Ablative Therapy + Systemic Therapy for Colorectal Cancer

Recruiting at 149 trial locations

Overseen By Aleksandar Jankov

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alliance for Clinical Trials in Oncology

Disqualifiers: Liver-only metastases, Unresectable primary tumors, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 5 years

364 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial compares total ablative therapy and usual systemic therapy to usual systemic therapy alone in treating patients with colorectal cancer that has spread to up to 4 body sites (limited metastatic). The usual approach for patients who are not participating in a study is treatment with intravenous (IV) (through a vein) and/or oral medications (systemic therapy) to help stop the cancer sites from getting larger and the spread of the cancer to additional body sites. Ablative means that the intention of the local treatment is to eliminate the cancer at that metastatic site. The ablative local therapy will consist of very focused, intensive radiotherapy called stereotactic ablative radiotherapy (SABR) with or without surgical resection and/or microwave ablation, which is a procedure where a needle is temporarily inserted in the tumor and heat is used to destroy the cancer cells. SABR, surgical resection, and microwave ablation have been tested for safety, but it is not scientifically proven that the addition of these treatments are beneficial for your stage of cancer. The addition of ablative local therapy to all known metastatic sites to the usual approach of systemic therapy could shrink or remove the tumor(s) or prevent the tumor(s) from returning.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have been on first-line systemic therapy for at least 16 weeks before joining the trial.

What data supports the effectiveness of the treatment Ablative Therapy + Systemic Therapy for Colorectal Cancer?

Research shows that new chemotherapy and biologic agents have improved survival rates for patients with metastatic colorectal cancer. Surgery, when combined with systemic therapy, has been shown to increase long-term survival in patients with liver and/or lung metastases. ^{1 2 3 4 5}

Is the combination of chemotherapy and targeted therapy generally safe for colorectal cancer patients?

Research shows that chemotherapy combined with targeted therapies like bevacizumab and cetuximab can have different safety profiles. Bevacizumab-based treatments may lower risks of skin and kidney issues but increase heart-related risks, while cetuximab-based treatments may increase skin and kidney problems. ^{6 7 8 9 10}

How is the Ablative Therapy + Systemic Therapy treatment for colorectal cancer different from other treatments?

This treatment combines ablative therapy, which targets and destroys cancer cells in specific areas, with systemic chemotherapy, which circulates throughout the body to kill cancer cells. This approach aims to increase the complete response rate and prolong the time to disease progression, offering a potentially more effective option compared to standard chemotherapy alone. ^{3 11 12 13 14}

Eligibility Criteria

Adults with colorectal cancer spread to up to 4 sites, excluding the brain and peritoneum. Must have had or be eligible for primary tumor resection, no more than 6 months of systemic therapy without disease progression, and meet specific health criteria like adequate blood counts and liver function.

Inclusion Criteria

My cancer did not worsen while on my last treatment.

My primary tumor has been removed or can be surgically removed.

My cancer does not have the BRAF V600E mutation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive total ablative therapy (TAT) consisting of SABR with or without surgical resection and/or microwave ablation, along with standard of care (SOC) chemotherapy. Imaging scans (CT, MRI, or PET/CT) are conducted throughout the trial.

Up to 5 years

Follow-up

Participants are monitored for safety, effectiveness, and recurrence after treatment. This includes assessments of overall survival, event-free survival, and time to local recurrence.

Up to 5 years

Treatment Details

Interventions

• Chemotherapy
• Microwave Ablation
• Resection
• Stereotactic Ablative Radiotherapy

Trial Overview The trial is comparing usual systemic therapy (like IV chemotherapy) alone versus adding total ablative therapy (intense radiotherapy called SABR, possibly combined with surgery or microwave ablation) to see if it better controls cancer that has spread in a limited way.

Participant Groups

Group I: Arm 1 (TAT, SOC chemotherapy Experimental Treatment 7 Interventions

Patients undergo TAT on study, consisting of SABR with or without surgical resection and/or microwave ablation. Patients also receive SOC chemotherapy on study. Patients also undergo CT or MRI or PET/CT scans throughout the trial.

Group II: Arm 2 (SOC chemotherapy) Active Control 4 Interventions

Patients receive SOC chemotherapy on study. Patients also undergo Patients also undergo CT or MRI or PET/CT scans throughout the trial.

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

Approved in European Union as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in United States as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Canada as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Japan as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in China as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Switzerland as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Recent advancements in cytotoxic and biologic agents have significantly improved survival rates for patients with metastatic colorectal cancer (mCRC).

Surgical intervention for liver and/or lung metastases has been shown to enhance long-term survival, highlighting the importance of integrating systemic chemotherapy with potentially curative surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy for metastatic colorectal cancer: current questions. Zuckerman, DS., Clark, JW.[2018]

The management of metastatic colorectal cancer (mCRC) requires a collaborative approach involving various specialists and is primarily based on chemotherapy combined with monoclonal antibodies targeting EGFR and VEGF.

Biomarkers such as RAS mutation and tumor sidedness are crucial for guiding EGFR-directed therapies, and additional molecular markers like BRAF mutations and MSI-status can expand treatment options for pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Systemic Therapy of Metastatic Colorectal Cancer]. Modest, DP., von Bergwelt-Baildon, M.[2019]

Recent advancements in chemotherapy and biologics have significantly improved treatment outcomes for colorectal cancer (CRC), particularly with the use of oxaliplatin in stage III colon cancer as the standard of care.

The introduction of KRAS mutational status as a predictive marker allows for more personalized treatment strategies in CRC, enhancing the potential for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of colorectal cancer]. Reinacher-Schick, A., Pohl, M., Schmiegel, W.[2021]

Recent advancements in colon cancer treatment have significantly improved patient outcomes, primarily due to new chemotherapy agents like irinotecan, oxaliplatin, and capecitabine, as well as biologic agents such as bevacizumab and cetuximab.

Clinical trials have established oxaliplatin/5-FU-based chemotherapy as a new standard for adjuvant therapy in earlier stage colon cancer, with ongoing research exploring the combination of biologic agents and chemotherapy to enhance cure rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New agents, combinations, and opportunities in the treatment of advanced and early-stage colon cancer. Natarajan, N., Shuster, TD.[2006]

Recent advancements in colorectal cancer treatment over the past 5 years have led to the introduction of new cytotoxic agents and targeted therapies that significantly prolong survival in patients with advanced disease.

The application of these novel therapies not only benefits advanced cases but has also been successfully used in the adjuvant setting, indicating a broader potential for improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of colorectal carcinoma: standard chemotherapy and beyond. Eng, C., Abbruzzese, JL.[2018]

In a study of 46,692 elderly colorectal cancer patients, those receiving intravenous chemotherapy experienced significantly higher rates of adverse events, particularly with oxaliplatin-based regimens, which caused more nausea, neutropenia, and neuropathy compared to fluorouracil alone.

Patients aged 70 and older were more likely to suffer from adverse effects such as infection, anemia, delirium, and heart disease, highlighting the need for careful patient selection and support when administering chemotherapy to older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of toxicity profiles of fluorouracil versus oxaliplatin regimens in a large population-based cohort of elderly patients with colorectal cancer. Cen, P., Liu, C., Du, XL.[2020]

In patients with unresectable RAS wild-type metastatic colorectal cancer, first-line bevacizumab-based chemotherapy significantly reduces the risk of dermatological and renal adverse events, but increases the risk of cardiovascular issues like hypertension and arrhythmia.

Conversely, cetuximab-based chemotherapy is associated with a higher incidence of dermatological and renal adverse events, particularly rashes and electrolyte disorders, highlighting the need for careful selection of targeted therapies based on safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Han, YN., Choi, YJ., Rhie, SJ.[2022]

The average annual cost of treating newly diagnosed colorectal cancer (CRC) patients was $97,400, with significant expenses attributed to chemotherapy, biologics, and various treatment settings, indicating a high financial burden on the healthcare system.

Healthcare costs for CRC treatment have increased by 73% from 2005 to 2009, primarily due to the adoption of new treatment regimens, the prevalence of metastasis, and the presence of comorbidities, highlighting the complexity and evolving nature of CRC management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medical costs associated with use of systemic therapy in adults with colorectal cancer. Seal, BS., Sullivan, SD., Ramsey, S., et al.[2023]

In patients with KRAS wild-type tumors, combining irinotecan-based chemotherapy with bevacizumab or cetuximab resulted in the longest median overall survival (OS) of 38 and 41 months, respectively, while KRAS-mutated patients had a median OS of 34 months with oxaliplatin-based treatments.

Patients receiving chemotherapy doses below 80% experienced lower overall survival compared to those maintaining doses above 80%, highlighting the importance of dose management in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival and Metastasis Resections in Patients with Metastatic Colorectal Cancer Using Electronic Medical Records. Heervä, E., Lavonius, M., Jaakkola, P., et al.[2018]

The combination of 5-fluorouracil-based regimens with molecularly targeted agents has significantly expanded treatment options for patients with metastatic colorectal cancer, which is crucial given its status as a leading cause of cancer-related death.

Proactive management of adverse events associated with these treatments can lead to uninterrupted therapy and improved quality of life for patients, as the efficacy of the treatment helps prolong wellness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecularly targeted therapy: toxicity and quality of life considerations in advanced colorectal cancer. Ribecco, AS., Pino, MS., Cipriani, G., et al.[2013]

Recent advancements in chemotherapy and biologics have significantly improved treatment outcomes for colorectal cancer (CRC), which remains a leading cause of cancer death, particularly in stage III colon cancer where combination therapy with oxaliplatin is now standard.

The introduction of KRAS mutational status as a predictive marker allows for more personalized treatment approaches in CRC, enhancing the potential for effective management of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Colorectal cancer - personalized, stage-adjusted tumour therapy]. Pohl, M., Schmiegel, W.[2015]

The study assessed the effects of doxorubicin and common chemotherapy drugs on the expression of BCL2 family genes in colorectal cancer cell lines, revealing significant changes in gene expression related to programmed cell death.

Results suggest that BCL2L12 may play a proapoptotic role during chemotherapy treatment, as its expression increases alongside other proapoptotic genes, indicating that these drugs activate the intrinsic apoptotic pathway in colorectal cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Effects of Treatment of Human Colorectal Cancer Cells with Natural and Classical Chemotherapeutic Drugs: Alterations in the Expression of Apoptosis-related BCL2 Family Members, Including BCL2L12. Kontos, CK., Avgeris, M., Vassilacopoulou, D., et al.[2019]

Recent advancements in treatment options for advanced colorectal cancer have significantly improved strategies, moving beyond traditional chemotherapy with 5-fluorouracil to include new cytotoxic drugs like oral fluoropyrimidines, irinotecan, and oxaliplatin.

These new therapies, along with targeted agents, are being integrated into combination protocols, enhancing the potential for long-term survival in patients with metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapy approaches in colorectal cancer. Grothey, A., Schmoll, HJ.[2019]

In a clinical trial involving 31 patients with liver metastasis from colorectal carcinoma, the combination of hepatic arterial chemoembolization and systemic 5-fluorouracil chemotherapy resulted in an overall response rate of 29%, with one complete response and eight partial responses observed.

Despite the treatment, the response rate and median time to disease progression (8 months) were similar to those achieved with standard systemic chemotherapy, leading researchers to conclude that this combined approach did not offer significant advantages and they do not plan to pursue it further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic chemoembolization combined with systemic infusion of 5-fluorouracil and bolus leucovorin for patients with metastatic colorectal carcinoma: A Southwest Oncology Group pilot trial. Leichman, CG., Jacobson, JR., Modiano, M., et al.[2013]

References

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

Systemic therapy for metastatic colorectal cancer: current questions. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

[Systemic Therapy of Metastatic Colorectal Cancer]. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

[Chemotherapy of colorectal cancer]. [2021]

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

New agents, combinations, and opportunities in the treatment of advanced and early-stage colon cancer. [2006]

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

The treatment of colorectal carcinoma: standard chemotherapy and beyond. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Comparison of toxicity profiles of fluorouracil versus oxaliplatin regimens in a large population-based cohort of elderly patients with colorectal cancer. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. [2022]

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

Medical costs associated with use of systemic therapy in adults with colorectal cancer. [2023]

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

Overall Survival and Metastasis Resections in Patients with Metastatic Colorectal Cancer Using Electronic Medical Records. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Molecularly targeted therapy: toxicity and quality of life considerations in advanced colorectal cancer. [2013]

11. Germany pubmed.ncbi.nlm.nih.gov

[Colorectal cancer - personalized, stage-adjusted tumour therapy]. [2015]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Molecular Effects of Treatment of Human Colorectal Cancer Cells with Natural and Classical Chemotherapeutic Drugs: Alterations in the Expression of Apoptosis-related BCL2 Family Members, Including BCL2L12. [2019]

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

New chemotherapy approaches in colorectal cancer. [2019]

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

Hepatic chemoembolization combined with systemic infusion of 5-fluorouracil and bolus leucovorin for patients with metastatic colorectal carcinoma: A Southwest Oncology Group pilot trial. [2013]