Drug Combination for Liver Cancer

Overseen By Teresa Ware, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Florida

Disqualifiers: Pregnancy, Breastfeeding, Major surgery, 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: Unknown

Duration: 32 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three drugs—sorafenib, sonidegib, and irinotecan—to determine their safety and effectiveness in treating liver cancer, specifically hepatocellular carcinoma. Researchers aim to identify the optimal doses for this combination to enhance treatment outcomes while minimizing side effects. The study seeks participants diagnosed with advanced liver cancer who are not responding to other treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking advancements in liver cancer treatment.

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.

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

Research has shown that combining the drugs sorafenib, sonidegib, and irinotecan might be safe and manageable for treating liver cancer. Sorafenib, already used for advanced liver cancer, generally improves survival rates and is well-tolerated. Sonidegib and irinotecan are also under exploration for their potential benefits in cancer treatment. Researchers are testing these drugs together to determine if they can be safely combined without causing excessive side effects. The goal is to find the right dose that works effectively while ensuring patient safety.

The study is in Phase 2, which helps researchers assess the treatment's safety for a larger group and determine the optimal dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for liver cancer because it offers a fresh approach compared to existing therapies like sorafenib alone. The combination of irinotecan, sonidegib, and sorafenib is unique because it integrates multiple mechanisms of action, potentially enhancing effectiveness. Irinotecan is a chemotherapy drug that disrupts cancer cell division, sonidegib targets the Hedgehog signaling pathway known to be active in some cancers, and sorafenib inhibits tumor growth by blocking specific proteins. By combining these three drugs, the treatment aims to tackle liver cancer from different angles, which could lead to better outcomes for patients.

What evidence suggests that this trial's drug combination could be effective for liver cancer?

Research shows that sorafenib is already approved and effectively treats liver cancer, specifically hepatocellular carcinoma. Sorafenib blocks proteins that enable cancer cells to grow, slowing the disease. In this trial, participants will receive a combination of sorafenib with sonidegib and irinotecan. Studies suggest that combining sorafenib with other drugs like sonidegib and irinotecan might enhance its effectiveness. Although detailed information about this specific combination in humans remains limited, each drug alone has shown promise in fighting cancer. Early trials indicate that using these drugs together could enhance their effectiveness against liver cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Ali Zarrinpar, MD, PhD

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

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.

Life expectancy of 12 weeks or more

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Irinotecan
• Sonidegib
• Sorafenib

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.

How Is the Trial Designed?

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 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 Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Sun Pharmaceutical Industries Ltd

Collaborator

Trials

2

Recruited

30+

Published Research Related to This Trial

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]

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, 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) 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]

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 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]

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]

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]

ZBH-1207, a novel derivative of irinotecan, shows significantly higher cytotoxicity against colorectal cancer (CRC) cells compared to its parent compound CPT-11 and its active metabolite SN38, as demonstrated through in vitro studies on seven tumor cell lines.

The mechanism of action for ZBH-1207 involves inducing apoptosis and cell cycle arrest in CRC cells, with increased expression of active caspase-3 and PARP, indicating a robust activation of the apoptosis signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel irinotecan derivative ZBH-1207 with different anti-tumor mechanism from CPT-11 against colon cancer cells. Zhao, D., Wu, D., Zhang, G., 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) 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]

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 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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-06019

Drug Combination Therapy (Sorafenib, Sonidegib, and ... This phase I clinical trial tests the safety, side effects, and best dose of sonidegib and irinotecan when given together with sorafenib in treating ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9560750/

Small molecule inhibitors targeting the cancers - PMC As a pan‐HER TKI, poziotinib has also been tested in other tumor types and yielded promising antitumor efficacy with manageable toxicity in HER2‐positive tumors ...

3. go.drugbank.com go.drugbank.com/conditions/DBCOND0030090

Hepatocellular Carcinoma (DBCOND0030090) Liver Transplantation Results in Hepatocellular Carcinoma ... Sorafenib in Combination in Advanced or Metastatic Liver Cancer (Hepatocellular Carcinoma).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10631438/

Real-world clinical effectiveness of sorafenib among ... In the United States, sorafenib monotherapy was approved in 2007 for first-line (1L) treatment of patients with unresectable hepatocellular carcinoma (uHCC) ...

5. europepmc.org europepmc.org/article/pmc/pmc8455877

Role of Small Molecule Targeted Compounds in Cancer Sorafenib is applied in renal cell cancer, hepatocellular carcinoma and thyroid cancer, based on FDA approval. Sorafenib is a multikinase inhibitor of Raf-1, B- ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4918267/

Sorafenib in advanced hepatocellular carcinoma Patients who received a half dose of sorafenib for more than 70% of treatment period had significantly longer treatment duration (median 6.8 vs 3 months) and ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0304419X1930160X

Harnessing the therapeutic potential of anticancer drugs ... For example, Nexavar® (sorafenib tosylate), an orally administered kinase inhibitor is used in the treatment of hepatocellular and renal cell carcinoma [17,18].