BI 1701963 + Trametinib for Advanced Cancer

Recruiting at 9 trial locations

Overseen By Boehringer Ingelheim

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Boehringer Ingelheim

Must not be taking: Ras inhibitors, Mapk inhibitors

Disqualifiers: Uncontrolled hypertension, Heart failure, Brain metastases, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: As long as participants benefit and can tolerate treatment

71 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot have had anticancer chemotherapy within 3 weeks before starting the trial drugs. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination BI 1701963 and Trametinib for advanced cancer?

Trametinib, when used in combination with another drug called dabrafenib, has shown positive results in treating certain types of lung cancer and melanoma, with good response rates and disease control. This suggests that combining Trametinib with other drugs, like BI 1701963, might also be effective in treating advanced cancers. ^{1 2 3 4 5}

What safety information is available for the combination of BI 1701963 and Trametinib in treating advanced cancer?

Trametinib, also known as Mekinist, has been studied for safety in various cancers, including melanoma. It is known to cause some adverse events (unwanted side effects), but these are generally manageable and do not always lead to stopping the treatment. In studies, trametinib has been combined with other drugs, and while adverse events can occur, they often lead to dose adjustments rather than discontinuation. ^{2 4 6 7 8}

What makes the drug combination BI 1701963 and Trametinib unique for advanced cancer?

The combination of BI 1701963 and Trametinib is unique because it targets the MAPK pathway, which is often deregulated in many cancers, by using Trametinib, a MEK inhibitor, alongside BI 1701963, potentially offering a novel approach to treating advanced cancers that may not respond well to other treatments. ^{1 2 4 9 10}

What is the purpose of this trial?

This is a study in adults with advanced cancer (solid tumours) in whom previous chemotherapy was not successful. Only people who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes cancer grow faster. The study tests 2 medicines called BI 1701963 and trametinib. BI 1701963 prevents reactivation of KRAS. In this study, BI 1701963 is given to humans for the first time. Trametinib is an approved medicine (MEK inhibitor). The purpose of this study is to find out the highest dose of BI 1701963 alone and in combination with trametinib the participants can tolerate. Another purpose is to check whether BI 1701963 in combination with trametinib is able to make tumours shrink. Participants can stay in the study as long as they benefit from treatment and can tolerate it. During this time, they get tablets of BI 1701963 and trametinib once daily. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participants' health.

Eligibility Criteria

Adults with advanced cancer (solid tumors) and a specific KRAS mutation, who have seen their disease progress despite standard treatments. They must be over 18, not pregnant if female of childbearing potential, and have at least one measurable tumor lesion. Participants should be in good physical condition (ECOG status 0 or 1) and have adequate organ function.

Inclusion Criteria

I have signed and understand the consent form for this trial.

I am a woman who can have children and have a negative pregnancy test.

I have received both chemotherapy and immunotherapy.

Exclusion Criteria

Mean resting corrected QT interval (QTcF) >470 msec

I do not have active or symptomatic brain metastases.

I haven't had cancer chemotherapy in the last 3 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of BI 1701963 alone and in combination with trametinib to determine the maximum tolerated dose

8-12 weeks

Weekly visits for dose adjustments and monitoring

Treatment

Participants receive daily tablets of BI 1701963 and trametinib, with regular monitoring of tumour size and health checks

As long as participants benefit and can tolerate treatment

Regular visits for monitoring and health checks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BI 1701963
• Trametinib

Trial Overview The trial is testing the safety and effectiveness of two drugs: BI 1701963 alone, which is new to humans, and combined with trametinib, an approved MEK inhibitor. The goal is to determine the highest tolerable doses that can shrink tumors in participants who will take these daily as tablets.

Participant Groups

Group I: BI 1701963 monotherapy Experimental Treatment 1 Intervention

Group II: BI 1701963 + Trametinib Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Boehringer Ingelheim

Lead Sponsor

Trials

2,566

Recruited

16,150,000+

Findings from Research

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

Trametinib is an effective oral MEK inhibitor specifically targeting MEK1 and MEK2, approved in the US for treating unresectable or metastatic malignant melanoma with specific BRAF mutations, demonstrating its antineoplastic activity.

The drug is currently undergoing extensive clinical development for various cancers, including phase III trials in combination with dabrafenib for melanoma and phase II trials for pancreatic cancer and non-small cell lung cancer, indicating its potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib: first global approval. Wright, CJ., McCormack, PL.[2023]

The combination of trametinib and afuresertib was poorly tolerated at the starting dose, leading to dose-limiting toxicities, but an intermittent dosing schedule showed better tolerability, suggesting a potential for safer administration.

Among 20 patients with advanced solid tumors, the study reported one partial response and four cases of stable disease, indicating some efficacy, but the overall response rate was low, warranting further investigation into alternative dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Tolcher, AW., Patnaik, A., Papadopoulos, KP., et al.[2015]

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a study of 27 metastatic BRAFV600mut melanoma patients, higher plasma concentrations of dabrafenib were linked to a greater likelihood of adverse events (AEs) that required dose reductions, with a significant threshold identified at 48 ng/ml.

While dabrafenib showed a strong correlation with AEs, trametinib concentrations did not differ significantly between patients who experienced AEs and those who did not, suggesting that dabrafenib's plasma levels are more critical for managing treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Rousset, M., Dutriaux, C., Bosco-Lévy, P., et al.[2018]

In a study involving 32 patients with solid tumors and lymphomas harboring non-V600 BRAF mutations, the MEK inhibitor trametinib showed limited efficacy, with only 1 patient (3%) achieving a partial response and a clinical benefit rate of 34%.

The median progression-free survival was 1.8 months and overall survival was 5.7 months, indicating that trametinib did not meet its primary endpoint of demonstrating significant clinical activity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). Johnson, DB., Zhao, F., Noel, M., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]

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

Trametinib: first global approval. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. [2016]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. [2015]

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

Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer. [2022]

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

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. [2018]

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

Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). [2023]

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

Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. [2022]