Crizotinib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Heart disease, Lung disease, GI abnormalities, 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: 3

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether crizotinib, a medication that blocks enzymes aiding cancer growth, is effective for individuals with advanced or treatment-resistant solid tumors, lymphoma, or multiple myeloma. It targets participants whose cancer exhibits a specific genetic issue known as MET amplification, where the gene produces too many copies of itself. This trial suits those who have not responded to other treatments and have this genetic condition. Participants will take crizotinib and undergo regular evaluations to assess the treatment's effectiveness. As a Phase 2 trial, the research focuses on measuring the treatment's efficacy 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 strong CYP3A4 inhibitors or inducers, and you must not need to use CYP3A substrates with narrow therapeutic indices. If you are taking any of these, you may need to stop or adjust them.

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

Research shows that crizotinib is generally well-tolerated by patients. Studies have found it effective against tumors, particularly in patients with a specific type of lung cancer linked to changes in the MET gene. The treatment is considered safe, with side effects usually being manageable.

Patients in these studies experienced some unwanted effects, but they were mostly mild to moderate. Crizotinib is already approved for treating certain types of cancer, indicating thorough safety testing. While every treatment can have side effects, current evidence suggests that crizotinib is a relatively safe option for those with specific genetic markers in their cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cancers involving MET amplification, which often rely on chemotherapy or non-specific kinase inhibitors, crizotinib specifically targets the MET gene alterations. This precision mechanism means it can potentially be more effective in blocking cancer cell growth while sparing normal cells, reducing side effects. Researchers are excited about crizotinib because it offers a targeted approach that could improve outcomes for patients with MET-amplified tumors, potentially leading to better response rates and longer periods without disease progression.

What evidence suggests that crizotinib might be an effective treatment for advanced or refractory cancer with MET gene amplification?

Research has shown that crizotinib, which participants in this trial will receive, can help treat certain cancers with a specific genetic change called MET gene amplification. In one study, patients with this genetic change had their cancer remain stable for about 3.4 months on average. Another study found that 62.5% of patients experienced tumor shrinkage. Crizotinib blocks substances that help cancer cells grow and spread, and it may also prevent tumors from forming new blood vessels. These findings suggest crizotinib could benefit patients with advanced cancers that have this genetic change. ^{1 2 3 6 7}

Who Is on the Research Team?

David S Hong

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for patients with advanced or treatment-resistant solid tumors, lymphoma, or multiple myeloma that have MET gene amplification. Participants should be those whose cancer has spread and who haven't responded to standard treatments.

Inclusion Criteria

Patients must have met applicable eligibility criteria in the Master MATCH Protocol EAY131/ NCI-2015-00054 prior to registration to treatment subprotocol

Patient must fulfill all eligibility criteria outlined in section 3.1 of MATCH Master protocol (excluding section 3.1.6) at the time of registration to treatment step (step 1, 3, 5, 7)

Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must not have clinically important abnormalities in rhythm, conduction or morphology of resting ECG, including complete left bundle branch block, third-degree heart block

Exclusion Criteria

I haven't had major surgery or minor procedures in the last month.

I do not have severe lung scarring or diseases, except for past radiation pneumonitis.

I haven't had a heart attack or severe heart issues in the last 3 months and my digestive system absorbs nutrients normally.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Treatment

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

Up to 3 years

Regular visits for radiologic evaluation and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Every 3 months for 2 years, then every 6 months for 1 additional year

What Are the Treatments Tested in This Trial?

Interventions

• Crizotinib

Trial Overview The effectiveness of Crizotinib, a tyrosine kinase inhibitor medication, is being tested on participants. The study involves taking the drug and undergoing radiologic exams, biopsies, and biospecimen collection to see how well it works against these cancers.

How Is the Trial Designed?

Group I: Subprotocol C1 (MET amplification) Experimental Treatment 4 Interventions

Patients receive crizotinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo radiologic evaluation and collection of blood samples throughout the study. Patients may undergo biopsy at screening, on study, and/or at end of treatment.

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 has an oral bioavailability of about 43%, and while a high-fat meal slightly decreases its absorption, this effect is not clinically significant, indicating that it can be taken with food without major concerns.

In two phase I clinical studies involving healthy volunteers, crizotinib was found to be safe, with no serious adverse events reported and only mild side effects, such as diarrhea, suggesting it is well-tolerated in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. Xu, H., O'Gorman, M., Boutros, T., et al.[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) 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, an ALK inhibitor, has been established as a new standard of care for advanced ALK-positive non-small cell lung cancer (NSCLC) due to its significant efficacy and favorable safety profile observed in phase I, II, and III trials.

Most adverse events associated with crizotinib are mild to moderate, and with proper monitoring and supportive care, dose interruptions can often be avoided, allowing patients to continue benefiting from the treatment even after initial disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. Cappuzzo, F., Moro-Sibilot, D., Gautschi, O., et al.[2018]

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]

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]

Citations

1. jto.org jto.org/article/S1556-0864(21)01710-X/fulltext

Crizotinib in Patients With MET-Amplified NSCLC The probability of survival at 12 months in the high, medium, and low MET-amplification groups was 46.8% (95% CI: 23.5–67.1), 28.6% (8.8–52.4), ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9771320/

Crizotinib efficacy and safety in patients with advanced ... Median progression free survival (PFS) was 7.2 months (95% confidence interval [CI]: 3.8–10.5), and median overall survival (OS) was 18.7 months ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.3108

Phase II study of crizotinib in patients with MET ... ORR was 14% (4/28, 90% CI: 5.0%-29.8%). Median PFS was 3.4 mo (90% CI: 1.8–3.7); median OS 7.1 mo (90% CI: 5.0–11.5). 4 pts with confirmed PR ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/30/23/5323/750203/Safety-Efficacy-and-Biomarker-Analysis-of

Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET ... In this study, crizotinib proved to be highly effective in patients with METmut aNSCLC. We identified an ORR of 62.5% (95% CI, 40.6–81.2) with a ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S016950022030475X

The clinical efficacy of combinatorial therapy of EGFR-TKI ... Nine patients achieved partial response, resulting in an overall response rate of 81.8 %. The median progression-free survival of the cohort was 5.8 months.

6. ascopubs.org ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.8001

Efficacy and safety of crizotinib in patients with advanced c- ... Conclusions: Crizotinib appears to have antitumor activity in patients with c-Met-amplified NSCLC and a generally tolerable and manageable AE profile. These ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S155608642101710X

Crizotinib in Patients With MET-Amplified NSCLC ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival ...