Adagrasib for Pancreatic Cancer

Overseen By Dan Zhao, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: QT prolongation, CYP3A substrate

Disqualifiers: Active brain metastases, Carcinomatous meningitis, Major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adagrasib, an investigational drug, can help control pancreatic cancer with a specific gene mutation called KRAS G12C. Researchers aim to assess the drug's safety and understand its effects. The trial suits individuals with pancreatic cancer that cannot be surgically removed or has metastasized, particularly if they have had no more than one prior treatment. Participants must have pancreatic cancer confirmed with the KRAS G12C mutation and be willing to follow trial guidelines. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot take medications with a known risk of QT prolongation, Torsades de Pointes, certain CYP3A substrates, strong CYP3A/P-gp inducers, strong BCRP inhibitors, or proton pump inhibitors. If you are on these, you must switch to alternatives before joining the study.

Is there any evidence suggesting that adagrasib is likely to be safe for humans?

Research has shown that adagrasib, also known as MRTX849, is generally well-tolerated by patients. In one study involving individuals with various solid tumors, including pancreatic cancer, most participants managed the treatment well. Some side effects occurred, but they were not severe for most. The study observed 63 participants taking adagrasib for over a year and found promising results in its effectiveness. While side effects can vary among individuals, the data suggests that adagrasib is a promising treatment option. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for pancreatic cancer, which often involve chemotherapy, Adagrasib (MRTX849) targets a specific genetic mutation known as KRAS G12. This mutation is a common driver of cancer growth, and Adagrasib specifically inhibits it, offering a more targeted approach compared to the broader attack of traditional chemotherapy. Researchers are excited about this treatment because it has the potential to be more effective for patients with this specific mutation, possibly leading to better outcomes with fewer side effects.

What evidence suggests that adagrasib might be an effective treatment for pancreatic cancer?

Research has shown that adagrasib, which participants in this trial will receive, may help treat pancreatic cancer with a specific KRAS G12 mutation. Studies have found that adagrasib works well in patients whose cancer continued to grow despite other treatments. It has effectively treated KRAS G12C-mutant solid tumors, leading to longer survival and high response rates. Another study found that adagrasib, sometimes used with other drugs, remained effective for similar KRAS mutations. This suggests that adagrasib could be a promising option for people with this type of pancreatic cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Dan Zhao, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic pancreatic cancer that has a specific mutation called KRAS G12C. Participants can have had only one prior therapy and must have recovered from its side effects. They should be in relatively good health (ECOG 0-2), not pregnant, willing to use contraception, and able to follow the study's procedures.

Inclusion Criteria

You are expected to live for at least three more months.

Patients who are biologically capable of having children and sexually active must agree to use an acceptable method of contraception

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study.

Exclusion Criteria

I have an active HIV, Hepatitis B, or Hepatitis C infection.

I cannot swallow pills.

I have previously been treated with a therapy targeting the KRAS G12C mutation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Adagrasib (MRTX849) monotherapy to assess antitumor activity and safety

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Adagrasib (MRTX849)

Trial Overview The focus of this trial is on adagrasib (MRTX849), an investigational drug targeting the KRAS G12C mutation in pancreatic cancer. The goal is to see if it can control the disease and assess its safety profile.

How Is the Trial Designed?

Group I: MRTX849 (Adagrasib) Experimental Treatment 1 Intervention

Helps to control pancreatic cancer that has a KRAS G12 mutation.

Adagrasib (MRTX849) 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
• KRAS G12C-mutated locally advanced or metastatic colorectal cancer

Approved in European Union as Krazati for:

• KRAS G12C mutation non-small cell lung cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Mirati Therapeutics Inc.

Industry 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

Published Research Related to This Trial

Recent research indicates that human pancreatic cancer is not an immune-privileged site, as previously thought, showing significant infiltration of CD8+ T cells that express PD-1.

The presence of these immune cells suggests that targeting immune checkpoints could be a promising therapeutic approach for treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pancreatic cancer microenvironment: an immunologic battleground. Pillarisetty, VG.[2021]

Immune checkpoint inhibitors, used in cancer treatment, can cause pancreatic injury in up to 4% of patients, leading to emergency department visits in about 1.9% of cases.

The management of this side effect requires a multidisciplinary approach involving various specialists, as it can result in both symptomatic and asymptomatic conditions, potentially causing long-term pancreatic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitor-Induced Pancreatic Injury: Imaging Findings and Literature Review. Porcu, M., Solinas, C., Migali, C., et al.[2022]

Adagrasib (KRAZATI™) is an effective oral treatment specifically targeting the KRAS G12C mutation in solid tumors, particularly non-small cell lung cancer (NSCLC), by locking the mutant protein in an inactive state, which prevents cancer cell signaling.

In December 2022, adagrasib received accelerated approval in the USA for adults with KRAS G12C-mutated NSCLC who have undergone prior systemic therapy, based on its promising response rates, although further confirmatory trials are needed to establish its clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib: First Approval. Dhillon, S.[2023]

A meta-analysis of 53 trials involving 6581 patients revealed that combined immune checkpoint inhibitors (ICIs) lead to significant gastrointestinal adverse events, with diarrhea occurring in 25.4% of patients, hepatitis in nearly 13%, and pancreatitis in about 7.5%.

The study highlights a high incidence of both mild and severe gastrointestinal adverse events associated with combined ICI treatments, indicating a need for further research to understand these effects and their impact on patient treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal treatment-related adverse events of combined immune checkpoint inhibitors: a meta-analysis. Karna, R., S Deliwala, S., Ramgopal, B., et al.[2023]

A study analyzing 2,364 cases of pancreatic adverse events (AEs) linked to immune checkpoint inhibitors (ICIs) found significant associations, particularly with ICI-associated pancreatitis and diabetes mellitus, indicating a notable risk for patients undergoing ICI treatment.

Combination therapy with ICIs showed a higher frequency of pancreatic AEs compared to monotherapy, suggesting that while the risk of these adverse events increases, the fatality rate remains lower, highlighting the importance of patient awareness regarding these potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. Zhang, Y., Fang, Y., Wu, J., et al.[2022]

In a study of 25 patients undergoing immunotherapy, imaging revealed that immune checkpoint inhibitor (ICI)-associated pancreatitis typically presents as mild acute interstitial pancreatitis, with no severe complications like necrotizing pancreatitis or pseudocysts observed.

All patients showed resolution of acute imaging findings with treatment, although pancreatic atrophy developed in 44% of cases, indicating that while the pancreatitis was mild and manageable, some long-term changes may occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging findings of immune checkpoint inhibitor associated pancreatitis. Das, JP., Postow, MA., Friedman, CF., et al.[2021]

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]

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]

In a phase II study of 27 patients with KRASG12C-mutant pancreatic ductal adenocarcinoma and other gastrointestinal tumors (excluding colorectal cancer), adagrasib monotherapy achieved a remarkable 100% disease control rate.

These preliminary results suggest that adagrasib may be a highly effective treatment option for patients with specific KRAS mutations in their tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib Moving Ahead in GI Cancers. [2022]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e16206

Outcomes of KRAS G12C inhibitors in metastatic ... Conclusions: Sotorasib and Adagrasib exhibited favorable therapeutic activity in KRAS p.G12C-mutated pancreatic cancer patients with tolerable ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10852394/

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C ... In this study, we observed notable clinical activity with adagrasib in pretreated patients with pancreatic cancer harboring KRASG12C mutations (>80% progressed ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05634525

NCT05634525 | Phase Ib Trial of the KRASG12C Inhibitor ... To evaluate the safety, tolerability and antitumor activity of Adagrasib (MRTX849) monotherapy in metastatic pancreatic cancer patients with KRASG12C mutation ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e20648

Clinical outcomes and safety profile of adagrasib in KRAS ... Adagrasib demonstrated robust efficacy in KRAS G12C-mutant solid tumors, with significant survival benefits and high response rates.

5. onclive.com onclive.com/view/adagrasib-cetuximab-maintains-efficacy-in-kras-g12c-mutated-advanced-mcrc

Adagrasib/Cetuximab Maintains Efficacy in KRAS G12C– ... Adagrasib plus cetuximab shows sustained efficacy in KRAS G12C-mutant mCRC with a 34% ORR per BICR and 43% per investigator review. The disease ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.519

KRYSTAL-1: Updated activity and safety of adagrasib ... Conclusions: Adagrasib monotherapy is well tolerated and demonstrates encouraging clinical activity in pretreated pts with PDAC and other GI ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37099736/

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C ... Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS G12C ...

8. asco.org asco.org/abstracts-presentations/ABSTRACT425082

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in ... Results: As of October 1, 2022, 64 pts with KRASG12C-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of ...

9. frontiersin.org frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1369136/full

Targeting KRAS mutations in pancreatic cancer Patients with KRASG12C mutated NSCLC (n = 126) were treated with sotorasib 960 mg OD and achieved an objective response rate (ORR) of 37.1% (95% CI, 28.6–46.1), ...