BI 1701963 + Trametinib for Advanced Cancer

Not currently recruiting at 10 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial targets individuals with advanced cancer who have not responded to previous chemotherapy and possess a specific KRAS mutation that accelerates cancer growth. It tests a new drug, BI 1701963 (an experimental treatment), both alone and with trametinib (also known as Mekinist, a cancer therapy), to determine the highest tolerable dose and its effectiveness in shrinking tumors. Participants will take tablets daily and undergo regular monitoring of tumor size and health. This trial suits those with a KRAS mutation in their tumor who have experienced disease progression despite other treatments. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new drug.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that trametinib, one of the medicines in the trial, is already approved for use, indicating known safety, which is promising for cancer treatment.

For BI 1701963, currently undergoing its first human tests, studies suggest it is generally well tolerated. In one study involving 31 patients, no severe side effects were reported, and some participants showed positive responses. This suggests potential safety, though it remains early in the testing process.

The trial primarily aims to determine the right dose and identify any unwanted effects, with a strong focus on safety. Participants will have their health closely monitored by doctors throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about BI 1701963 and Trametinib for advanced cancer because they offer a new approach to treatment. Unlike standard therapies that often target the cancer cells directly, BI 1701963 inhibits a protein called SOS1, which is involved in the signaling pathways that drive cancer cell growth. This mechanism can potentially block the cancer's ability to grow and spread more effectively. Additionally, Trametinib targets the MEK pathway, another key player in cancer progression, providing a complementary attack on the cancer cells. Together, these treatments offer a promising strategy that could enhance effectiveness compared to existing options.

What evidence suggests that BI 1701963 and trametinib could be effective for advanced cancer with a KRAS mutation?

Research has shown that trametinib, a drug that blocks certain proteins involved in cancer growth, effectively treats some cancers, with about 47% of patients with biliary tract cancer responding to it. In this trial, some participants will receive BI 1701963 as a monotherapy, a new treatment designed to stop a common cancer growth pathway called KRAS. Early studies and lab tests indicate that BI 1701963 can effectively block KRAS, potentially preventing cancer cells from multiplying. Other participants will receive a combination of BI 1701963 and trametinib. Together, these drugs have shown promising results in shrinking tumors, suggesting that the combination might be more effective than using either drug alone. These findings offer hope that this combination could help patients with KRAS-mutated cancers. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04111458

NCT04111458 | A Study to Test Different Doses of BI ... 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04835714

A Study to Find a Safe and Effective Dose of BI 1701963 ... A KRAS mutation makes cancer grow faster. The study tests 2 medicines called BI 1701963 and BI 3011441. BI 1701963 and BI 3011441 prevent activation of KRAS.

3. aacrjournals.org aacrjournals.org/cancerres/article/81/13_Supplement/CT210/669966/Abstract-CT210-Trial-in-Process-Phase-1-studies-of

Trial in Process: Phase 1 studies of BI 1701963, a SOS1 ... Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9271439/

The treatment of advanced non-small cell lung cancer ... A phase I study of BI-1701963 in KRAS-positive advanced cancers is being conducted (NCT04111458) but preliminary results are available and of 31 patients ...

5. boehringer-ingelheim.com boehringer-ingelheim.com/us/media/press-releases/boehringer-ingelheim-advances-first-pan-kras-inhibitor-bi-1701963-clinical-testing

BI Advances First Pan-KRAS Inhibitor Boehringer Ingelheim today presented promising preclinical data from its pan-KRAS program including the novel, oral inhibitor BI 1701963.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.TPS3651

A phase I, open-label, dose-escalation trial of BI 1701963 ... A first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. Primary objectives are to determine the maximum tolerated ...

7. fightcolorectalcancer.org fightcolorectalcancer.org/clinical-trial/nct04111458/

A Study to Test Different Doses of BI 1701963 Alone and ... Unlike other KRAS inhibitors currently in clinical trials, this pan-KRAS inhibitor aims to hit all the most prevalent KRAS mutant alleles, by targeting SOS1 as ...

8. researchgate.net researchgate.net/publication/345220039_Abstract_1091_BI-3406_and_BI_1701963_Potent_and_selective_SOS1KRAS_inhibitors_induce_regressions_in_combination_with_MEK_inhibitors_or_irinotecan

BI-3406 and BI 1701963: Potent and selective SOS1 ... The combination of BI 1701963 with trametinib or irinotecan showed strong antitumor effect in KRAS-mutated colorectal cancer PDX models. A phase 1, multicenter ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0305737220301754

MEK inhibitor resistance mechanisms and recent ... The combination of dabrafenib with trametinib was also able to achieve an overall response rate of 47% for biliary tract cancer [14], [15], [38]. Though the ...