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

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing Adagrasib, a new drug, to see if it can help control pancreatic cancer in patients with a specific genetic mutation (KRAS G12C). The drug works by blocking this mutation to stop the cancer from growing.

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.

What data supports the idea that Adagrasib for Pancreatic Cancer is an effective drug?

The available research shows that Adagrasib has a 100% disease control rate in patients with a specific type of pancreatic cancer and other similar tumors. This means that in the study, all patients who were evaluated showed no progression of their disease while on the drug. This is a strong indication that Adagrasib is effective for treating this type of cancer. ^{1 2 3 4 5}

What safety data exists for Adagrasib in treating pancreatic cancer?

The provided research does not contain specific safety data for Adagrasib (MRTX849, Krazati) in treating pancreatic cancer. The studies focus on immune checkpoint inhibitors and their associated pancreatic adverse events, but do not mention Adagrasib or its safety profile. ^{6 7 8 9 10}

Is the drug Adagrasib a promising treatment for pancreatic cancer?

Yes, Adagrasib is a promising drug for pancreatic cancer. In a study, it showed a 100% disease control rate in patients with KRASG12C-mutant pancreatic cancer and other similar tumors. This means it was effective in stopping the disease from getting worse in all the patients studied. ^{1 2 3 4 5}

Research Team

Dan Zhao, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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 (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 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]

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]

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]

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]

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]

References

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

Adagrasib Moving Ahead in GI Cancers. [2022]

2. 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]

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

Another KRAS Inhibitor Holds Its Own. [2021]

4. 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]

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

Adagrasib: First Approval. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. [2022]

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

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

8. Ireland pubmed.ncbi.nlm.nih.gov

Imaging findings of immune checkpoint inhibitor associated pancreatitis. [2021]

9. France pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitor-Induced Pancreatic Injury: Imaging Findings and Literature Review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal treatment-related adverse events of combined immune checkpoint inhibitors: a meta-analysis. [2023]