Crizotinib for Cancer with ALK Genetic Changes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: ALK inhibitors, CYP3A4 drugs

Disqualifiers: Non small cell lung cancer, ALCL, interstitial lung disease, pneumonitis, 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 crizotinib (also known as Xalkori), a treatment that may stop cancer growth by blocking a specific protein called ALK, which some cancer cells require to grow. Researchers aim to determine if crizotinib can shrink tumors or halt their growth in patients with cancers that have a genetic change known as ALK rearrangement. This trial suits individuals whose cancer has this ALK genetic change and who do not have non-small cell lung cancer or anaplastic large cell lymphoma. Participants should not have previously used similar ALK-targeted treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot use drugs or foods that strongly affect CYP3A4, an enzyme that processes many medications. If you're on such medications, 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 is generally well-tolerated by patients with ALK-positive cancers. One study found that 75% of patients who had already received many treatments were still alive after one year of using crizotinib, suggesting it is relatively safe for long-term use.

In other studies, about 60% of patients experienced noticeable tumor shrinkage, indicating that crizotinib is effective and supports its safety for treating cancer with ALK genetic changes. While any treatment carries risks, the evidence so far suggests that crizotinib is a good option for those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Crizotinib is unique because it targets genetic changes specifically associated with ALK-positive cancers. Unlike traditional chemotherapy that broadly attacks fast-dividing cells, crizotinib is an ALK inhibitor, meaning it directly interferes with the abnormal protein produced by the mutated ALK gene, potentially leading to more precise and effective treatment with fewer side effects. Researchers are excited about crizotinib because it offers a targeted approach that could significantly improve outcomes for patients with cancers driven by ALK genetic alterations.

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

Research shows that crizotinib, which participants in this trial will receive, works well for cancers with ALK genetic changes. In earlier studies, crizotinib caused tumors to shrink in about 60% of patients with ALK-positive non-small cell lung cancer (NSCLC). Another study found that 75% of patients treated with crizotinib were still alive after one year. On average, patients taking crizotinib lived nearly 8 months without their disease worsening. These findings suggest that crizotinib effectively manages cancers with ALK changes by blocking the ALK protein that cancer cells need to grow. ^{1 2 3 5 6}

Who Is on the Research Team?

Alice T Shaw

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for patients with various cancers that have a specific genetic change called ALK rearrangement. They must not have non-small cell lung cancer or certain lymphomas, no history of interstitial lung disease, and cannot be allergic to crizotinib. Prior treatments with ALK inhibitors disqualify them, as do untreated brain metastases or those on certain drugs affecting liver enzymes.

Inclusion Criteria

My recent ECG showed no significant heart issues.

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

My cancer has an ALK gene change.

Exclusion Criteria

My brain metastases are stable, treated, or not needing treatment.

I have never had interstitial lung disease or pneumonitis.

You are allergic to crizotinib or similar drugs.

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. Follow-up occurs 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 trial tests Crizotinib's effectiveness in shrinking or stopping the growth of cancers with the ALK genetic change. It's a phase II study where all participants receive Crizotinib to see how well it works against these types of cancer cells.

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 (XALKORI) is an effective treatment for patients with ALK-positive non-small cell lung cancer (NSCLC), showing an objective response rate of 61% in one trial and 50% in another, with median response durations of 48 and 42 weeks, respectively.

The drug was granted accelerated approval due to its high response rates and durability, and later received full approval after demonstrating improved progression-free survival in patients previously treated with platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Malik, SM., Maher, VE., Bijwaard, KE., et al.[2022]

Crizotinib is an effective treatment for adults with ALK-positive advanced non-small cell lung cancer (NSCLC), showing significant improvements in progression-free survival and quality of life compared to standard chemotherapy in ongoing phase I/II and phase III studies involving previously treated patients.

The treatment is generally well tolerated, although it can cause liver transaminase elevations and neutropenia as common adverse events; however, the long-term survival benefit remains uncertain due to confounding factors in the data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Frampton, JE.[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 36 ALK-positive metastatic NSCLC patients treated with crizotinib, neutropenia was associated with significantly improved progression-free survival (PFS), with a median PFS of 31.9 months compared to 12.8 months for those without neutropenia.

The study suggests that while other adverse events like hepatic or cardiac toxicities did not impact PFS, neutropenia could serve as a potential predictor for better treatment outcomes in patients receiving crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis. Gürsoy, P., Çakar, B., Nart, D., et al.[2022]

Crizotinib is an effective treatment for patients with ALK-positive non-small-cell lung cancer (NSCLC), showing significant clinical benefits and leading to its early approval by the USFDA in 2011.

Despite its effectiveness in inducing remissions and prolonging patient survival, there are concerns about emerging resistance to crizotinib therapy, highlighting the need for ongoing research and development of new treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib: A comprehensive review. Sahu, A., Prabhash, K., Noronha, V., et al.[2022]

Crizotinib (Xalkori) has shown excellent efficacy in treating advanced ALK-positive non-small cell lung cancer (NSCLC), with objective response rates of 61% in phase I and 51% in phase II studies, significantly outperforming standard therapies that have response rates below 10%.

The treatment is well tolerated, with common side effects being mild gastrointestinal issues and visual disturbances, and it has led to improvements in patients' quality of life, including reduced fatigue and cough.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ALK-positive non-small cell lung cancer. Bang, YJ.[2018]

Crizotinib is an effective small-molecule inhibitor targeting the ALK tyrosine kinase receptor and c-Met, showing significant activity against tumors with ALK rearrangements, particularly in non-small cell lung cancer (NSCLC).

In clinical studies, patients with ALK-positive NSCLC treated with crizotinib exhibited high response rates and prolonged progression-free survival, leading to its approval for advanced ALK-positive NSCLC in August 2011.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib for the treatment of patients with advanced non-small cell lung cancer. Bowles, DW., Weickhardt, AJ., Doebele, RC., et al.[2021]

Crizotinib (Xalkori) has been approved by the FDA for treating recurrent or refractory ALK-positive myofibroblastic tumors in both adults and children aged one year and older, highlighting its efficacy in this specific cancer type.

Common side effects include vision disorders and nausea in adults, while pediatric patients may experience a broader range of effects such as vomiting, diarrhea, and abdominal pain, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cancer Drug Crizotinib. Aschenbrenner, DS.[2023]

In a study of 106 patients with ALK-positive non-small cell lung cancer, 6.5% exhibited primary resistance to crizotinib, resulting in a median progression-free survival of only 1.2 months, compared to 47.0 months for long-term responders.

Patients who received next-generation ALK inhibitors after crizotinib progression had significantly better survival outcomes than those who only received supportive care, highlighting the potential for improved treatment strategies in this resistant population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical features and outcomes of ALK rearranged non-small cell lung cancer with primary resistance to crizotinib. Ma, D., Zhang, Y., Xing, P., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3936578/

Activity and safety of crizotinib in patients with ALK-positive ... Here, we have shown that crizotinib use in a heavily pretreated ALK-positive NSCLC population was associated with a 1-year survival rate of 75%.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1408440

First-Line Crizotinib versus Chemotherapy in ALK-Positive ... In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with ALK-positive NSCLC ...

3. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/xalkori

Xalkori | European Medicines Agency (EMA) A study involving 347 previously treated ALK-positive adult patients showed that those taking Xalkori lived on average for nearly 8 months without their disease ...

4. nature.com nature.com/articles/s41392-023-01538-w

Envonalkib versus crizotinib for treatment-naive ALK- ... The 12-month PFS rate of alectinib was 68.4%, vs. 48.7% for crizotinib. In addition, ALK variants do not affect the efficacy of alectinib in ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00581

Lorlatinib Versus Crizotinib in Patients With Advanced ALK ... In the phase III CROWN study, lorlatinib showed improved benefit over crizotinib in patients with previously untreated, advanced, ALK-positive ...

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)04788-X/fulltext

Final overall survival analysis of the Phase III ALEX study Median OS was 81.1 months in the alectinib arm and 54.2 months in the crizotinib arm (HR 0.78; 95% CI 0.56–1.08).