Chemotherapy + Bevacizumab for Metastatic Colorectal Cancer

(SCOTI Trial)

Recruiting at 8 trial locations

Overseen By Howard S. Hochster

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rutgers, The State University of New Jersey

Must not be taking: Investigational agents

Disqualifiers: TAS-102, CNS metastases, active malignancy, 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: 14

Duration: Until disease progression or adverse events

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is to evaluate the disease control rate and time to progression of the sequential combination of oxaliplatin with an alternative anti-metabolite Trifluridine/tipiracil hydrochloride mixture, TAS-102,(TAS-OX) as well as irinotecan in combination with TAS-102 oxaliplatin(TAS-OX) + Bevacizumab in late-line metastatic colorectal cancer (mCRC)

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 cannot participate if you are currently on other investigational agents or have had anticancer therapy within the last two weeks.

What data supports the effectiveness of the drug combination of chemotherapy and Bevacizumab for metastatic colorectal cancer?

Research shows that combining irinotecan with other chemotherapy drugs like fluorouracil and leucovorin significantly improves survival rates in metastatic colorectal cancer patients. Additionally, the combination of trifluridine/tipiracil (TAS-102) with bevacizumab has been shown to be effective and safe for treating this condition. ^{1 2 3 4 5}

Is the combination of chemotherapy and Bevacizumab safe for treating metastatic colorectal cancer?

The combination of chemotherapy drugs like Irinotecan and Oxaliplatin with Bevacizumab has been studied for safety in treating metastatic colorectal cancer. Common side effects include anemia (low red blood cell count), neutropenia (low white blood cell count), fatigue, nausea, and diarrhea. These side effects were generally manageable, but some patients needed dose adjustments or stopped treatment due to these reactions. ^{1 5 6 7 8}

What makes the drug combination of chemotherapy and bevacizumab unique for metastatic colorectal cancer?

This drug combination is unique because it includes TAS-102 (trifluridine/tipiracil), which is used with bevacizumab to treat patients who are not eligible for intensive therapy, offering an alternative for those who have not responded to standard treatments. The combination has shown efficacy in improving survival rates in patients with metastatic colorectal cancer. ^{5 9 10 11 12}

Research Team

Howard S. Hochster

Principal Investigator

Cancer Institute of New Jersey Rutgers

Eligibility Criteria

This trial is for adults with stage IV colon cancer that's worsened after standard treatments, including chemotherapy and antibody therapy. Candidates must have normal albumin levels, measurable disease progression, acceptable organ function, and a life expectancy of at least three months. Pregnant or breastfeeding individuals, those with severe allergies to the drugs used in this study or certain medical conditions are excluded.

Inclusion Criteria

I am 18 years old or older.

I can take pills by mouth.

Progression of disease documented on the most recent scan

Exclusion Criteria

I have previously taken the medication TAS-102.

I need treatment for cancer that has spread to my brain and is causing symptoms.

I couldn't handle irinotecan before because it caused severe diarrhea.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TAS-102, oxaliplatin, irinotecan with bevacizumab in alternating cycles until disease progression or adverse events

Until disease progression or adverse events

14-day cycles with in-person visits on day 1 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 100 months

Treatment Details

Interventions

• Bevacizumab
• Irinotecan
• Oxaliplatin
• TAS-102

Trial Overview The study tests a sequential combination treatment for metastatic colorectal cancer using TAS-102 alternated with oxaliplatin (TAS-OX) and irinotecan plus bevacizumab. It aims to assess how well the disease is controlled and how long before it progresses.

Participant Groups

Group I: Tolerability of TAS-102, oxaliplatin, irinotecan with bevacizumab Experimental Treatment 1 Intervention

Each treatment cycle will be fourteen days long. TAS-102 25 mg/m2 will be taken orally twice daily on days 1-5 of each cycle. Oxaliplatin 85 mg/m2 infusion will be given on day one for one cycle alternating with Irinotecan 150 mg/m2 infusion, which will be given on day one the next cycle.

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

Approved in United States as Camptosar for:

• Colorectal cancer

Approved in European Union as Irinotecan for:

• Colorectal cancer

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

Findings from Research

In a phase I/II trial involving 31 patients with metastatic colorectal cancer, a triple combination therapy of camptosar, oxaliplatin, and tomudex showed a manageable safety profile with a 50% response rate among evaluable patients.

The recommended doses for the combination therapy were established, and the median progression-free survival was 7.3 months, while the overall median survival was 16.6 months, suggesting potential effectiveness for further studies in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A National Cancer Institute of Canada Clinical Trials Group Study--IND.135: Phase I/II study of irinotecan (camptosar), oxaliplatin and raltitrexed (tomudex) (COT) in patients with advanced colorectal cancer. Maroun, JA., Jonker, D., Seymour, L., et al.[2018]

The introduction of irinotecan and oxaliplatin has nearly doubled survival rates for patients with metastatic colorectal cancer, marking a significant advancement in treatment after decades of relying solely on 5-fluorouracil.

Combining chemotherapy with biologic agents that target tumor growth pathways has shown improved response and survival rates, and the addition of oxaliplatin to standard treatments has enhanced disease-free survival in adjuvant settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developments in combination chemotherapy for colorectal cancer. Goetz, MP., Grothey, A.[2018]

Irinotecan has shown significant activity against advanced colorectal cancer when combined with traditional chemotherapy agents like fluorouracil, leading to clinical responses including complete remissions in patients.

The combination therapies have acceptable toxicity profiles, with neutropenia and delayed diarrhea being the most common side effects, indicating that irinotecan could be a safe option for treatment, although further large-scale phase III studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

Irinotecan significantly improves survival rates in patients with metastatic colorectal cancer when used as a second-line treatment, showing a median survival of 17.4 months compared to 14.1 months with 5-FU/leucovorin alone.

The combination of irinotecan with 5-FU/leucovorin resulted in a higher response rate (40.8% vs 23.1%) and longer time to disease progression (6.7 months vs 4.4 months), while manageable side effects like neutropenia were noted, but serious complications remained low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. Douillard, JY.[2018]

In a study of 19 patients with metastatic colorectal cancer, the combination of biweekly TAS-102 and bevacizumab resulted in a median progression-free survival of 5.6 months and overall survival of 11.5 months, indicating its efficacy as a third-line treatment.

The treatment was generally safe, with only one patient experiencing severe neutropenia (grade 3 or more), suggesting that this combination therapy may effectively manage cancer while minimizing serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer. Ishizaki, T., Mazaki, J., Enomoto, M., et al.[2021]

In a clinical trial involving 800 patients with metastatic colorectal cancer, TAS-102 significantly improved overall survival, with a median survival of 7.1 months compared to 5.3 months for the placebo group, indicating its efficacy as a treatment option.

While TAS-102 was effective, it also had notable adverse reactions, including anemia and neutropenia, leading to dose reductions in 13.7% of patients and discontinuation in 3.6%, highlighting the importance of monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: TAS-102. Marcus, L., Lemery, SJ., Khasar, S., et al.[2022]

Trifluridine/tipiracil (TAS-102) has a favorable safety profile for patients with metastatic colorectal cancer (mCRC), showing a low incidence of common adverse events like nausea, diarrhea, and fatigue, which can help improve patient adherence to treatment.

Oncology nurses play a crucial role in educating patients about managing treatment-related adverse events, which is essential for maintaining adherence to this oral chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Colorectal Cancer: Management With Trifluridine/Tipiracil . White, T., Larson, H., Minnella, A., et al.[2017]

In a study of 70 patients with metastatic colorectal cancer who had previously failed multiple therapies, TAS-102 demonstrated a median progression-free survival (PFS) of 6.0 months and an overall survival (OS) of 10.0 months, indicating its effectiveness in a real-world setting.

Combining TAS-102 with bevacizumab resulted in significantly better disease control rates (75.9% vs. 40-50% for other combinations), PFS (6.3 months vs. 3.0 months), and OS (12.0 months vs. 6.0-6.5 months), suggesting that this combination therapy may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study. Nie, C., Xu, W., Chen, B., et al.[2023]

In a phase 3 study involving 856 patients with unresectable metastatic colorectal cancer, trifluridine-tipiracil plus bevacizumab showed similar progression-free survival compared to capecitabine plus bevacizumab, with median times of 9.4 months and 9.3 months respectively.

The safety profiles of the two treatments differed significantly, with trifluridine-tipiracil plus bevacizumab leading to higher rates of neutropenia and anemia, while capecitabine plus bevacizumab was associated with more cases of hand-foot syndrome, indicating that both treatments have distinct safety considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. André, T., Falcone, A., Shparyk, Y., et al.[2023]

In a study of 35 patients with refractory metastatic colorectal cancer, the combination of trifluridine/tipiracil (TAS-102) and bevacizumab showed a disease control rate of 51.6% and a median overall survival of 9.3 months, indicating its efficacy in this challenging patient population.

The treatment was generally safe, with the most common severe side effects being neutropenia, asthenia, and nausea/vomiting, but importantly, there were no treatment-related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting. Martínez-Lago, N., Chucla, TC., De Castro, BA., et al.[2022]

Bevacizumab, a monoclonal antibody that inhibits VEGF, has been shown to significantly improve overall survival in patients with metastatic colorectal cancer when combined with standard chemotherapy regimens, such as 5-fluorouracil and leucovorin, in both the US and Europe.

In contrast, vatalanib, a tyrosine kinase inhibitor targeting VEGF, has not demonstrated any benefit in treating metastatic colorectal cancer, highlighting the importance of selecting effective antiangiogenic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-angiogenic treatment and colorectal cancer]. André, T., Tournigand, C., Abbas, F., et al.[2015]

In a phase II study involving 153 patients with unresectable metastatic colorectal cancer, the combination of trifluridine/tipiracil plus bevacizumab (TT-B) demonstrated a median progression-free survival (PFS) of 9.2 months, which was longer than the 7.8 months observed with capecitabine plus bevacizumab (C-B).

Both treatment regimens were well tolerated, but TT-B was associated with a higher incidence of severe neutropenia (47% vs. 5% for C-B), while C-B led to more cases of severe hand-foot syndrome (12% vs. 0%) and diarrhea (8% vs. 1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Van Cutsem, E., Danielewicz, I., Saunders, MP., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A National Cancer Institute of Canada Clinical Trials Group Study--IND.135: Phase I/II study of irinotecan (camptosar), oxaliplatin and raltitrexed (tomudex) (COT) in patients with advanced colorectal cancer. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Developments in combination chemotherapy for colorectal cancer. [2018]

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

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. [2018]

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

Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. [2018]

5. Greece pubmed.ncbi.nlm.nih.gov

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer. [2021]

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

FDA Approval Summary: TAS-102. [2022]

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

Metastatic Colorectal Cancer: Management With Trifluridine/Tipiracil . [2017]

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

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. [2023]

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

Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Anti-angiogenic treatment and colorectal cancer]. [2015]

12. England pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. [2022]