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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a personalized approach to dosing irinotecan (also known as Camptosar or CPT-11), a medication for treating pancreatic and colorectal cancers. Researchers aim to determine if adjusting the dose based on a patient's genetic makeup, specifically their UGT1A1 genotype, is more effective than the standard dosing method. Individuals with confirmed pancreatic cancer (any stage) or advanced colorectal cancer who have not previously received irinotecan may be suitable candidates. As an unphased trial, this study provides patients the opportunity to contribute to innovative research that could personalize cancer treatment.

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 prior data suggests that genotype-guided dosing of Irinotecan is safe?

Research has shown that adjusting the dose of irinotecan based on a person's genetic makeup can be safer for some patients. Specifically, studies have found that altering the dose according to the UGT1A1 gene significantly lowers the risk of febrile neutropenia, a condition where a low white blood cell count increases infection risk. In simpler terms, this dosing method reduces the chance of side effects related to low immunity.

Moreover, past patients safely took higher doses of irinotecan as part of specific treatment plans. While not everyone will have the same experience, this suggests that using genetic information to guide dosing can make irinotecan more tolerable for many people. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the genotype-guided use of irinotecan for colorectal and pancreatic cancer because it personalizes treatment based on a patient’s genetic makeup. Unlike standard chemotherapy approaches, which often treat all patients the same, this method aims to tailor the dosage of irinotecan to maximize effectiveness while minimizing side effects. By focusing on genetic differences, this approach has the potential to improve outcomes and reduce adverse reactions, offering a more targeted and patient-specific therapy.

What evidence suggests that genotype-guided dosing of Irinotecan could be effective for colorectal and pancreatic cancer?

Research has shown that Irinotecan can significantly improve survival rates for patients with metastatic colorectal cancer when used as a second treatment option. In this trial, participants in the "Genocare Guided" arm will receive Irinotecan with doses adjusted based on the UGT1A1 gene, which affects how the body processes the drug. Studies indicate that this approach can enhance safety by reducing the risk of febrile neutropenia, a serious side effect involving fever and low white blood cell counts. Most studies suggest that increasing the Irinotecan dose leads to better results, especially when considering the patient's genetics. This personalized approach can make the treatment more effective and safer. Meanwhile, participants in the "Usual Care" arm will receive standard treatment without genotype-guided adjustments. ^{1 2 3 6 7}

Who Is on the Research Team?

Reema A Patel, MD

Principal Investigator

University of Kentucky

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 (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]

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]

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]

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]

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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38828490/

Longitudinal patient-reported outcomes on genotype ...

Although protocol-mandated dose reductions were guided by CTCAE not PRO-CTCAE responses, the median time to dose reduction of 2.53 months, and ...

2.

academic.oup.com

academic.oup.com/oncolo/article/29/9/780/7686623

Longitudinal patient-reported outcomes on genotype-guided ...

96% of patients and clinician-patient pairs completed at least 80% of PRO-CTCAE forms available to them with 79% achieving 100% completion.

3.

withpower.com

withpower.com/trial/phase-malignant-neoplasm-of-pancreas-4-2022-707b4

Genotype-Guided Irinotecan for Colorectal and Pancreatic ...

Irinotecan significantly improves survival rates in patients with metastatic colorectal cancer when used as a second-line treatment, showing a median survival ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S113063432300137X

Efficacy and safety of high doses of irinotecan in patients ...

With regard to the studies that evaluated both efficacy and safety, six out of seven (85.7%) were in favor of increasing irinotecan dose according to the ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3574

Safety and pharmacokinetic analysis of UGT1A1 genotype- ...

Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with ...

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S0959804921012648

UGT1A1 genotype-guided dosing of irinotecan

UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan.

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01183494

A Genotype-guided Study of Irinotecan Administered in ...

Earlier studies have shown that higher doses of irinotecan can be used safely as part of the FOLFIRI combination, but it is unclear whether these same doses ...