HBI-2438 for Cancer with KRAS G12C Mutation

Not currently recruiting at 13 trial locations

Overseen By Gloria Lee, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: HUYABIO International, LLC.

Must not be taking: Steroids, Immunosuppressants, KRAS inhibitors

Disqualifiers: Concurrent malignancy, CNS metastases, Cardiovascular disease, Autoimmune diseases, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called HBI-2438 for individuals with advanced solid tumors that have a specific genetic change, the KRAS G12C mutation. The goal is to determine the optimal dose of HBI-2438 for future studies and to understand how the body processes the drug. Individuals with this mutation who have not found success with other treatments might be suitable candidates. Participants will take the medication orally, starting with small doses that gradually increase to identify the best amount. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before starting the trial.

Is there any evidence suggesting that HBI-2438 is likely to be safe for humans?

Research shows that HBI-2438 is a new treatment under testing for cancers with a specific change in the KRAS G12C gene. This oral treatment works to block the change that promotes cancer growth.

In lab studies, HBI-2438 has shown promise in stopping tumor growth. However, since human testing is still in its early stages, information about its safety remains limited. The current trial focuses on finding the right dose and checking for any side effects.

This is a Phase 1 trial, which aims to determine the treatment's safety and optimal dose. As the first step in human testing, this phase involves more unknowns. However, it helps ensure the treatment's safety before advancing to later stages with more patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cancer?

HBI-2438 is unique because it targets the KRAS G12C mutation specifically, which is a common driver in several cancers but has been challenging to treat with existing therapies. While most treatments for cancers with this mutation have relied on general chemotherapy or targeted therapies with broader focus, HBI-2438 works by directly inhibiting the mutated KRAS protein, potentially offering more precise and effective intervention. Researchers are excited about this treatment because its oral administration and targeted action could lead to fewer side effects and improved outcomes for patients compared to the current standards of care.

What evidence suggests that HBI-2438 might be an effective treatment for cancer with KRAS G12C mutation?

Previous studies targeting the KRAS G12C mutation in cancer patients have shown promise. One study with patients having this mutation in non-small cell lung cancer (NSCLC) reported that 40.5% of patients responded to the treatment, and 91.9% had their disease controlled. These results suggest that drugs targeting the KRAS G12C mutation can effectively manage the disease. Researchers are developing new drugs targeting KRAS mutations, representing a major breakthrough after many years of research. HBI-2438, which participants in this trial will receive, is one such experimental treatment that aims to block KRAS G12C, potentially offering new hope for patients with these hard-to-treat cancers. ^{4 6 7 8 9}

Who Is on the Research Team?

Alberto Bessudo, MD

Principal Investigator

California Cancer Associates for Research and Excellence, Inc. (cCare)

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have a specific genetic change called KRAS G12C mutation. They should be able to swallow pills, have at least one measurable tumor, and good organ function. They must not benefit from standard treatments and should not have serious heart issues or unresolved severe side effects from past cancer therapy.

Inclusion Criteria

I can swallow pills and don't have major stomach or intestine issues.

At least 1 measurable target lesion that meets the definition of RECIST v1.1

I am fully active or can carry out light work.

Exclusion Criteria

I have brain metastases but haven't needed steroids for them in the last 4 weeks.

I have not been treated with KRAS G12C inhibitors before.

I haven't taken high-dose steroids or immunosuppressants in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive HBI-2438 in ascending doses to determine the maximum tolerated dose

21 days per cycle

Multiple visits for dose escalation monitoring

Expansion

Additional participants with brain metastases receive HBI-2438 at the recommended dose

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• HBI-2438

Trial Overview

The study tests different doses of HBI-2438 in patients to find the highest dose they can take without too many side effects (maximum tolerated dose) and to see how the body processes the drug (pharmacokinetic profile).

How Is the Trial Designed?

Group I: Dose Escalation and Expansion Experimental Treatment 1 Intervention

HBI-2438 will be given orally in ascending doses (escalation cohort), until the maximum tolerated dose or recommended Phase 2 dose is reached. Up to 6-8 patients will then be enrolled in the expansion cohort at the recommended dose.

Who Is Running the Clinical Trial?

HUYABIO International, LLC.

Lead Sponsor

Trials

12

Recruited

960+

Published Research Related to This Trial

KRAS mutations are found in about 30% of all cancers and nearly 50% of metastatic colorectal cancer cases, playing a crucial role in cancer progression by activating pathways that promote cell growth and migration.

The KRAS p.G12C mutation is linked to a poorer prognosis in metastatic colorectal cancer and is emerging as a promising target for new therapies, highlighting the potential for developing specific inhibitors to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS p.G12C Mutation in Metastatic Colorectal Cancer: Prognostic Implications and Advancements in Targeted Therapies. Ottaiano, A., Sabbatino, F., Perri, F., et al.[2023]

In a study of non-small cell lung cancer (NSCLC) patients, up to 8% had co-occurring KRAS mutations alongside the common KRAS G12C mutation, which can affect treatment outcomes.

The presence of additional KRAS mutations, particularly KRAS c.35G>T, led to resistance against the G12C-specific inhibitor AZ'8037, indicating that comprehensive genotyping of KRAS mutations is crucial for effective treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition. Vaclova, T., Chakraborty, A., Sherwood, J., et al.[2022]

The KRASp.G12C mutation, found in 12% of advanced non-small cell lung cancer (NSCLC) cases, is a promising biomarker for selecting patients who may benefit from targeted therapies like sotorasib, which has shown significant efficacy in improving progression-free survival and quality of life compared to traditional treatments.

Despite the potential of KRAS inhibitors, the presence of co-mutations and resistance mechanisms in KRAS mutant NSCLC complicates treatment, highlighting the need for combination therapies and the identification of predictive biomarkers to personalize treatment strategies for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun. Bungaro, M., Novello, S., Passiglia, F.[2023]

In a study of 1,194 patients with KRAS-mutant non-small cell lung cancer (NSCLC), 46% had KRAS G12C mutations, which were associated with a higher tumor mutation burden and PD-L1 expression compared to non-G12C mutations.

Despite these differences, the overall survival rates and responses to therapies, including immune checkpoint inhibitors, were similar between patients with KRAS G12C and non-G12C mutations, suggesting that treatment strategies should be tailored to the specific characteristics of KRAS G12C mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C-Mutant Non-Small Cell Lung Cancer. Arbour, KC., Rizvi, H., Plodkowski, AJ., et al.[2022]

KRAS is a commonly mutated oncogene in aggressive solid tumors like colorectal, lung, and pancreatic cancer, making it a critical target for cancer treatment.

Recent advancements have led to the approval of specific inhibitors for the KRAS G12C mutation, such as adagrasib and sotorasib, for treating lung cancer, marking a significant step forward in targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Mutated KRAS Genes to Treat Solid Tumours. Krishnan, T., Roberts-Thomson, R., Broadbridge, V., et al.[2022]

The discovery of the KRAS G12C inhibitor represents a significant advancement in treating cancers with KRAS mutations, which were previously considered 'undruggable' due to the instability of RAS proteins.

Combining KRAS G12C inhibitors with immune checkpoint inhibitors (ICIs) may enhance treatment efficacy and help overcome resistance in patients with KRAS-mutant cancers, highlighting a promising new strategy in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRAS: Crossroads of Signaling and Immune Inhibition. Kato, S., Fujiwara, Y., Hong, DS.[2022]

KRAS G12C mutations are important in several cancers, particularly non-small cell lung cancer (NSCLC), where targeted therapies have shown more success compared to colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC).

The review discusses the biochemical mechanisms of KRAS targeting, treatment resistance, and ongoing clinical trials for KRAS G12C inhibitors in CRC, indicating a need for further research to improve therapeutic outcomes in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Qunaj, L., May, MS., Neugut, AI., et al.[2023]

In a study of 604 patients with surgically resected lung adenocarcinoma, those with KRASG12C mutations experienced worse disease-free survival (DFS) compared to patients with other KRAS mutations, indicating a more aggressive disease course.

KRASG12C tumors exhibited higher rates of lymphovascular invasion and a greater tumor mutation burden, suggesting that these tumors have distinct and more aggressive genomic features, highlighting the need for targeted therapies like KRASG12C inhibitors to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma. Jones, GD., Caso, R., Tan, KS., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12207871/

KRAS mutated NSCLC: past, present, and future directions in ...

KRAS is the most mutated oncogenic driver gene in NSCLC with mutation rates approaching 30% and patients with these mutations are known to have poor outcomes.

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05485974

A Dose Escalation Study of HBI-2438 in Patients With Solid ...

A Phase 1 dose escalation study in patients with advanced solid tumors harboring KRAS G12C mutation to determine the maximum tolerated dose and recommended ...

3.

ehoonline.biomedcentral.com

ehoonline.biomedcentral.com/articles/10.1186/s40164-023-00453-8

The current landscape of using direct inhibitors to target KRAS ...

In the recently published phase 1 study among KRAS G12C mutant NSCLC patients, a confirmed ORR and disease control rate (DCR) of 40.5% and 91.9% ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11593150/

Clinical Advances and Challenges in Targeting KRAS ...

After 40 years of research, patients with KRAS G12C-mutated lung cancer can now benefit from novel KRAS-targeting drugs. However, the efficacy is far from ...

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S0169500224004203

The next-generation KRAS inhibitors…What comes after ...

Currently, sotorasib and adagrasib have been approved by the US FDA to treat patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05485974

NCT05485974 | A Dose Escalation Study of HBI-2438 in ...

HBI-2438 is an orally administered KRAS G12C Inhibitor and will be dosed once daily throughout the escalation and expansion phase. Up to 44 subjects will be ...

7.

aacrjournals.org

aacrjournals.org/mct/article/22/12_Supplement/A097/730531/Abstract-A097-HBI-2438-HUYABIO-selective-KRASG12C

HBI-2438, HUYABIO selective KRAS G12C inhibitor with BBB ...

HBI-2438, HUYABIO selective KRAS G12C inhibitor with BBB penetration, inhibited tumor growth in a metastatic brain model as single agent.

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10543081/

Prognostic and therapeutic impact of the KRAS G12C ...

This paper reviews the literature on KRAS G12C mutations, with a focus on the epidemiology and prognosis of KRAS G12C within CRC.

9.

lungcancerjournal.info

lungcancerjournal.info/article/S0169-5002(24)00420-3/fulltext

The next-generation KRAS inhibitors…What comes after ...

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.