Combination Therapy for Non-Small Cell Lung Cancer

Overseen By Yasir Elamin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors, Strong CYP3A inducers

Disqualifiers: Leptomeningeal disease, Recent malignancy, 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

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and side effects of a combination treatment for individuals with advanced or recurrent ALK-positive non-small cell lung cancer. The treatment includes ensartinib, which may slow cancer cell growth, along with the chemotherapy drugs carboplatin and pemetrexed, and bevacizumab, a monoclonal antibody. The goal is to assess whether this combination can help control the disease. The trial seeks participants diagnosed with stage IIIC or IV ALK-positive non-small cell lung cancer who are not candidates for certain other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires stopping the use of certain medications, such as strong CYP3A inhibitors, strong CYP3A inducers, and CYP3A substrates with a narrow therapeutic window. Additionally, any anticancer herbal medications should be stopped before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ensartinib, a key drug in this trial, is already approved by the FDA for treating ALK-positive non-small cell lung cancer, indicating its general safety for humans. In earlier studies, ensartinib was well tolerated, with most side effects being manageable.

Carboplatin, another treatment in the trial, is widely used for non-small cell lung cancer. Research indicates it is often combined with other drugs and is generally safe, though it can cause side effects like low blood cell counts.

Pemetrexed is also commonly used for lung cancer. Studies have shown it to be effective, with side effects similar to many other chemotherapy drugs, such as tiredness and nausea.

Lastly, bevacizumab is known for helping to stop tumor growth. It has been used in many cancer treatments and is generally safe, but it can sometimes cause high blood pressure and bleeding issues.

Overall, the treatments in this trial have been studied before and are generally considered safe, though they come with the usual side effects of cancer drugs. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for non-small cell lung cancer (NSCLC) because it brings together a unique mix of treatments that might enhance effectiveness. Unlike the standard of care, which often includes individual agents like carboplatin and pemetrexed, this approach integrates ensartinib, a newer type of drug known as a tyrosine kinase inhibitor, which specifically targets certain mutations in cancer cells. Moreover, the addition of bevacizumab, an anti-angiogenesis agent, helps cut off the tumor's blood supply, potentially improving outcomes. By combining these agents, researchers hope to attack the cancer from multiple angles, possibly leading to better control of the disease and improved patient outcomes.

What evidence suggests that this combination therapy could be effective for non-small cell lung cancer?

Research has shown that ensartinib works well for ALK-positive non-small cell lung cancer (NSCLC) by blocking enzymes that tumors need to grow. In this trial, participants will receive a combination of treatments, including ensartinib, carboplatin, pemetrexed, and bevacizumab. Carboplatin and pemetrexed are chemotherapy drugs that kill cancer cells or stop them from spreading, and studies have found them effective for treating advanced non-small cell lung cancer. Bevacizumab, a monoclonal antibody, helps stop tumors from growing and spreading. When combined with chemotherapy, it can significantly improve survival for patients with advanced NSCLC. This combination of treatments is under study for its potential to effectively control the disease. ^{2 3 4 6 7}

Who Is on the Research Team?

Yasir Y. Elamin

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with ALK-positive non-small cell lung cancer at stage IIIC, IV, or recurrent who can swallow pills and have a life expectancy of over 12 weeks. They may be treatment-naive or have had prior treatments but must meet specific blood count and organ function criteria. Pregnant women, those with recent serious heart issues, other cancers within 2 years (except certain skin/cervical cancers), active infections, or severe medical conditions are excluded.

Inclusion Criteria

I can swallow and keep down pills.

My blood clotting time is normal or managed if I'm on blood thinners.

You are expected to live for at least 12 more weeks.

Exclusion Criteria

You are allergic to the dye used in the ensartinib 100 mg capsule.

I haven't had cancer in the last 2 years, except for certain skin cancers, cervical cancers, or any cured cancer.

I haven't had serious heart or stroke issues in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive ensartinib, carboplatin, pemetrexed, and bevacizumab. Treatment repeats every 21 days for up to 4 cycles.

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients receive ensartinib and bevacizumab. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Variable, based on disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Carboplatin
• Ensartinib
• Pemetrexed

Trial Overview The trial is testing the combination of Ensartinib (a growth-blocking enzyme inhibitor) with Carboplatin and Pemetrexed (chemotherapy drugs), plus Bevacizumab (a monoclonal antibody that hinders tumor spread). The goal is to find the optimal dose of Ensartinib and assess its effectiveness alongside these drugs in controlling advanced lung cancer.

How Is the Trial Designed?

Group I: Treatment (ensartinib, carboplatin, pemetrexed, bevacizumab) Experimental Treatment 4 Interventions

INDUCTION THERAPY: Patients receive ensartinib PO QD on days 1-21, carboplatin IV over 15-60 minutes on day 1, pemetrexed IV over 10 minutes on day 1 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ensartinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a study of 108 patients with advanced non-squamous non-small cell lung cancer (NSCLC), adding bevacizumab to pemetrexed as maintenance therapy significantly improved progression-free survival (PFS) compared to pemetrexed alone, with PFS of 7.0 months versus 5.4 months.

Patients who responded partially to initial treatment had a median overall survival of 29.6 months with the addition of bevacizumab, compared to 23.3 months with pemetrexed alone, suggesting a potential survival benefit from the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321. Kasai, T., Mori, K., Nakamura, Y., et al.[2023]

In a study of 1,534 patients with advanced non-squamous non-small cell lung cancer, the combination of platinum/paclitaxel/bevacizumab resulted in a significantly higher overall response rate (ORR) of 40.8% compared to 32.7% for platinum/pemetrexed.

Despite the better ORR with the paclitaxel/bevacizumab regimen, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two treatment groups, suggesting that both regimens are similarly effective and should be chosen based on side effect profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Chemotherapeutic Regimens Frequently Used in Metastatic Non-squamous NSCLC Treatment. Krejci, D., Opalka, P., Krejci, J., et al.[2021]

Pemetrexed is an effective treatment for relapsed or chemotherapy-refractory non-small cell lung cancer (NSCLC), showing similar response and survival rates to taxotere but with less toxicity.

When combined with platinum analogs or other chemotherapy agents like gemcitabine or vinorelbine, pemetrexed produces equivalent responses and overall survival outcomes, suggesting it is a viable option in NSCLC treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of pemetrexed in non-small cell lung cancer. Longo-Sorbello, GS., Chen, B., Budak-Alpdogan, T., et al.[2022]

In a study of 25 patients with stage IIIa lung adenocarcinoma, the combination of bevacizumab with pemetrexed and carboplatin as neoadjuvant chemotherapy showed a safety profile with manageable adverse events, including some cases of fatigue, neutropenia, and hypertension.

No severe perioperative complications such as hemorrhage or thromboembolic events were observed, suggesting that the neoadjuvant treatment is well-tolerated and safe for patients undergoing surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin in Patients with IIIa Lung Adenocarcinoma]. Zhang, S., Xu, P., Yuan, C., et al.[2019]

In a study involving 939 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed, carboplatin, and bevacizumab (PemCBev) did not show a significant improvement in overall survival compared to paclitaxel, carboplatin, and bevacizumab (PacCBev), with median overall survival times of 12.6 and 13.4 months, respectively.

However, PemCBev demonstrated a significantly better progression-free survival (6.0 months vs. 5.6 months) and had a different toxicity profile, with more cases of anemia and thrombocytopenia, while PacCBev was associated with higher rates of neutropenia and alopecia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Patel, JD., Socinski, MA., Garon, EB., et al.[2022]

In a study of 72 patients with advanced non-small cell lung cancer, the combination of bevacizumab and pemetrexed resulted in a significantly longer overall survival time of 14 months compared to 11 months for those receiving only pemetrexed.

While the combination therapy showed improved overall response and disease control rates, these differences were not statistically significant, indicating that while the combination may enhance survival, it does not drastically change response rates compared to pemetrexed alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of bevacizumab concomitant with pemetrexed in patients with advanced non-small cell lung cancer. Zhang, YM., Li, YQ., Liu, ZH., et al.[2022]

In a study of 29 non-small-cell lung cancer patients treated with pemetrexed, 21% developed acute kidney injury (AKI) despite having an initial eGFR above the recommended threshold of 45 mL/min, indicating potential renal toxicity even in patients considered safe for treatment.

Patients with a baseline eGFR below 60 mL/min were more likely to experience AKI, suggesting that careful monitoring and management of renal function and risk factors are essential when administering pemetrexed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. Rombolà, G., Vaira, F., Trezzi, M., et al.[2021]

In a study involving 361 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed and carboplatin (Pem+Cb) did not show a significant advantage in progression-free survival without grade 4 toxicity compared to paclitaxel, carboplatin, and bevacizumab (Pac+Cb+Bev).

While both treatment regimens were generally well tolerated, Pem+Cb was associated with higher rates of grade 3/4 anemia and thrombocytopenia, whereas Pac+Cb+Bev had more cases of grade 3/4 neutropenia and alopecia, indicating differing toxicity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. Zinner, RG., Obasaju, CK., Spigel, DR., et al.[2022]

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The efficacy of bevacizumab combined with platinum- ... Clinical studies have demonstrated that bevacizumab confers significant survival benefits in patients with advanced NSCLC (Yang et al., 2018).

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Emerging Safety Data for Bevacizumab in Advanced Non– ... Clinically relevant bevacizumab-associated adverse events reported in clinical trials to date include bleeding, hypertension, proteinuria, thrombotic events, ...