MEK162 + Imatinib for Gastrointestinal Stromal Tumor

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Imatinib

Must not be taking: MEK inhibitors

Disqualifiers: Uncontrolled diabetes, Brain metastasis, HIV, 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 combination of two medicines, MEK162 and imatinib (also known as Gleevec), to assess their effects on people with Gastrointestinal Stromal Tumor (GIST), a type of cancer in the digestive system. The trial aims to determine if these medicines can control the tumor and identify any side effects. People with GIST that has returned after previous treatment or those newly diagnosed may be suitable for this trial. As a Phase 1 and Phase 2 trial, it focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but it does mention that patients in the Phase II portion should not have been treated with any systemic therapy for GIST, except for certain cases with imatinib. It's best to discuss your specific medications with the trial team.

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

Research shows that combining MEK162 with imatinib is under careful study for safety in patients with Gastrointestinal Stromal Tumor (GIST). Previous studies have found that imatinib alone works well for many patients, but its effectiveness can diminish over time. Researchers are testing whether adding MEK162 can improve results without causing excessive side effects.

Early results suggest that this combination is generally well-tolerated. The most common side effects include fatigue, skin rash, and mild swelling. Importantly, researchers adjusted the dose of MEK162 to enhance long-term tolerability, aiming to balance efficacy and patient comfort.

The combination remains under study, but the adjustments aim to enhance treatment safety. Always consult a healthcare provider to understand potential risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of MEK162 and Imatinib for treating gastrointestinal stromal tumors (GIST) because it offers a new approach beyond the standard treatment. Most treatments for GIST, like Imatinib alone, work by inhibiting specific proteins that drive tumor growth. However, MEK162 introduces a different mechanism by targeting a separate pathway involved in cell division and survival, potentially enhancing the anti-tumor effects when used alongside Imatinib. This dual-action strategy aims to improve treatment efficacy and delay resistance, which is a common challenge with current therapies.

What evidence suggests that MEK162 and imatinib could be effective for Gastrointestinal Stromal Tumor?

Studies have shown that imatinib is a breakthrough treatment for gastrointestinal stromal tumors (GIST). This medicine blocks certain signals in cancer cells, stopping their growth. However, over time, many patients find imatinib less effective. In this trial, participants will receive a combination of imatinib with another drug, MEK162, or binimetinib. Research suggests that this combination may offer additional benefits. Early results indicate that it can slow tumor growth and improve survival rates for people with advanced GIST. By attacking the cancer in different ways, this combination might be more effective than imatinib alone. ^{1 2 3 6 7}

Who Is on the Research Team?

Ping Chi

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with confirmed Gastrointestinal Stromal Tumor (GIST) who can take pills, have not been treated before or are off previous treatment for 3 months. They must be in good health based on specific blood tests and heart function, agree to use birth control if necessary, and cannot have a history of certain eye diseases, uncontrolled medical conditions like diabetes or hypertension, recent major surgery side effects, or active infections.

Inclusion Criteria

My diagnosis is a gastrointestinal stromal tumor (GIST).

My GIST has worsened despite taking imatinib.

I am newly diagnosed with GIST or haven't taken imatinib for 3+ months.

Exclusion Criteria

I have had serious heart issues or procedures in the last 6 months.

My high blood pressure is not controlled despite taking medication.

I have a muscle disorder that causes high levels of an enzyme in my blood.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Participants receive MEK162 and imatinib with dose escalation to determine the maximum tolerated dose

1 year

Monthly visits for dose escalation and monitoring

Phase II Treatment

Participants receive MEK162 at the revised RP2D and imatinib to evaluate response rate

2 years

Monthly visits for treatment and response evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Imatinib Mesylate
• MEK162

Trial Overview The trial is testing the combination of two drugs: MEK162 and Imatinib Mesylate (Gleevec), which patients will take orally. The study aims to see how well these drugs work together against untreated advanced GIST by monitoring their effects through biopsies and regular blood draws.

How Is the Trial Designed?

Group I: MEK162 in Combination With Imatinib Mesylate Experimental Treatment 4 Interventions

Pts will be treated with the combination therapy of MEK162 \& imatinib. The phase Ib portion of the study, pts will receive imatinib at 400 mg once daily \& MEK162 at the standard 3+3 escalation doses. Phase Ib expansion cohort, pts will receive the RP2D: imatinib 400 mg once daily (standard of care first line imatinib dose) \& MEK162 at the RP2D twice daily. The phase II portion of the study, pts will receive imatinib at 400 mg once daily \& MEK162 at the RP2D. The MEK162 RP2D was originally determined based on the phase Ib escalation data \& it was established as 45 mg BID. After the completion of the phase Ib dose expansion \& initiation of phase II, the MEK162 RP2D was reduced to 30 mg BID30 for better long term tolerability. Patient's will now begin MEK162 at the revised RP2D of 30 mg BID. 1 cycle is 28 days. If no progression of the tumor is seen, pts will continue on therapy. Pts who have progression of disease will proceed directly to second line therapy as per standard of care.

Imatinib Mesylate is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as Gleevec for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Approved in European Union as Glivec for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Approved in Canada as Imatinib Mesylate for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Approved in Japan as Imatinib Mesylate for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Approved in China as Imatinib Mesylate for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Approved in Switzerland as Imatinib Mesylate for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumor
• Hypereosinophilic Syndrome
• Dermatofibrosarcoma Protuberans
• Systemic Mastocytosis

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

In a study of 39 patients with gastrointestinal stromal tumors (GISTs) treated with imatinib mesylate, 59% achieved a partial response and 18% had stable disease, demonstrating effectiveness consistent with published data.

Imatinib mesylate was well tolerated, with only mild side effects reported, such as peri-orbital edema and skin rash, indicating a favorable safety profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of imatinib mesylate in gastrointestinal stromal tumours: Pan-Birmingham Cancer Network experience. Wong, DW., Lupton, SC., Bhatt, L., et al.[2015]

Imatinib, a tyrosine kinase inhibitor, has significantly improved the prognosis for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST), showing high rates of cytogenetic and molecular responses across all phases of CML.

The drug is well tolerated, with only mild adverse effects such as joint pain and gastrointestinal symptoms, primarily occurring in the first two years of treatment, making it a safe and effective oral option for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. Wolf, D., Rumpold, H.[2021]

In a study of 62 patients with gastrointestinal stromal tumors (GIST) treated with imatinib mesylate for a median of 26 months, four distinct patterns of disease progression were identified, which have different implications for patient outcomes.

Patients with new cystic lesions (NCL) showed a significantly higher response to increased doses of imatinib and had better overall survival compared to those with new solid lesions (NSL) or general progression (GP), highlighting the importance of recognizing progression patterns for treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Ryu, MH., Lee, JL., Chang, HM., et al.[2022]

Imatinib mesylate has shown a high clinical response rate of 81.6% in patients with gastrointestinal stromal tumors (GIST), with 53.7% achieving a partial response and 27.9% having stable disease.

While most patients experienced only mild toxicities (grade 1 or 2), 21.1% had more severe side effects (grade 3 or higher), indicating that imatinib is relatively safe but can still cause significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of imatinib for gastrointestinal tumor]. Mizunuma, N.[2015]

In a study of 12 cases of gastric mesenchymal tumors, 67% were identified as GISTs, with gastrointestinal bleeding being the most common symptom and a significant number presenting with palpable abdominal masses.

Imatinib Mesylate showed a good response in a case of metastatic GIST, highlighting its potential as a palliative treatment option, especially when combined with surgical resection for advanced lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastric GISTs. Personal experience. Mingolla, GP., Riccio, PA., Linguerri, R., et al.[2015]

In a study of 16 patients with advanced gastrointestinal stromal tumors (GISTs) treated with imatinib mesylate, FDG PET imaging effectively identified treatment responders within just one week, showing a 65% reduction in SUV for responders compared to a 16% increase for non-responders.

FDG PET not only predicted treatment outcomes with a high sensitivity of 93% but also provided better early response evaluation than traditional imaging methods, indicating its potential as a valuable tool for monitoring treatment efficacy and managing patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate for the treatment of gastrointestinal stromal tumours: best monitored with FDG PET. Jager, PL., Gietema, JA., van der Graaf, WT.[2022]

STI571 (imatinib mesylate) has shown significant therapeutic effects in reducing tumor size in patients with advanced gastrointestinal stromal tumors (GISTs) who had previously failed other treatments, based on a retrospective analysis of 5 cases.

The treatment was well-tolerated, with no serious drug-related side effects reported, highlighting its potential as a safe and effective alternative to conventional chemotherapy for advanced GISTs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Imatinib mesylate STI571 therapy for five patients with advanced gastrointestinal stromal tumors]. Shen, KT., Hou, YY., Qin, XY., et al.[2015]

In a randomized phase III trial involving 713 patients, adjuvant treatment with imatinib significantly improved recurrence-free survival after surgical resection of localized gastrointestinal stromal tumors, with only 8% recurrence in the imatinib group compared to 20% in the placebo group.

Imatinib was well tolerated, with manageable side effects, indicating it is a safe option for patients following surgery for gastrointestinal stromal tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Dematteo, RP., Ballman, KV., Antonescu, CR., et al.[2022]

Imatinib mesylate is the standard first-line treatment for chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), effectively targeting specific tyrosine kinases and significantly improving patient prognosis.

The treatment is generally well tolerated with a low risk of severe side effects, and long-term use shows excellent tolerability, with concerns like cardiotoxicity being largely exaggerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of imatinib in CML and GIST: long-term considerations. Thanopoulou, E., Judson, I.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8937014/

Phase II Trial of Imatinib Plus Binimetinib in Patients With ... Despite the clinical success of imatinib, most patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib and succumb to their ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01991379

MEK162 in Combination With Imatinib Mesylate in Patients ... The purpose of this study is to evaluate the effects, good and/or bad, of MEK162 and imatinib on the patient and on Gastrointestinal Stromal Tumor (GIST).

3. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT01991379/

Clinical Trial: NCT01991379 The purpose of this study is to evaluate the effects, good and/or bad, of MEK162 and imatinib on the patient and on Gastrointestinal Stromal ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2503651/

Treatment of gastrointestinal stromal tumor: focus on imatinib ... The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST.

5. curetoday.com curetoday.com/view/new-treatment-combo-shows-benefit-for-patients-with-gist

New Treatment Combo Shows Benefit for Patients with GIST Among patients with advanced gastrointestinal stromal tumors, Gleevec and Mektovi was associated with benefits in progression and survival.

6. gisttrials.org gisttrials.org/iLRG/details.php?Trial=338

trial detail - GIST clinical trials Brief Summary: The purpose of this study is to test the safety and tolerability of the combination of pexidartinib and MEK162. This study tests different ...

7. gistinfo.org gistinfo.org/wp-content/uploads/Chi_24-progress.pdf

Principal Investigator: Ping Chi MD, PhD, MSKCC 1 Moreover, while imatinib or MEK162 alone mostly stabilized tumor growth, the combination of imatinib and MEK162 leads to complete responses even at reduced ...