Divarasib for Liver Disease

Overseen By Reference Study ID Number: GP45713 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Genentech, Inc.

Disqualifiers: Metabolic, Cardiovascular, Neurological, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1, open-label, single-dose, parallel-cohort study to determine the pharmacokinetics (PK) of divarasib in healthy participants and participants with varying degrees of hepatic impairment, as defined by Child-Pugh classification.

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's best to discuss this with the trial team or your doctor.

What safety data exists for Divarasib or similar treatments?

There is no specific safety data available for Divarasib, but similar treatments like regorafenib, a type of tyrosine kinase inhibitor, have been associated with liver-related side effects. These include increased levels of liver enzymes and bilirubin, which can indicate liver damage, so regular liver function tests are recommended. ^{1 2 3 4 5}

Research Team

Clinical Trials

Principal Investigator

Genentech, Inc.

Eligibility Criteria

This trial is for male or female adults who are not able to bear children, have a BMI between 18.0 and 45.0 kg/m2, and suffer from chronic liver disease that's been stable for at least one month before screening. It excludes those with fluctuating or unstable liver conditions.

Inclusion Criteria

I have had a stable liver condition for more than 6 months.

My liver function is impaired but has been stable for the last month.

My BMI is between 18.0 and 45.0.

Exclusion Criteria

My heart's electrical cycle is longer than normal, and I have liver issues.

My liver disease has worsened in the last month.

I have had fluid removed from my abdomen within the last 3 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single oral dose of Divarasib on Day 1

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and pharmacokinetics after receiving the dose

2-4 weeks

Treatment Details

Interventions

• Divarasib

Trial Overview The study tests how Divarasib, a drug under investigation, behaves in the body (its pharmacokinetics) of healthy individuals compared to those with different levels of liver impairment as classified by the Child-Pugh score.

Participant Groups

Group I: Cohort 4 Experimental Treatment 1 Intervention

Participants will receive a single oral dose of Divarasib on Day 1.

Group II: Cohort 3 Experimental Treatment 1 Intervention

Participants will receive a single oral dose of Divarasib on Day 1.

Group III: Cohort 2 Experimental Treatment 1 Intervention

Participants will receive a single oral dose of Divarasib on Day 1.

Group IV: Cohort 1 Experimental Treatment 1 Intervention

Participants will receive a single oral dose of Divarasib on Day 1.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

A meta-analysis of 2,213 subjects from 14 trials revealed that regorafenib, an oral multi-kinase inhibitor, significantly increases the risk of hepatic toxicities, with notable elevations in liver enzymes such as AST (32% incidence) and ALT (27% incidence).

Patients treated with regorafenib showed a high-grade risk of bilirubin elevation (5%) and AST elevation (6%), indicating the need for regular monitoring of liver function during treatment to manage potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk of regorafenib-induced hepatotoxicity. Zhao, B., Zhao, H.[2019]

A meta-analysis of nine randomized controlled trials showed that PD-1 inhibitors significantly increase the risk of developing all-grade hepatic adverse events (AEs) in cancer patients, although high-grade AEs were not significantly affected compared to chemotherapy or everolimus.

The combination of nivolumab and ipilimumab resulted in a notably higher risk of all-grade and high-grade hepatic AEs compared to ipilimumab alone, indicating that while PD-1 inhibitors can be effective, they also carry a risk of liver-related side effects, primarily of lower severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Zhang, X., Ran, Y., Wang, K., et al.[2018]

In a study of 311 hepatocellular carcinoma patients treated with sorafenib, 88 patients experienced dermatological adverse events, with 7.4% developing skin lesions that required histological examination, including keratoacanthomas and squamous-cell carcinomas.

The skin lesions showed significant molecular changes, such as HRAS and KRAS mutations and increased MAPK pathway activation, but these did not negatively affect patient prognosis, suggesting that while monitoring is necessary, these lesions may indicate a compensatory response rather than a worsening condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutational profile of skin lesions in hepatocellular carcinoma patients under tyrosine kinase inhibition: a repercussion of a wide-spectrum activity. da Fonseca, LG., Fuster-Anglada, C., Carrera, C., et al.[2021]

This meta-analysis of 12 randomized control trials found that the use of tyrosine kinase inhibitors (TKIs) significantly increases the risk of high-grade hepatotoxicity, with odds 4.35 times higher compared to control groups.

Patients receiving TKIs are at a greater risk for liver enzyme elevations, specifically alanine transaminase and aspartate transaminase, indicating the need for careful monitoring of liver function during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Teo, YL., Ho, HK., Chan, A.[2022]

In a meta-analysis of 3691 patients treated with tyrosine kinase inhibitors (TKIs), hepatotoxicity occurred in 23-40% of patients, indicating a significant risk of liver toxicity associated with these medications.

Despite the high incidence of liver enzyme increases, only about 5% of patients experienced severe (high grade) toxicity, suggesting that while monitoring is essential, most patients may tolerate TKIs without severe liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy. Iacovelli, R., Palazzo, A., Procopio, G., et al.[2021]

References

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

Incidence and risk of regorafenib-induced hepatotoxicity. [2019]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. [2018]

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

Mutational profile of skin lesions in hepatocellular carcinoma patients under tyrosine kinase inhibition: a repercussion of a wide-spectrum activity. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy. [2021]