MK-1084 + Pembrolizumab for Solid Cancers

Recruiting in Palo Alto (17 mi)

+68 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: NSAIDs, Steroids, others

Disqualifiers: CNS metastases, Active infection, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called MK-1084, alone or with other treatments, in patients with advanced cancers that have a specific mutation. The drug aims to block this mutation to stop or slow down the cancer. Another drug, Sotorasib, was the first approved treatment for this type of cancer.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are in Arm 4, you must be able to interrupt aspirin or other NSAIDs for a few days around the administration of pemetrexed.

What data supports the effectiveness of the drug pembrolizumab in treating solid cancers?

Pembrolizumab has shown effectiveness in treating various solid tumors, including non-small cell lung cancer and melanoma, by improving survival rates and showing high response rates with minimal side effects. ^{1 2 3 4 5}

Is the combination of MK-1084 and Pembrolizumab safe for humans?

Pembrolizumab, also known as Keytruda, has been used in various cancer treatments and is generally considered safe, but it can cause side effects like fatigue, cough, and nausea. Serious side effects, such as pneumonitis (lung inflammation), occur in a small percentage of patients. Always discuss potential risks with your healthcare provider. ^{1 2 3 6 7}

What makes the drug MK-1084 + Pembrolizumab unique for treating solid cancers?

The combination of MK-1084 and Pembrolizumab is unique because it involves using Pembrolizumab, a PD-1 inhibitor that helps the immune system attack cancer cells, alongside MK-1084, which may have a different mechanism of action. This combination could potentially enhance the effectiveness of the immune response against solid tumors compared to using Pembrolizumab alone. ^{1 2 3 5 6}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have a specific mutation (KRAS G12C). Participants must have measurable disease, proper organ function, and agree to contraception. It's not suitable for pregnant or breastfeeding women, those with active infections like HIV or hepatitis, certain eye conditions, recent vaccines, autoimmune diseases requiring treatment, CNS metastases/carcinomatous meningitis, or who can't take required supplements.

Inclusion Criteria

My NSCLC is untreated, has a KRAS G12C mutation, and PD-L1 score of 1% or more.

My colorectal cancer is advanced, cannot be surgically removed, and has a specific KRAS G12C mutation.

My cancer can be measured and my organs work well.

Exclusion Criteria

I meet the specific medication requirements for Arm 4.

I am willing to take specific medications for the trial.

I do not have an infection that needs treatment with drugs.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MK-1084 alone or in combination with other therapies, with cycles varying between 3 and 4 weeks depending on the arm, for up to 24 months

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 56 months

Treatment Details

Interventions

• MK-1084 (Small Molecule Inhibitor)
• Pembrolizumab (Checkpoint Inhibitor)

Trial Overview The study tests MK-1084 alone and combined with Pembrolizumab in patients with KRAS G12C mutant tumors. It aims to assess the effectiveness and safety of these treatments in different groups: some untreated NSCLC cases; others who've had systemic therapy; and various stages of colorectal cancer after previous therapies failed.

Participant Groups

Group I: Arm 6 Experimental Treatment 5 Interventions

Participants will receive MK-1084 daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.

Group II: Arm 5 Experimental Treatment 2 Interventions

Participants will receive MK-1084 daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.

Group III: Arm 4 Experimental Treatment 4 Interventions

Participants will receive MK-1084 daily oral dose plus an intravenous infusion of pembrolizumab (200 mg) once every 21-day cycle for up to 35 cycles (up to \~24 months). Participants will also receive carboplatin (per label) and pemetrexed (per label) once every 21-day cycle for the first 4 cycles.

Group IV: Arm 3 Experimental Treatment 1 Intervention

Participants will receive alternate formulation of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.

Group V: Arm 2 Experimental Treatment 2 Interventions

Participants will receive MK-1084 daily oral escalating dose of up to 800 mg plus pembrolizumab given as a 200 mg intravenous infusion once every 21-day cycle up to a total of 35 cycles (up to \~24 months). Treatment with MK-1084 will continue until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.

Group VI: Arm 1 Experimental Treatment 1 Intervention

Participants will receive daily oral escalating doses of up to 800 mg of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Cross Cancer Institute ( Site 0033) Edmonton, Canada

Kingston Health Sciences Centre-Kingston General Hospital Site ( Site 0036) Kingston, Canada

The Moncton Hospital ( Site 0037) Moncton, Canada

MEDICAL COLLEGE OF WISCONSIN-Cancer Center Clinical Trials Office ( Site 0262) Milwaukee, WI

More Trial Locations

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp. Lead Sponsor

Merck Sharp & Dohme LLC Lead Sponsor

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022] A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

3. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022] On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test, as follows: (a) first-line treatment of patients with mNSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.Approval was based on two randomized, open-label, active-controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In KEYNOTE-010, patients with disease progression on or after platinum-containing chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001 comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with chemotherapy.

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023] Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017] Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023] Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021] On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.