MRTX849 for Cancer

Recruiting at 274 trial locations

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Mirati Therapeutics Inc.

Disqualifiers: Intestinal disease, Major gastric surgery, Other active cancer

No Placebo Group

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a new pill called MRTX849 (adagrasib) for patients with advanced cancers that have a specific genetic change called KRAS G12C. The pill aims to block this change and stop the cancer from growing. Adagrasib is similar to another approved treatment and is intended for patients with this genetic change who have already received other treatments.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is MRTX849 (Adagrasib) safe for humans?

Adagrasib (MRTX849) is generally well tolerated in humans, with most side effects being mild to moderate, such as diarrhea, nausea, and fatigue. These side effects usually appear early in treatment and can be managed with medication and monitoring, leading to a low rate of treatment discontinuation. ^{1 2 3 4 5}

How is the drug MRTX849 unique in treating cancer?

MRTX849 (Adagrasib) is unique because it specifically targets a mutation in the KRAS gene, which is a common driver of cancer growth and has been historically difficult to target with drugs. This makes it a novel option for patients with cancers driven by this mutation, offering a targeted approach where few effective treatments exist. ^{6 7 8 9 10}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with advanced solid tumors that have a specific mutation called KRAS G12C. They should have tried all standard treatments without success or declined them, and their cancer must be inoperable or spread to other parts of the body. People can't join if they have another active cancer, serious gut diseases, major stomach surgery history, trouble swallowing pills, or HER2 positive breast cancer.

Inclusion Criteria

My cancer cannot be removed by surgery or has spread to other parts of my body.

I have NSCLC and either there's no standard treatment available or I've declined it.

My cancer has a KRAS G12C mutation.

Exclusion Criteria

I do not have any other active cancer.

I have been diagnosed with HER2 positive breast cancer.

I have had major stomach surgery or can't swallow pills.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Exploration

Dose escalation of MRTX849 to determine maximum tolerated dose

12 months

Regular visits for dose escalation and monitoring

Phase 1b Expansion

Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849

12 months

Regular visits for safety and pharmacokinetic assessments

Phase 2

Evaluation of clinical activity of MRTX849 in separate cohorts stratified by histological diagnosis, prior treatment history or co-mutation status

20 months

Regular visits for clinical activity evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• MRTX849 (Small Molecule Drug)

Trial Overview The study tests MRTX849 (adagrasib) to see how safe it is and how well patients tolerate it. It also looks at what the drug does inside the body and whether it works against cancers with the KRAS G12C mutation. Patients may also receive other drugs like Pembrolizumab, Afatinib, or Cetuximab as part of their treatment.

Participant Groups

Group I: Pilot Phase 1b Combination with Pembrolizumab Experimental Treatment 2 Interventions

Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with pembrolizumab in patients with NSCLC

Group II: Pilot Phase 1b Combination with Cetuximab in PDAC Experimental Treatment 2 Interventions

Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with pancreatic adenocarcinoma (PDAC)

Group III: Pilot Phase 1b Combination with Cetuximab in NSCLC Experimental Treatment 2 Interventions

Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with NSCLC

Group IV: Pilot Phase 1b Combination with Cetuximab Experimental Treatment 2 Interventions

Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with CRC

Group V: Pilot Phase 1b Combination with Afatinib Experimental Treatment 2 Interventions

Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with afatinib in patients with NSCLC

Group VI: Phase 2 Combination with Cetuximab Experimental Treatment 2 Interventions

Phase 2 evaluation of the clinical activity of MRTX849 in combination with cetuximab in patients with CRC

Group VII: Phase 2 Experimental Treatment 1 Intervention

Separate cohorts of patients stratified by histological diagnosis, prior treatment history or co-mutation status (e.g., STK11) for evaluation of clinical activity of MRTX849

Group VIII: Phase 1b Expansion Experimental Treatment 1 Intervention

Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849 to recommend Phase 2 regimens

Group IX: Phase 1 Dose Exploration Experimental Treatment 1 Intervention

Dose escalation of MRTX849 to determine maximum tolerated dose

Who Is Running the Clinical Trial?

Mirati Therapeutics Inc.

Lead Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Findings from Research

Adagrasib (MRTX849) is a promising treatment for patients with KRAS-mutant non-small cell lung cancer (NSCLC) and brain metastases, showing the ability to penetrate the central nervous system and achieve effective concentrations in cerebrospinal fluid.

In preclinical models and preliminary clinical data from two patients, adagrasib demonstrated tumor regression in brain metastases, indicating its potential efficacy in treating this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Sabari, JK., Velcheti, V., Shimizu, K., et al.[2023]

Adagrasib (MRTX849) is a KRASG12C inhibitor that has been administered to 853 patients with KRASG12C-mutated solid tumors, showing a favorable safety profile with mostly mild to moderate treatment-related adverse events (TRAEs) that are manageable and lead to low treatment discontinuation rates.

Common TRAEs include gastrointestinal issues and hepatic toxicities, which can be effectively managed through dose adjustments and supportive medications, highlighting the importance of clinician awareness and patient education for optimal treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib. Zhang, J., Johnson, M., Barve, M., et al.[2023]

In a phase I/IB study involving 25 patients with advanced KRASG12C-mutant solid tumors, adagrasib (600 mg twice daily) demonstrated significant antitumor activity, with 53.3% of patients with non-small-cell lung cancer achieving a confirmed partial response after a median follow-up of 19.6 months.

Adagrasib was well tolerated, with the most common side effects being nausea (80%), diarrhea (70%), and fatigue (45%), indicating a manageable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). Ou, SI., Jänne, PA., Leal, TA., et al.[2023]

Adagrasib (MRTX849) is a selective inhibitor targeting the KRASG12C mutation, which is common in non-small cell lung cancer (NSCLC) and linked to poor patient outcomes.

Recent Phase I/II studies have demonstrated that adagrasib shows promising efficacy and tolerability, marking a significant advancement in the treatment of KRASG12C-driven NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib. Brazel, D., Arter, Z., Nagasaka, M.[2022]

The KRYSTAL-1 study found that adagrasib (MRTX849), a KRASG12c inhibitor, is generally well tolerated by patients with non-small cell lung cancer, indicating a favorable safety profile.

Adagrasib demonstrated significant efficacy in treating non-small cell lung cancer with the KRASG12c mutation, and it also showed some activity in colorectal cancer and other solid tumors, although to a lesser extent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Another KRAS Inhibitor Holds Its Own. [2021]

Avapritinib is a targeted protein kinase inhibitor that has shown a remarkable overall response rate of 95% in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the PDGFRA D842V mutation, with a median duration of response of 22.1 months.

While avapritinib is effective, it is associated with common side effects such as nausea, fatigue, and mild cognitive impairment, as well as rarer but serious events like severe encephalopathy and bleeding, highlighting the importance of monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of avapritinib in the treatment of gastrointestinal stromal tumours harbouring the PDGFRA D842V mutation. Trullas-Jimeno, A., Delgado, J., Garcia-Ochoa, B., et al.[2021]

Avapritinib, a selective kinase inhibitor, was well tolerated in a study of 59 Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST), with a recommended dose of 300 mg once daily and no dose-limiting toxicities reported.

The drug demonstrated significant anti-tumor activity, particularly in patients with PDGFRA D842V mutations, achieving an objective response rate of 75% and a clinical benefit rate of 86%, while also showing notable efficacy in patients receiving it as a fourth-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study. Li, J., Zhang, X., Deng, Y., et al.[2023]

ASP8374 is a fully human monoclonal antibody that effectively blocks the TIGIT immune checkpoint, leading to increased production of interferon (IFN)-γ and enhanced T-cell activation, especially when combined with pembrolizumab, an anti-PD-1 antibody.

In mouse tumor models, ASP8374 demonstrated anti-tumor efficacy both alone and in combination with anti-PD-L1 or anti-PD-1 antibodies, suggesting its potential as a therapeutic option for advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of ASP8374, a fully-human, antagonistic anti-TIGIT monoclonal antibody. Shirasuna, K., Koelsch, G., Seidel-Dugan, C., et al.[2022]

Avapritinib, a novel inhibitor targeting PDGFRA D842V mutations, demonstrated a manageable safety profile with no treatment-related deaths and a maximum tolerated dose of 400 mg in a study involving 82 patients with advanced gastrointestinal stromal tumors.

In patients specifically with PDGFRA D842V mutations, avapritinib showed significant antitumor activity, with 88% of patients achieving an overall response, including 9% complete responses and 79% partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Heinrich, MC., Jones, RL., von Mehren, M., et al.[2020]

Avapritinib is a selective tyrosine kinase inhibitor specifically targeting PDGFRA and KIT mutations, and it has been approved in the USA for treating gastrointestinal stromal tumors (GIST) with PDGFRA exon 18 mutations, including the D842V variant.

The drug is currently under regulatory review in the USA as a 4th-line treatment for GIST and is also being evaluated in the EU for the same indication, highlighting its potential as a significant treatment option for patients with advanced GIST.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avapritinib: First Approval. Dhillon, S.[2021]

References

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

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. [2023]

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

Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib. [2023]

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

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). [2023]

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

A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib. [2022]

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

Another KRAS Inhibitor Holds Its Own. [2021]

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

The EMA assessment of avapritinib in the treatment of gastrointestinal stromal tumours harbouring the PDGFRA D842V mutation. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Characterization of ASP8374, a fully-human, antagonistic anti-TIGIT monoclonal antibody. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. [2020]

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

Avapritinib: First Approval. [2021]