BAY2862789 for Non-Small Cell Lung Cancer

Recruiting in Palo Alto (17 mi)

+25 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Bayer

Must not be taking: Immunosuppressants, Corticosteroids, Live vaccines, others

Disqualifiers: Transplant, Immunodeficiency, Autoimmune, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Researchers are looking for a better way to treat people who have advanced solid tumors including a specific kind of lung cancer (non-small cell lung cancer, NSCLC). Advanced solid tumors are types of cancer that have spread to nearby tissue, lymph nodes, and/or to distant parts of the body and that are unlikely to be cured or controlled with currently available treatments. BAY2862789 works by blocking an enzyme in T-cells, thereby activating them. T-cells are a type of immune cell that are known to have an anti-cancer effect. The main purpose of this first-in-human study is to learn: * how safe different doses of BAY2862789 are, * the degree to which medical problems caused by BAY2862789 can be tolerated (also called tolerability), * what maximum amount (dose) can be given, and * how BAY2862789 moves into, through and out of the body. To answer this, the researchers will look at: * the number and severity of medical problems participants have after taking BAY2862789 for each dose level. These medical problems are also referred to as adverse events. An adverse event is considered "serious" when it leads to death, puts the participants' lives at risk, requires hospitalization, causes disability, causes a baby being born with medical problems or is otherwise medically important. * the (average) total level of BAY2862789 in the blood (also called AUC) after intake of single and multiple doses. * the (average) highest level of BAY2862789 in the blood (also called Cmax) after intake of single and multiple doses. Doctors and their team keep track of all medical problems that participants have during the study, even if they do not think the medical problem might be related to the study treatment. In addition, the researchers want to know if and how the participants' tumors change after taking BAY2862789. The dose escalation will be done to find the most appropriate dose that can be given. For this, each participant will receive one of the increasing doses of Bay 2862789. More groups might be investigated based on new data that emerges. For this, each participant will receive one of the increasing doses of BAY2862789. Participants in the study will take the study treatment until their tumor gets worse (also known as 'disease progression'), until they have medical problems, until they leave the study, or until the study is terminated. Each participant will be in the study for several months, including a test (screening) phase of up to 28 days, few months of treatment depending on the participant's benefit, and a follow up phase after the end of treatment. The following approximate numbers of visits to the study site are planned: two during the screening phase, six in the first treatment month, one to three per month in the following periods. During the study, the study team will: * take blood and urine samples * do physical examinations * check vital signs such as blood pressure, heart rate, body temperature * examine heart health using ECG (electrocardiogram) * check cancer status using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scans * take tumor samples (if required) * pregnancy test The treatment period ends with a visit no later than 7 days after the last BAY2862789 dose. The study doctors and their team will check the participants' health and any changes in cancer about 30 and 90 days after the last dose and every 12 weeks thereafter. This follow-up period ends if the cancer worsens, if a new anti-cancer treatment is started, or until the participant leaves the study. In addition, the study doctors and their team will contact the participant every 12 weeks to learn about the participant's survival. This ends no later than 12 months after the last participant started treatment or by the end of the study, whichever comes first. If the study participant benefits from treatment, continuation of treatment with BAY2862789 beyond the duration of this study might be possible.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had certain treatments like systemic anti-cancer therapy or investigational agents within 4 weeks before starting the trial. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug BAY2862789 for non-small cell lung cancer?

The research highlights the role of GLK (also known as MAP4K3) in promoting lung cancer metastasis and recurrence, suggesting that targeting this pathway could be beneficial. Although not directly about BAY2862789, these findings imply that inhibiting GLK might help reduce cancer spread and improve outcomes in non-small cell lung cancer.

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Eligibility Criteria

Adults with advanced solid tumors, including non-small cell lung cancer (NSCLC), who have tried all beneficial treatments or find them unsuitable. They must be in good physical condition, agree to use contraception for 6+ months post-treatment, and provide tumor samples. NSCLC patients should've had PD1/L-1 and platinum therapy; those with certain mutations are ineligible.

Inclusion Criteria

Agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment

I am fully active or restricted in physically strenuous activity but can do light work.

My tumor was tested for specific genetic changes as per guidelines.

Exclusion Criteria

Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment

I have another cancer that is growing or was treated in the last 3 years.

I have new brain metastases found on a recent MRI/CT scan.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

2 visits (in-person)

Treatment

Participants receive BAY2862789 in a dose escalation format to determine the maximum tolerated dose and assess safety and efficacy

Several months

6 visits in the first month, 1-3 visits per month thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment, with health checks and cancer status assessments

Up to 12 months

Every 12 weeks

Open-label extension (optional)

Participants may continue treatment with BAY2862789 if they benefit from it, beyond the main study duration

Participant Groups

BAY2862789 is being tested for safety at various doses, tolerability, maximum dose levels, and how it affects the body and tumors. It's a first-in-human study involving two parts: finding an appropriate dose then expanding that dose to more participants as a tablet until disease progression or unacceptable side effects occur.

Group I: Dose Escalation Experimental Treatment 1 Intervention

Participants will take BAY2862789 oral doses.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Mississippi Medical Center Jackson, MS

Advent Health Orlando, FL

South Texas Accelerated Research Therapeutics, LLC San Antonio, TX

Advent Health Celebration, FL

More Trial Locations

Who Is Running the Clinical Trial?

Bayer Lead Sponsor

References

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

MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1. [2021] Overexpression of the serine/threonine kinase GLK/MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif-containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1. SIGNIFICANCE: These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.

2. England pubmed.ncbi.nlm.nih.gov

LKB1 mutations are not associated with the efficacy of first-line and second-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC): a post hoc analysis of the TAILOR trial. [2021] Label="PURPOSE">In patients with advanced lung adenocarcinoma, the impact of LKB1 mutations on cytotoxic chemotherapy efficacy remains poorly explored. Here, we aimed at investigating the potential impact of LKB1 mutational status on chemotherapy efficacy in advanced non-small-cell lung cancer (NSCLC) patients enrolled in the TArceva Italian Lung Optimisation tRial (TAILOR) trial.

3. Switzerland pubmed.ncbi.nlm.nih.gov

Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations. [2020] Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart. We validated the Birinapant cells response and its mechanism of action to be dependent on LKB1 deletion. Indeed, we demonstrated the ability of this compound to induce apoptosis, through activation of caspases in the LKB1-deleted clone only. Expanding our results, we found that the presence of KRAS mutations could mediate Birinapant resistance in a panel of NSCLC cell lines. The combination of Birinapant with Ralimetinib, inhibitor of p38α, restores the sensitivity of LKB1- and KRAS-mutated cell lines to the IAP inhibitor Birinapant. Our study shows how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. In addition, combination of Birinapant and a KRAS pathway inhibitor, as Ralimetinib, could be useful for patients with LKB1 and KRAS-mutated NSCLC.

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

GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer. [2022] Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of total lung cancers; 40% to 60% of NSCLC patients die of cancer recurrence after cancer resection. Since GLK (also named MAP4K3) induces activation of NF-κB, which contributes to tumor progression, we investigated the role of GLK in NSCLC. GLK protein levels of 190 samples from pulmonary tissue arrays and 58 pulmonary resection samples from stage I to stage III NSCLC patients were studied using immunohistochemistry or immunoblotting. High levels of GLK proteins were detected in pulmonary tissues from NSCLC patients. Elevated GLK protein levels were correlated with increased recurrence risks and poor recurrence-free survival rates in NSCLC patients after adjusting for pathologic stage, smoking status, alcohol status, and EGFR levels. Thus, GLK is a novel prognostic biomarker for NSCLC recurrence.

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

Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one Scaffold. [2021] Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.