Erlotinib + Cabozantinib for Non-Small Cell Lung Cancer

Recruiting at 417 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, CYP3A4 inducers

Disqualifiers: Prior erlotinib, Major thrombotic events, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, ongoing until disease progression or unacceptable toxicity

125 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating non-small cell lung cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not be on strong CYP3A4 inducers or therapeutic doses of certain anticoagulants. If you are taking any of these, you may need to stop or adjust them before joining the trial.

What data supports the effectiveness of the drug combination Erlotinib and Cabozantinib for treating non-small cell lung cancer?

Research shows that Cabozantinib, when used alone or with Erlotinib, targets specific proteins involved in lung cancer growth, and has been studied in patients with non-small cell lung cancer. Erlotinib is already approved for advanced non-small cell lung cancer, and Cabozantinib has shown activity in various cancers, suggesting potential effectiveness when combined. ^{1 2 3 4 5}

What makes the drug combination of Erlotinib and Cabozantinib unique for treating non-small cell lung cancer?

The combination of Erlotinib and Cabozantinib is unique because it targets multiple pathways involved in cancer growth, with Erlotinib inhibiting the epidermal growth factor receptor (EGFR) and Cabozantinib targeting MET, VEGFR, and other kinases, potentially offering a more comprehensive approach to treating non-small cell lung cancer, especially in patients with EGFR wild-type tumors. ^{1 3 6 7 8}

Research Team

Joel W Neal

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with Stage IV non-small cell lung cancer who have a specific mutation in the EGFR gene, have received 1-2 prior chemotherapy treatments, and can swallow tablets. They should not have had certain previous cancer therapies or major health issues that could affect their participation.

Inclusion Criteria

Your heart's electrical activity, measured by the QT interval, should be less than 500 milliseconds.

Discontinued treatment with any other type of investigational agent >= 4 weeks prior to registration

Your disease can be measured using specific guidelines for evaluating tumor response.

Exclusion Criteria

I am HIV positive and on antiretroviral therapy.

I have been diagnosed with chronic active hepatitis B.

I am currently taking certain medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive erlotinib, cabozantinib, or both, orally daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, ongoing until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 2 years, then every 6 months for up to 5 years.

5 years

Treatment Details

Interventions

• Cabozantinib S-malate
• Erlotinib Hydrochloride

Trial Overview The study is testing how well erlotinib hydrochloride and cabozantinib-s-malate work alone or together as second or third line therapy for patients. These drugs block enzymes needed by tumor cells to grow, but it's unclear if combining them offers better results.

Participant Groups

Group I: Arm Z (erlotinib+cabozantinib; step II) Experimental Treatment 3 Interventions

Patients achieving disease progression in Arm A or Arm B may receive erlotinib and cabozantinib as patients in Arm C. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm C (erlotinib+cabozantinib) Experimental Treatment 3 Interventions

Patients receive erlotinib as patients in Arm A and cabozantinib as patients in Arm B. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm B (cabozantinib) Experimental Treatment 2 Interventions

Patients receive cabozantinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group IV: Arm A (erlotinib) Experimental Treatment 2 Interventions

Patients receive erlotinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase Ib/II study involving 64 patients with progressive non-small cell lung cancer (NSCLC) who had previously received erlotinib, cabozantinib alone showed a modest objective response rate (ORR) of 8.2%, indicating some efficacy as a treatment option.

However, in the phase II portion, the combination of cabozantinib and erlotinib did not yield any responses in patients with acquired resistance to erlotinib, suggesting that cabozantinib did not effectively re-sensitize these patients to erlotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Wakelee, HA., Gettinger, S., Engelman, J., et al.[2023]

Cabozantinib demonstrated clinical activity in patients with non-small-cell lung carcinoma (NSCLC), showing a 10% objective response rate and a 38% overall disease-control rate after 12 weeks of treatment, particularly in patients with KRAS mutations.

The treatment was associated with manageable safety concerns, with common grade 3/4 adverse events including fatigue and palmar-plantar erythrodysesthesia, although there was one serious treatment-related adverse event (hemorrhage) reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma. Hellerstedt, BA., Vogelzang, NJ., Kluger, HM., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. [2023]

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

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib. [2022]

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

Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. [2022]

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

Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. [2022]

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

Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer. [2018]