-thirds of patients, but it is crucial that this treatment does not compromise the quality of surgical procedures or pathological examinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Established data and practical recommendations concerning pre- and postoperative chemotherapy of rectal cancer]. Rougier, P., Mitry, E., Clavéro-Fabri, MC., et al.[2009]

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]

Over the past 15 years, outcomes for colorectal cancer patients have improved due to better scheduling of 5-fluorouracil and the introduction of new drugs like irinotecan and oxaliplatin.

Research is ongoing to identify molecular markers that can help tailor chemotherapy treatments to individual patients, aiming to enhance efficacy and reduce the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular markers of chemotherapeutic response and toxicity in colorectal cancer. Braun, MS., Quirke, P., Seymour, MT.[2015]

In a study of 48 patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy using the FOLFOX regimen, 50% showed a positive histopathological response, which included both complete and partial responses.

Patients who responded to chemotherapy had a significantly better 3-year disease-free survival rate of 86% compared to 62% for nonresponders, highlighting the importance of tumor response in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Even a partial pathological response is associated with lower relapse rates in patients with operable rectal cancer undergoing neoadjuvant chemotherapy. Koizumi, M., Yamada, T., Shinji, S., et al.[2021]

In a study of 16 patients with 5-fluorouracil-resistant metastatic colorectal cancer, irinotecan (CPT-11) demonstrated a partial response rate of 6.3% and a high rate of stable disease (43.7%), indicating its efficacy in this challenging patient population.

The median survival time for patients treated with CPT-11 was 69.6 weeks, with no toxic deaths reported, suggesting that CPT-11 is a safe and beneficial treatment option for patients resistant to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity and benefit of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma pre-treated with fluorouracil-based chemotherapy. Ratanatharathorn, V., Sirachainan, E., Jirajarus, M., et al.[2018]

Citations

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Low-Dose Cyclophosphamide Induces Antitumor T-Cell ... This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28855352/

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Efficacy of Palliative Metronomic Cyclophosphamide ... Results: A total of 82 patients received palliative mCTX at a dose of 50 to 150 mg/day either continuously or with a pause of 1 week per cycle.

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5. cancernetwork.com cancernetwork.com/view/mva-5t4-low-dose-cyclophosphamide-mcrc-showed-survival-benefit

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A comparative study of the real-world safety and ... The addition of pembrolizumab to metronomic cyclophosphamide and bevacizumab was not associated with an improved response rate, PFS, or OS.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00656123

Study of Colon GVAX and Cyclophosphamide in Patients ... Study of Colon GVAX and Cyclophosphamide in Patients With Metastatic Colorectal Cancer ; ClinicalTrials.gov ID NCT00656123 ; Sponsor Sidney Kimmel Comprehensive ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4046727/

Cancer Risk after Cyclophosphamide Treatment in ... We showed that cyclophosphamide therapy gives a threefold increase in the risk of cancer within 10–15 years after the start of treatment for iMN. For a 55-year- ...