Divarasib for Liver Disease

Not currently recruiting at 3 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called divarasib to understand its effects in people with liver impairment. Participants will receive a single dose of the treatment, and researchers will observe its effects. The study includes several groups to assess responses at different levels of liver impairment. Suitable candidates have stable liver impairment or cirrhosis for at least six months. As a Phase 1 trial, participants will be among the first to receive this treatment, aiding researchers in understanding its effects.

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.

Is there any evidence suggesting that Divarasib is likely to be safe for humans?

Research has shown that divarasib has a good safety record in early studies. Most reported side effects were mild, manageable, and resolved on their own. This indicates that any side effects were not serious and could be controlled or disappeared without treatment. Although more research is needed to confirm these results, early data suggest that participants generally tolerate divarasib well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for liver disease focus on managing symptoms or slowing disease progression, often through medications like antivirals or immunosuppressants. But Divarasib stands out because it targets the underlying disease mechanisms at the molecular level. Researchers are excited about Divarasib because it offers a novel approach by potentially interrupting specific pathways involved in liver disease progression. Additionally, its administration as a single oral dose could simplify treatment regimens and improve patient compliance. These features give Divarasib the potential to be a game-changer in how liver diseases are treated.

What evidence suggests that divarasib might be an effective treatment for liver disease?

Research shows that divarasib is a promising treatment, particularly for solid tumors with a specific change called KRAS G12C. Studies have demonstrated a strong initial response rate of 53.4% in these tumors, which is impressive. Divarasib has also achieved good overall response rates (ORR) and disease control rates (DCR), helping to keep the disease stable. Patients taking divarasib have experienced long-lasting effects and a good safety profile, with manageable side effects. Although more research is needed on its use in liver disease, early data suggests promising effectiveness. Participants in this trial will receive a single oral dose of divarasib, and the study will further explore its potential benefits for liver disease. ^{2 6 7 8 9}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Genentech, Inc.

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11251097/

Efficacy and toxicity of KRASG12C inhibitors in advanced ... KRAS G12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors.

2. nature.com nature.com/articles/s41591-023-02696-8

Divarasib plus cetuximab in KRAS G12C-positive ... The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04449874

NCT04449874 | A Study to Evaluate the Safety, ... This is a Phase I dose-escalation and dose-expansion study that will evaluate the safety, pharmacokinetics (PK), and preliminary activity of GDC-6036

4. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/metabolic-disorder/Liver_Failure/a-study-to-evaluate-the-pharmacokinetics-of-divarasib-i-38270.html

Clinical trial for Liver Failure-Genentech A Member of th... A Study to Evaluate the Pharmacokinetics of Divarasib in Healthy Participants and Participants With Impaired Hepatic Function · Basic Details · Study Summary.

5. journals.sagepub.com journals.sagepub.com/doi/10.1177/11795549251331759

Potency and Safety of KRAS G12C Inhibitors in Solid Tumors Garsorasib achieved an ORR of 40.5%, and Divarasib showed a notably higher ORR of 53.4%, suggesting that Divarasib may induce a stronger initial ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572139/

An updated overview of K-RAS G12C inhibitors in advanced ... Early clinical data indicate that divarasib may offer better efficacy and a favorable safety profile, although additional studies are needed to confirm these ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S155608642401503X

P3.12D.07 Divarasib Versus Adagrasib or Sotorasib in ... The observed adverse events were mostly low grade, manageable, and reversible. The phase 3 trial presented here will evaluate the efficacy and ...

8. onclive.com onclive.com/view/divarasib-plus-cetuximab-demonstrates-promising-clinical-activity-and-manageable-safety-in-kras-g12c-mutant-crc

Divarasib Plus Cetuximab Demonstrates Promising ... Early efficacy data for patients treated at all dose levels demonstrated a confirmed ORR of 24%; patients treated with a 400-mg dose (n = 39) ...

9. cancernetwork.com cancernetwork.com/view/divarasib-combo-appears-promising-in-pretreated-kras-g12c-nsclc

Divarasib Combo Appears “Promising” in Pretreated KRAS ... The divarasib combination particularly demonstrated “promising” activity in a cohort of patients who received prior KRAS G12C inhibitors.