Drug Combination for Liver Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Ali Zarrinpar, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Florida

Disqualifiers: Pregnancy, Breastfeeding, Major surgery, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This study will test the hypothesis that a novel combination of three drugs (sorafenib, sonidegib, and irinotecan), in conjunction with individually optimized doses, can be safely administered and lead to improved clinical outcomes in patients with hepatocellular carcinoma compared to standard of care. The main objective of this study is to establish safe dose ranges for the coadministration of sorafenib, sonidegib, and irinotecan in patients with hepatocellular carcinoma. Furthermore, we will collect data to inform the application of an artificial intelligence/computational approach to individual dosing of combination chemotherapy. Individualization of dosing will be achieved by using Phenotypic Personalized Medicine (PPM) to maximize treatment efficacy in patients with hepatocellular carcinoma, while minimizing toxicity. Drug efficacy will be assessed by measuring plasma circulating tumor DNA (ctDNA). Toxicity will be assessed by quantitating organ injury and patient tolerability. Recommended dosing for future studies will be based on the totality of the data.

Do I need to stop my current medications for the trial?

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

What data supports the effectiveness of the drug combination for liver cancer?

Irinotecan, one of the drugs in the combination, has shown significant antitumor activity in colorectal cancer, and when combined with other drugs, it has been effective in treating advanced stages of this cancer. This suggests potential effectiveness in other cancers, like liver cancer, although direct evidence for liver cancer is not provided. ^{1 2 3 4 5}

Is the drug combination generally safe for humans?

Irinotecan, also known as Camptosar or CPT-11, has been studied in various cancer treatments and has shown an acceptable safety profile, though it can cause side effects like neutropenia (low white blood cell count) and diarrhea. The safety of this drug can vary based on genetic factors, as seen in studies with colorectal cancer patients, where different doses were tolerated depending on genetic makeup. ^{2 6 7 8 9}

What makes the drug combination of Irinotecan, Sonidegib, and Sorafenib unique for liver cancer treatment?

This drug combination is unique because it combines Irinotecan, which inhibits DNA topoisomerase I to prevent cancer cell replication, with Sonidegib and Sorafenib, which target different pathways in cancer cells, potentially offering a multi-faceted approach to treating liver cancer. ^{10 11 12 13 14}

Research Team

Ali Zarrinpar, MD, PhD

Principal Investigator

University of Florida

Eligibility Criteria

Adults over 18 with advanced-stage liver cancer (HCC) confirmed by biopsy, who can't have or haven't improved with surgery or local treatments. They should be relatively active (ECOG ≤2), have a life expectancy of at least 12 weeks, and not be dealing with other serious cancers. Their liver must still work fairly well (Child-Pugh A or B7), and they need to have at least one measurable tumor that hasn’t been treated.

Inclusion Criteria

Must have lab values consistent with Platelet count ≥ 60,000, Hemoglobin ≥8.0 g/dL, INR ≤2.5, Albumin ≥2.5 g/dL, Total bilirubin ≤5 mg/dL, ALT & AST ≤5 times the upper limit of normal, Creatinine ≤ 2 times the upper limit of normal

My liver is functioning well enough, not severely impaired.

I am 18 years old or older.

Exclusion Criteria

Inability to follow up with treatment center for up to 12 weeks after enrollment

Subjects who are pregnant or breastfeeding

I expect to have major surgery during the study period.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a novel combination of three drugs (sorafenib, sonidegib, and irinotecan) with individually optimized doses to establish safe dose ranges and improve clinical outcomes

32 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of drug efficacy and toxicity

4 weeks

Treatment Details

Interventions

• Irinotecan (Other)
• Sonidegib (Other)
• Sorafenib (Other)

Trial Overview The trial is testing a new combination of three drugs: sorafenib, sonidegib, and irinotecan. It aims to find safe doses for these drugs when used together in liver cancer patients. The study will use AI to personalize drug dosing for each patient to maximize benefits while reducing side effects. Success will be measured by looking at changes in ctDNA levels in the blood and how well patients tolerate treatment.

Participant Groups

Group I: Irinotecan, Sonidegib, and Sorafenib Experimental Treatment 3 Interventions

Subjects will be assigned to a dose of each drug following a 3 + 3 design

Irinotecan is already approved in Japan, Canada for the following indications:

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 Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Dr. Stephen J. Motew

University of Florida

Chief Executive Officer since 2024

MD cum laude from the University of Illinois at Chicago School of Medicine, Master's in Healthcare Administration from the University of North Carolina at Chapel Hill

Dr. Timothy E. Morey

University of Florida

Chief Medical Officer since 2023

MD and Bachelor's from the University of Florida

Sun Pharmaceutical Industries Ltd

Collaborator

Trials

2

Recruited

30+

Findings from Research

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 study of 23 patients with advanced gastric cancer, the combination therapy of irinotecan (CPT-11) and S-1 resulted in a promising overall response rate of 47.8% and a median time to progression of 210 days.

The treatment was associated with low rates of severe toxicity, with only 17.4% experiencing grade 3 or 4 hematological issues and 8.7% facing non-hematological toxicity, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). Uedo, N., Narahara, H., Ishihara, R., et al.[2018]

The study found that administering SN38 followed by ZD1839 in colon cancer cell lines resulted in a synergistic effect, enhancing the treatment's efficacy, while the reverse order led to antagonistic effects.

ZD1839 effectively inhibited EGFR phosphorylation without changing its expression, and it helped maintain SN38-induced DNA damage and apoptosis, suggesting a potential mechanism for improved therapeutic outcomes when using the sequential regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental study of effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with irinotecan]. Xu, JM., Li, YM., Wang, Y., et al.[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]

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]

The maximum tolerated dose (MTD) of irinotecan for patients with the UGT1A1 *1/*1 genotype is 310 mg/m2, while for those with the *1/*28 genotype, it is 260 mg/m2, indicating that genetic differences can influence drug tolerance in metastatic colorectal cancer treatment.

Bevacizumab does not significantly affect the pharmacokinetics of irinotecan, suggesting that the dosing adjustments based on genotype can be made without concern for altered drug metabolism due to this additional treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Toffoli, G., Sharma, MR., Marangon, E., et al.[2022]

Irinotecan, a derivative of camptothecin, has shown significant activity against recurrent malignant glioma in clinical trials, confirming its potential as a treatment option for this aggressive brain tumor.

Combining irinotecan with alkylating agents like BCNU or temozolomide enhances its antitumor effects, leading to ongoing Phase II trials to evaluate these combinations in adults with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Friedman, HS., Keir, ST., Houghton, PJ.[2018]

The combination of irinotecan, epirubicin, and capecitabine has shown an acceptable toxicity profile in an open-label phase I study involving patients with metastatic adenocarcinomas, indicating it may be a safe treatment option.

The study is still ongoing, as the dose-limiting toxicity has not yet been reached, and further investigations will determine the optimal sequencing of the regimen to enhance clinical efficacy in treating upper gastrointestinal malignancies and breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, epirubicin, and capecitabine in metastatic adenocarcinomas: preliminary results of a phase I study. Becerra, CR.[2018]

Irinotecan (CPT-11) demonstrated activity in treating recurrent malignant gliomas, with 15% of patients showing a confirmed partial response and 55% achieving stable disease for over 12 weeks, based on a study of 60 patients.

The treatment was associated with limited toxicity, primarily mild side effects like neutropenia and nausea, but the low plasma concentrations of the drug suggest that concurrent use of anticonvulsants and dexamethasone may reduce its effectiveness by enhancing drug clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan therapy in adults with recurrent or progressive malignant glioma. Friedman, HS., Petros, WP., Friedman, AH., et al.[2022]

In a phase II study involving 34 patients with advanced pancreatic cancer, CPT-11 (irinotecan) showed a partial response rate of 9%, with responses lasting around 7.2 to 7.8 months.

The treatment had manageable side effects, including diarrhea and leukocytopenia, with a median survival of 5.2 months, indicating that while CPT-11 is moderately effective, its side effects can be controlled with appropriate care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Wagener, DJ., Verdonk, HE., Dirix, LY., et al.[2020]

Irinotecan, when combined with cisplatin, shows promising antitumor activity in upper gastrointestinal cancers, with initial trials indicating a favorable response rate and manageable toxicity, particularly in gastric cancer.

A phase I trial confirmed the safety and tolerability of the weekly cisplatin and irinotecan regimen, and a phase II trial is currently evaluating its effectiveness in metastatic or recurrent esophageal cancer, suggesting potential as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and cisplatin in upper gastrointestinal malignancies. Enzinger, PC., Ilson, DH., Saltz, LB., et al.[2018]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

CPT-11 (irinotecan) is an effective anticancer drug that inhibits DNA topoisomerase 1 and has shown activity against solid tumors, including those resistant to other treatments, based on results from three European phase I trials.

The optimal dosage schedule for CPT-11 was determined to be 350 mg/m2 administered as an intravenous infusion once every 3 weeks, as it provided the highest dose intensity with manageable toxicity, particularly with the use of high-dose loperamide for diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies. Armand, JP., Extra, YM., Catimel, G., et al.[2020]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). [2018]

3. China pubmed.ncbi.nlm.nih.gov

[Experimental study of effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with irinotecan]. [2018]

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

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

5. 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]

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

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. [2022]

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

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. [2018]

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

Irinotecan, epirubicin, and capecitabine in metastatic adenocarcinomas: preliminary results of a phase I study. [2018]

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

Irinotecan therapy in adults with recurrent or progressive malignant glioma. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A novel irinotecan derivative ZBH-1207 with different anti-tumor mechanism from CPT-11 against colon cancer cells. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. [2020]

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

Irinotecan and cisplatin in upper gastrointestinal malignancies. [2018]

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

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. [2018]

14. England pubmed.ncbi.nlm.nih.gov

Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies. [2020]