Genotype-Guided Irinotecan for Colorectal and Pancreatic Cancer

Overseen By Reema A Patel, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Reema A. Patel

Must not be taking: Irinotecan

Disqualifiers: Pregnancy, Uncontrolled illness, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

178 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective, randomized study designed to compare genotype-guided dosing to usual care in patients with pancreas cancer and colorectal cancer who are UGT1A1 intermediate metabolizers (\*1/\*28) (heterozygotes) and usual UGT metabolizers (\*1/\*1). All patients will be assessed for UGT1A1 genotype at screening and those with intermediate or usual UGT1A1 genotypes (\*1/\*28, \*1/\*1) will be randomized to genotype-guided dosing versus usual care.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Irinotecan for colorectal and pancreatic cancer?

Research shows that Irinotecan, when used with other drugs like 5-fluorouracil, improves survival rates in patients with metastatic colorectal cancer. It has been effective as a second-line treatment, meaning it's used when initial treatments don't work, and studies suggest it could be beneficial in combination therapies. ^{1 2 3 4 5}

Is irinotecan generally safe for humans?

Irinotecan, also known as CPT-11, can cause severe side effects, especially in people with certain genetic traits. Studies show that it can lead to serious blood-related toxicities and other severe reactions, particularly in patients with specific gene variations. ^{1 6 7 8 9}

What makes the drug Irinotecan unique for treating colorectal and pancreatic cancer?

Irinotecan is unique because it is used in a genotype-guided approach, meaning treatment is tailored based on a patient's genetic makeup, which can help predict and manage potential side effects like hematologic toxicity (blood-related side effects). This personalized approach aims to improve treatment effectiveness and reduce adverse effects compared to standard treatments. ^{1 2 3 5 10}

Research Team

Reema A Patel, MD

Principal Investigator

University of Kentucky

Eligibility Criteria

This trial is for adults over 18 with stage I-IV pancreatic or stage III-IV colorectal cancer who are about to start treatment. They must have a certain UGT1A1 gene type, good organ function, and an ECOG performance status of ≤1. Pregnant women, those not planned for treatment, previous irinotecan users, or patients with uncontrolled illnesses that could affect therapy adherence cannot join.

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

I have had surgery or radiation, but no treatments with irinotecan.

My cancer can be measured by tests or scans.

Exclusion Criteria

I do not have any severe illnesses that my doctor thinks could interfere with the treatment.

Pregnant women are excluded from this study

I am not scheduled for any cancer treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive genotype-guided dosing or usual care for pancreas and colorectal cancer

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Irinotecan

Trial Overview The GENOCARE trial is testing whether adjusting the dose of Irinotecan based on the patient's specific genotype (UGT1A1) leads to better outcomes than usual care in treating pancreatic and colorectal cancers. Participants will be randomly assigned to either receive genotype-guided dosing or standard treatment.

Participant Groups

Group I: Genocare Guided Experimental Treatment 1 Intervention

Group II: Usual Care Active Control 1 Intervention

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?

Reema A. Patel

Lead Sponsor

Trials

2

Recruited

210+

Findings from Research

In a study of 400 high-risk stage III colon cancer patients receiving chemotherapy, those with the UGT1A1*28 homozygous mutation experienced significantly higher rates of severe hematologic toxicity (50%) compared to those with the UGT1A1*1 homozygous genotype (16.2%).

The -3156G>A UGT1A1 polymorphism was found to be a strong predictor of early severe hematologic toxicity, with a hazard ratio of 8.4 for patients with the A/A genotype compared to the G/G genotype, indicating the importance of genetic testing before treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Côté, JF., Kirzin, S., Kramar, A., 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]

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]

The alternating treatment regimen of irinotecan (CPT-11) and high-dose 5-fluorouracil (5-FU) with leucovorin (LV) showed a 37% objective response rate in 35 patients with metastatic colorectal cancer, indicating significant efficacy as a first-line therapy.

The treatment was well-tolerated, with no toxic deaths reported and manageable side effects, including a 43% incidence of neutropenia and 14% diarrhea, making it a viable outpatient option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of irinotecan alternated with a weekly schedule of high-dose leucovorin and 48-hour 5-fluorouracil infusion in patients with metastatic colorectal cancer. Rosati, G., Rossi, A., Reggiardo, G., et al.[2018]

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]

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]

In a phase I trial involving 23 patients with metastatic or recurrent colorectal cancer, the recommended doses for S-1 and irinotecan (CPT-11) were established at 80 mg/m² and 225 mg/m², respectively, with manageable dose-limiting toxicities including grade 3 ileus and diarrhea.

The combination treatment showed promising efficacy, with an objective response rate of 41% in patients with measurable disease, indicating that further phase II trials are justified to explore this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer. Choi, YH., Kim, TW., Lee, SS., et al.[2018]

Irinotecan (CPT-11) has been shown to significantly enhance the effectiveness of colorectal cancer treatment, especially in cases resistant to traditional therapies like 5-fluorouracil (5-FU), due to its mechanism of inhibiting topoisomerase I.

The drug's administration can be optimized through therapeutic drug monitoring and pharmacokinetic adjustments, which can reduce toxicity and improve patient outcomes, including overall survival and time to relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients. Di Paolo, A., Bocci, G., Danesi, R., et al.[2019]

In a study of metastatic colorectal cancer patients, specific gene polymorphisms in the irinotecan metabolic pathway were linked to higher rates of severe toxicities (Grade 3/4).

The presence of at least one SLCO1B1 521 T allele, one ABCB1 1236 C allele, and one UGT1A1*28 variant 7 repeat significantly increased the risk of these toxicities, suggesting that genetic testing could help predict patient responses to irinotecan treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ABCB1, SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan. Rhodes, KE., Zhang, W., Yang, D., et al.[2019]

Combining irinotecan hydrochloride (SN-38) with cisplatin significantly enhances the anticancer effects against colorectal cancer, as shown by a study using freshly isolated cancer cells from 20 patients.

The study found that even at lower concentrations, the combination of SN-38 and cisplatin produced a strong synergistic effect, suggesting a promising strategy for improving chemotherapy outcomes in advanced colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro augmentation of antitumor effect in combination with CPT-11 and CDDP for human colorectal cancer. Tsunoda, T., Tanimura, H., Hotta, T., et al.[2019]

References

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

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. [2018]

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

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

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

The role of irinotecan in colorectal cancer. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A phase II study of irinotecan alternated with a weekly schedule of high-dose leucovorin and 48-hour 5-fluorouracil infusion in patients with metastatic colorectal cancer. [2018]

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

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

6. Thailand 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. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer. [2018]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients. [2019]

9. United Arab Emirates pubmed.ncbi.nlm.nih.gov

ABCB1, SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan. [2019]

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

In vitro augmentation of antitumor effect in combination with CPT-11 and CDDP for human colorectal cancer. [2019]