Adagrasib + SRS for Lung Cancer with Brain Metastases
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Ryan Gentzler, MD
Must not be taking: CYP3A inhibitors, CYP3A inducers
Disqualifiers: KRAS G12C inhibitor, Active infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This is a single arm phase 2 trial is to evaluate the efficacy of SRS plus adagrasib for the treatment of brain metastases for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC). A total of 30 patients will be enrolled on this study.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but you cannot take medications that strongly affect the CYP3A enzyme. If you are on such medications, you need to stop them at least 7 days before starting the trial treatment.
What data supports the effectiveness of the drug Adagrasib for lung cancer with brain metastases?
Research shows that Adagrasib, a drug targeting a specific mutation in lung cancer, shrank brain metastases in 33% of patients in a clinical trial. It also demonstrated a strong response rate in lung cancer patients, suggesting potential effectiveness for brain metastases.
12345Is the combination of Adagrasib and SRS safe for humans?
Adagrasib, also known as MRTX849, has been shown to be generally well tolerated in patients with non-small cell lung cancer, with most side effects being related to the digestive system. Serious side effects occurred in about 45% of patients, but no new safety concerns have emerged over time, indicating that its long-term safety is manageable.
12367What makes the drug Adagrasib unique for treating lung cancer with brain metastases?
Adagrasib is unique because it is an oral drug that specifically targets the KRASG12C mutation, which is common in certain lung cancers, and it can penetrate the brain to help control brain metastases. This is important because brain metastases are difficult to treat, and Adagrasib has shown promise in shrinking them in some patients.
12345Eligibility Criteria
This trial is for adults over 18 with stage IV non-small cell lung cancer (NSCLC) that has spread to the brain and have a specific mutation called KRAS G12C. They should be relatively healthy, able to perform daily activities with ease or minor difficulty, and have not treated their brain metastases yet. Up to 10 untreated brain tumors are allowed, but none larger than 3 cm.Inclusion Criteria
Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
I am 18 years old or older.
My lung cancer is at stage IV or has returned and spread after treatment.
+10 more
Exclusion Criteria
Treatment with any investigational drug within 28 days prior to registration.
Pregnant or breastfeeding.
I have been treated with a KRAS G12C inhibitor before.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive oral adagrasib 600mg twice daily and SRS for the treatment of brain metastases
3 months
Regular visits for SRS and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
52 months
Participant Groups
The study tests how well Adagrasib combined with Stereotactic Radiosurgery (SRS), which is a precise form of radiation therapy, works in treating NSCLC patients whose cancer has spread to the brain. All participants will receive this combination treatment.
1Treatment groups
Experimental Treatment
Group I: Adagrasib + SRS (Stereotactic Radiosurgery)Experimental Treatment2 Interventions
All patients will receive oral adagrasib 600mg twice daily for every cycle and SRS which will be administered as standard of care. Initiation of adagrasib and treatment with SRS will occur within 3 weeks of each other, in whichever order. Patients may have received SRS prior to study enrollment. Cycle 1 Day 1 will begin on the first day of adagrasib dosing. Adagrasib should be held the day before and the day of SRS. There is no maximum duration of treatment.
Adagrasib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Krazati for:
- KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)
- KRAS G12C-mutated locally advanced or metastatic colorectal cancer
🇪🇺 Approved in European Union as Krazati for:
- KRAS G12C mutation non-small cell lung cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Virginia Health SystemCharlottesville, VA
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Who Is Running the Clinical Trial?
Ryan Gentzler, MDLead Sponsor
University of VirginiaCollaborator
Mirati Therapeutics Inc.Industry Sponsor
References
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. [2023]Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized.
Adagrasib Response Remains Strong in NSCLC. [2022]In the phase II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib yielded an overall response rate of 43% and a disease control rate of 80% in patients with previously treated KRASG12C-mutant non-small cell lung cancer. After a median follow up of 12.9 months, overall survival was 11.7 months. The drug also shrank brain metastases in 33% of patients who had them.
Another KRAS Inhibitor Holds Its Own. [2021]According to the KRYSTAL-1 study, the KRASG12c inhibitor adagrasib, also known as MRTX849, is largely well tolerated and shows considerable efficacy in patients with non-small cell lung cancer harboring this mutation. The drug is also active, albeit more modestly, in colorectal cancer and several other solid tumor types.
First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). [2023]Label="PURPOSE">Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.
Trials, Tribunals, and Opportunities for Lung Cancer KRASG12C Brain Metastases. [2022]The activity of KRAS inhibitors against brain metastases is relatively unexplored. The recent work on preclinical models and preliminary data from the ongoing KRYSTAL-1 phase Ib clinical trial support the potential of adagrasib (MRTX849) to penetrate the central nervous system and provide control of KRASG12C brain metastases. See related article by Sabari et al., p. 3318.
Adagrasib's Efficacy Sustained in KRASG12C NSCLC. [2023]According to the latest update from KRYSTAL-1, adagrasib shows durable efficacy in patients with advanced, previously treated KRASG12C non-small cell lung cancer. At 2 years, approximately one in three patients were still alive, and no new toxicities emerged, indicating that the KRASG12C inhibitor's long-term safety is manageable.
Adagrasib: a novel inhibitor for KRASG12C-mutated non-small-cell lung cancer. [2023]Adagrasib is a recently US FDA-approved novel KRASG12C targeted therapy with clinical efficacy in patients with advanced, pretreated KRASG12C-mutated non-small-cell lung cancer. KRYSTAL-I reported an objective response rate of 42.9% with median duration of response of 8.5 months. Treatment-related adverse events were primarily gastrointestinal and occurred in 97.4% of patients, with grade 3+ treatment-related adverse events occurring in 44.8% of patients. This review details the preclinical and clinical data for adagrasib in the treatment of non-small-cell lung cancer. We also outline practical clinical administration guidelines for this novel therapy, including management of toxicities. Finally, we discuss the implications of resistance mechanisms, summarize other KRASG12C inhibitors currently in development and outline future directions for adagrasib-based combination therapies.