ctDNA-Guided Therapy for Colorectal Cancer

Overseen By University of California Irvine Medical

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Irvine

Must not be taking: Investigational agents

Disqualifiers: Metastases, Recent surgery, Uncontrolled illness, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of drugs, irinotecan and TAS-102, to evaluate their effectiveness in treating colorectal cancer. The focus is on patients whose cancer cells display a specific genetic marker, ctDNA, linked to colon adenocarcinoma. This trial offers a new approach for those who have undergone surgery for colorectal cancer and whose tests reveal this ctDNA marker after chemotherapy. Participants must be able to swallow tablets and should not have had major surgery or chemotherapy recently. As a Phase 1 trial, the research aims to understand how the treatment works in people, providing participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents or have had recent chemotherapy or radiotherapy within 2 weeks before starting the trial.

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

Research has shown that combining TAS-102 (trifluridine/tipiracil) with irinotecan is generally well-tolerated. In one study, nearly half of the patients experienced significant side effects, known as grade 3/4 treatment-related adverse events (TRAEs). The most common side effects included a drop in white blood cells (neutropenia), diarrhea, and low platelets, which are crucial for blood clotting.

Although these side effects may sound serious, medical care can manage them. Neutropenia occurred in about one-third of patients, diarrhea in about one-sixth, and low platelets in just over one-tenth.

These studies help doctors anticipate and manage these side effects. For those considering joining a trial, this information provides insight into the treatment's safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of irinotecan and TAS-102 for colorectal cancer because it offers a unique approach to treatment. Unlike standard therapies, which often focus solely on chemotherapy drugs like 5-FU or oxaliplatin, this combination leverages TAS-102, a novel oral agent that targets cancer cell DNA to prevent replication, paired with irinotecan, a well-known chemotherapy agent that disrupts DNA repair. This dual-action strategy aims to enhance effectiveness by attacking cancer cells from different angles. Moreover, the addition of G-CSF when necessary may help manage side effects, potentially making the treatment more tolerable for patients.

What evidence suggests that this treatment might be an effective treatment for colon adenocarcinoma?

This trial will evaluate the combination of TAS-102 and irinotecan, known as "TASIRI," for treating colorectal cancer. Research has shown that using TAS-102 with irinotecan may aid in treating this condition. In one study, most patients' cancer did not worsen for approximately 9.2 months, and about 25.8% of patients experienced tumor shrinkage. Another study found that 18.3% of patients had their tumors shrink, with some experiencing full or partial reduction. These results suggest this treatment might help control cancer growth and improve outcomes for people with colorectal cancer. ^{3 5 6 7 8}

Who Is on the Research Team?

Farshid Dayyani

Principal Investigator

Chao Family Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with colon adenocarcinoma who have completed at least 3 months of adjuvant chemotherapy and are ctDNA positive. They must be able to swallow tablets, have a life expectancy over 3 months, and an ECOG performance status ≤2. Women of childbearing potential must use contraception.

Inclusion Criteria

My blood test shows cancer markers after 3 months of chemotherapy.

Life expectancy of greater than 3 months

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

Inability to comply with study and follow-up procedures as judged by the Investigator

I do not have any serious illnesses or social situations that would stop me from following the study's requirements.

Patients who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TAS-102 and irinotecan in 14-day cycles for at least 3 months

12 weeks

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Irinotecan
• TAS-102

Trial Overview The study tests the effectiveness of TAS-102 combined with irinotecan in patients with ctDNA positive colon adenocarcinoma after surgery. It's a phase 1b trial where all participants receive this combination treatment without being randomly assigned to different groups.

How Is the Trial Designed?

Group I: TASIRI Experimental Treatment 4 Interventions

Patients randomized to the experimental arm ("TASIRI") will be treated with TAS-102 25mg/m2 p.o. on days 1-5 and irinotecan 180mg/m2 i.v. on day 1 every 14 days. If ANC \<1500/uL on day 1 of a cycle, then G-CSF will be added on day 6 for three days.

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?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Natera, Inc.

Industry Sponsor

Trials

56

Recruited

50,700+

Taiho Pharmaceutical Co., Ltd.

Industry Sponsor

Trials

67

Recruited

18,600+

Masayuki Kobayashi

Taiho Pharmaceutical Co., Ltd.

Chief Executive Officer since 2012

Background in political and law studies

Harold Keer

Taiho Pharmaceutical Co., Ltd.

Chief Medical Officer since 2024

MD

Published Research Related to This Trial

Irinotecan, a topoisomerase I inhibitor, has shown significant antitumor activity against colorectal cancer, both in patients who have not received chemotherapy and those who are resistant to fluorouracil (5-FU).

Phase III studies indicate that combining irinotecan with 5-FU and leucovorin is more effective than standard 5-FU/leucovorin treatments, and these combinations are being tested in clinical trials for treating early-stage colon cancer, potentially improving survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan-based combinations for the adjuvant treatment of stage III colon cancer. Saltz, L.[2018]

In a phase II study involving 45 patients with advanced colorectal cancer, the combination of oral S-1 and weekly irinotecan showed an overall response rate of 48.9%, indicating significant efficacy as a first-line treatment.

The treatment was well-tolerated, with manageable grade 3 or 4 toxicities, including neutropenia (8.9%) and diarrhea (6.7%), suggesting it may be a safer alternative compared to conventional chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Phase II Study of a New Effective S-1 and Irinotecan Combination Schedule in Patients with Unresectable Metastatic or Recurrent Colorectal Cancer. Ogata, Y., Tanaka, T., Akagi, Y., et al.[2021]

In a phase II study involving 39 patients with advanced colorectal cancer, the combination of irinotecan and 5-fluorouracil showed promising efficacy, with 8 patients achieving an objective response and 12 experiencing disease stabilization, leading to surgical resection in some cases.

The treatment was generally well tolerated, with hematologic toxicity being the most common serious side effect (29% of patients), while the median duration of response was 14 months and median survival was 11 months, indicating a favorable outcome for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective phase II trial of iriontecan, 5-fluorouracil, and leucovorin in combination as salvage therapy for advanced colorectal cancer. Gil-Delgado, MA., Guinet, F., Castaing, D., et al.[2019]

Irinotecan is approved as a second-line treatment for metastatic colorectal cancer and has shown promising single-agent activity in Phase II studies for first-line treatment, with response rates comparable to standard regimens.

Due to its high cost and lack of definitive evidence showing superiority over current first-line treatments, routine use of irinotecan as a single agent may not be justified, although combination therapies with fluorouracil and molecular markers could help identify suitable patients for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in the first-line treatment of colorectal cancer. Saltz, LB.[2018]

Irinotecan (CPT-11) demonstrated efficacy in treating advanced colorectal cancer, achieving an overall response rate of 18% in a study of 213 patients, including both chemotherapy-naive and pretreated individuals.

The treatment was associated with manageable adverse effects, primarily neutropenia and delayed diarrhea, with severe side effects occurring in a minority of treatment cycles, indicating that while CPT-11 is effective, careful monitoring for these toxicities is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. Rougier, P., Bugat, R., Douillard, JY., et al.[2018]

In a study of 154 patients with advanced colorectal cancer, three different regimens combining irinotecan (CPT-11) with 5-fluorouracil (5-FU) and folinic acid (FA) showed overall response rates of 33%, 42%, and 30%, indicating that all regimens were effective in treating the disease.

The biweekly regimen (arm B) was particularly noteworthy for having a significantly lower incidence of severe neutropenia (8% of patients) compared to the other regimens, while all three regimens had similar rates of severe delayed diarrhea (15% to 22%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer. Bouzid, K., Khalfallah, S., Tujakowski, J., et al.[2020]

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]

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]

CPT-11 (irinotecan) has demonstrated promising efficacy in treating advanced colorectal cancer, with an overall response rate of 18% and a median duration of response of 9.1 months in a study of 178 patients, indicating its potential effectiveness even after failure of 5-FU therapy.

The main side effects of CPT-11 include neutropenia and delayed diarrhea, which are manageable, with recovery from neutropenia typically occurring by day 22, suggesting that while there are significant adverse events, they can be effectively controlled.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Rougier, P., Bugat, R.[2018]

Irinotecan (CPT-11) is effective as a second-line treatment for advanced colorectal cancer and shows improved antitumor activity when combined with 5-fluorouracil compared to 5-fluorouracil alone, suggesting potential for first-line use.

While single-agent CPT-11 has demonstrated activity in first-line treatment, its response rates are not superior to standard 5-fluorouracil regimens; however, using molecular markers may help identify patients who could benefit more from CPT-11.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of irinotecan in colorectal cancer. Saltz, LB.[2019]

Citations

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Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) ... In the present study, the median PFS was 9.2 months, and the median OS was not reached. ORR and DCR were 25.8% and 93.5%, respectively. These ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.155

Phase II study of trifluridine/tipiracil (TAS-102) plus ... As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2214963

Trifluridine–Tipiracil and Bevacizumab in Refractory ... Among patients with refractory metastatic colorectal cancer, treatment with FTD–TPI plus bevacizumab resulted in longer overall survival than FTD–TPI alone.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0936655523002431

REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients ... Our study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and PFS outcomes were higher than the efficacy ...

5. academic.oup.com academic.oup.com/oncolo/article/29/5/e601/7609538

Efficacy and Safety of Trifluridine/Tipiracil-Containing ... Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory ...

6. nature.com nature.com/articles/s41416-024-02885-3

Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) ... Concerning safety, all-grade TRAEs occurred in all patients, and grade 3/4 TRAEs occurred in 48.6% of them. The most common TRAEs were bone ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38990451/

Phase I study of trifluridine/tipiracil (TAS-102) plus ... The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11067808/

Efficacy and Safety of Trifluridine/Tipiracil-Containing ... This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC.