Crizotinib for Cancer with ROS1 Genetic Changes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, ROS1 inhibitors

Disqualifiers: NSCLC, Interstitial lung disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called crizotinib to determine if it can shrink or halt the growth of cancer with a genetic change known as ROS1 translocation. Crizotinib blocks a protein essential for cancer cell growth. The trial targets individuals whose cancer involves the ROS1 gene but excludes those with non-small cell lung cancer (NSCLC) with ROS1 changes. Participants should not have certain heart issues or lung diseases, such as interstitial lung disease or pneumonitis. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you do not use drugs or foods that are known potent CYP3A4 inhibitors or inducers, as these can affect how crizotinib works. If you are taking any of these, you may need to stop them before joining the trial.

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

Research has shown that crizotinib has been tested for safety in people with specific genetic changes in their cancer. For patients with ROS1-positive cancer, crizotinib's safety profile was similar to its use in ALK-positive cancer. Most side effects were mild or moderate, indicating they were not very serious.

The FDA has already approved crizotinib to treat ROS1-positive metastatic non-small-cell lung cancer. This approval indicates thorough testing for this condition, supporting its safety record. Overall, studies suggest that crizotinib is safe and effective for treating cancers with ROS1 changes. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Crizotinib is unique because it targets ROS1 genetic changes in cancer cells, which is different from the standard treatments that typically focus on other genetic mutations or pathways. Most treatments for similar cancers, like chemotherapy, attack rapidly dividing cells in general, but crizotinib specifically inhibits the activity of enzymes responsible for tumor growth in ROS1-positive cancers. Researchers are excited about crizotinib because it offers a more targeted approach, potentially leading to fewer side effects and better outcomes for patients with these specific genetic changes.

What evidence suggests that crizotinib might be an effective treatment for cancer with ROS1 genetic changes?

Research has shown that crizotinib effectively treats cancers with specific genetic changes called ROS1. Studies have found that crizotinib can shrink tumors or halt their growth in patients with ROS1-related non-small-cell lung cancer (NSCLC). In one study, about two-thirds of patients experienced tumor shrinkage. Another study found that 72% of patients saw their tumors shrink, and 85% were still alive after one year. These results suggest that crizotinib is a promising treatment for patients with this genetic change in their cancer. Participants in this trial will receive crizotinib to further evaluate its effectiveness. ^{2 3 6 7 8}

Who Is on the Research Team?

Aaron S Mansfield

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for cancer patients with a specific genetic change called ROS1 translocation, excluding those with non-small cell lung cancer (NSCLC) or a history of lung disease. Participants must have normal heart rhythms and not be allergic to crizotinib or similar compounds. They can't use certain drugs that affect crizotinib's metabolism and shouldn't have used any ROS1 inhibitors before.

Inclusion Criteria

Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol

My recent ECG showed no significant heart issues.

My cancer has a specific genetic change in the ROS1 gene.

Exclusion Criteria

Patients must not have known hypersensitivity to crizotinib or compounds of similar chemical or biologic composition

I am not using any strong medications or foods that affect drug metabolism.

I have never been treated with ROS1 inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive crizotinib orally twice daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Every 2 cycles for the first 26 cycles, then every 3 cycles thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 3 months if less than 2 years from study entry, and then every 6 months for year 3.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Crizotinib

Trial Overview The study tests Crizotinib, which may inhibit the growth of cancers by blocking the protein ROS1. It's for patients whose cancers are identified to have this targetable genetic alteration. The goal is to see if Crizotinib can shrink these cancers or halt their progression.

How Is the Trial Designed?

Group I: Treatment (crizotinib) Experimental Treatment 1 Intervention

Patients receive crizotinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Crizotinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in European Union as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Japan as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Canada as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Crizotinib is an effective oral tyrosine kinase inhibitor specifically targeting ALK, which is found in about 5% of non-small-cell lung cancers (NSCLCs), and has been approved for treating advanced ALK-rearranged NSCLC.

Clinical trials have demonstrated that crizotinib is superior to standard chemotherapy for patients with ALK-positive NSCLC, highlighting its efficacy in this specific cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib in the treatment of non--small-cell lung cancer. Rothschild, SI., Gautschi, O.[2021]

Crizotinib is an effective treatment for adults with ALK-rearranged non-small-cell lung cancer, but managing its common side effects is essential for maintaining treatment continuity and achieving optimal survival rates.

While some side effects like visual disturbances and bradycardia are generally mild, serious cardiac and liver-related adverse events require careful monitoring, particularly for QT interval prolongation and liver function, to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? Girard, N., Audigier-Valette, C., Cortot, AB., et al.[2018]

In a study of 35 Chinese patients with advanced non-small-cell lung cancer (NSCLC) harboring ROS1 rearrangements, crizotinib demonstrated a high objective response rate of 71.4% and a disease control rate of 94.3%, indicating its efficacy in real-world clinical practice.

The median progression-free survival was 11 months and median overall survival was 41 months, with crizotinib being well tolerated despite some common adverse effects like elevated transaminases and vision disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib in Chinese Patients with ROS1-Rearranged Advanced Non‒Small-Cell Lung Cancer in Routine Clinical Practice. Liu, C., Yu, H., Chang, J., et al.[2022]

In a phase II trial involving 127 East Asian patients with ROS1-positive advanced non-small-cell lung cancer (NSCLC), crizotinib showed a high objective response rate of 71.7%, indicating significant antitumor activity.

The treatment was well tolerated, with no new safety concerns reported, and patients experienced durable responses, with a median duration of response of 19.7 months and a median progression-free survival of 15.9 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. Wu, YL., Yang, JC., Kim, DW., et al.[2022]

ROS1 fusion events occur in 1%-2% of non-small-cell lung cancer (NSCLC) patients and are associated with specific patient demographics, including younger individuals, women, and non-smokers, indicating a distinct molecular subtype of NSCLC.

Crizotinib is the only approved treatment for ROS1-rearranged NSCLC, showing significant benefits in progression-free survival and quality of life, and is recommended as the standard first-line therapy for patients with this genetic alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective. Bebb, DG., Agulnik, J., Albadine, R., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10854608/

Real-World Outcomes of Crizotinib in ROS1-Rearranged ... At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0169500224003507

Efficacy and safety of crizotinib in the treatment ... Crizotinib is safe and effective in treating ROS1-rearranged aNSCLC in first and later lines of therapy based on RWE. •. Meta-analysis of 14 crizotinib ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12068926/

Therapeutic Outcomes of ROS1‐Positive Advanced NSCLC Thirty‐six patients used crizotinib as an initial ROS1 inhibitor, with an ORR for crizotinib = 66.7% (95% CI: 50.5%–82.8%), and in patients with ...

4. becarispublishing.com becarispublishing.com/doi/10.57264/cer-2024-0043

Real-world studies of crizotinib in patients with ROS1 ... Patients with ROS1-rearranged NSCLC who received crizotinib treatment achieved an objective response rate (ORR) of 72%, a 12-month OS rate of 85 ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1406766

Crizotinib in ROS1-Rearranged Non–Small-Cell Lung ... Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6726257/

Crizotinib inhibition of ROS1-positive tumours in advanced ... The safety profile of crizotinib in patients with ROS1-positive disease was similar to that seen in the ALK-positive treatment environment: grades 1 and 2 ...

7. pfizer.com pfizer.com/news/press-release/press-release-detail/xalkori_crizotinib_approved_by_u_s_fda_for_the_treatment_of_patients_with_ros1_positive_metastatic_non_small_cell_lung_cancer

XALKORI® (crizotinib) Approved by U.S. FDA for the ... ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)31237-2/fulltext

Crizotinib in ROS1-rearranged advanced non-small-cell ... Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced ...