Pevonedistat + Chemotherapy for Non-Small Cell Lung Cancer

Not currently recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Checkpoint inhibitors

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, Psychiatric illness, Cardiopulmonary 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

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with advanced non-small cell lung cancer (NSCLC) that hasn't responded well to previous treatments. The combination includes pevonedistat, a drug that may inhibit cancer cell growth, along with two chemotherapy drugs, carboplatin and paclitaxel, which help kill or stop the spread of cancer cells. The trial aims to determine if this combination is more effective than standard chemotherapy. Suitable candidates are patients with stage IIIB or IV NSCLC who have experienced disease progression after prior treatments, including checkpoint inhibitors and platinum-based chemotherapies. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take certain medications that are strong enzyme inducers, like ritonavir, efavirenz, or nevirapine, during the study.

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

Research has shown that pevonedistat, when combined with other treatments, is generally safe for patients with non-small cell lung cancer. In past studies, combining pevonedistat with chemotherapy drugs like docetaxel demonstrated promising safety results. Most patients tolerated the combination well, with manageable side effects.

Carboplatin and paclitaxel, well-known chemotherapy drugs, have been used for many years to treat cancer. They are considered safe, but like most chemotherapy, they can cause side effects. These may include nausea, tiredness, or low blood cell counts, which doctors monitor closely during treatment.

Overall, earlier studies found that the combination of pevonedistat with carboplatin and paclitaxel was fairly well-tolerated. However, as with any treatment, there is a risk of side effects, and discussing these with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for non-small cell lung cancer?

Researchers are excited about combining Pevonedistat with chemotherapy for non-small cell lung cancer because it introduces a novel mechanism of action. Unlike traditional treatments that primarily target cell division, Pevonedistat inhibits a protein called NEDD8-activating enzyme, which can disrupt cancer cell survival pathways, potentially enhancing the effectiveness of standard chemotherapy drugs like carboplatin and paclitaxel. This combination could offer a more potent way to tackle cancer cells, possibly leading to better outcomes for patients who haven't responded well to existing therapies.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Studies have shown that pevonedistat, when combined with other chemotherapy drugs, can help treat non-small cell lung cancer (NSCLC). Research suggests that pevonedistat blocks certain enzymes that cancer cells need to grow, making it harder for the cancer to spread. In other studies, pevonedistat combined with the drug docetaxel showed promising results for treating NSCLC that returned after treatment. This trial tests the combination of pevonedistat with standard chemotherapy drugs carboplatin and paclitaxel to see if it can further improve patient outcomes. This combination could potentially enhance chemotherapy effectiveness and offer new hope for those battling advanced stages of NSCLC. ^{1 2 3 6 7}

Who Is on the Research Team?

Ticiana A Leal

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with stage IIIB or IV non-small cell lung cancer (NSCLC) who have previously been treated with immunotherapy. They must have a life expectancy of at least 12 weeks, acceptable liver and kidney function, controlled CNS metastases if present, and no severe heart or lung conditions. Participants need to agree to use contraception and cannot be pregnant.

Inclusion Criteria

I can understand and am willing to sign the consent form, or I have someone who can do it for me.

I agree to use effective birth control during the study.

My liver function tests are within the required range.

Exclusion Criteria

I have a serious lung condition like COPD, lung scarring, or fibrosis.

I have severe liver problems or cirrhosis.

I will not donate sperm during the study or for 4 months after the last dose.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive paclitaxel, carboplatin, and pevonedistat intravenously. Treatment repeats every 21 days for at least 4 cycles.

12 weeks

4 cycles, each with multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days, every 3 months for 1 year, and then every 6 months until 5 years.

5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Paclitaxel
• Pevonedistat

Trial Overview

The study tests the effectiveness of combining MLN4924 (Pevonedistat) with Carboplatin and Paclitaxel in NSCLC patients who didn't respond well to prior treatments. It aims to see if this combination is better than standard chemotherapy by blocking enzymes that help cancer cells grow.

How Is the Trial Designed?

Group I: Treatment (paclitaxel, carboplatin, pevonedistat) Experimental Treatment 3 Interventions

Patients receive paclitaxel IV over 3 hours on day 1, carboplatin IV over 30-60 minutes on day 1, and pevonedistat IV over 1 hour on days 1, 3, and 5. Treatment repeats every 21 days for at least 4 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

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

In a phase II trial involving 51 patients with untreated stage IIIB and IV non-small cell lung cancer, the combination of carboplatin and paclitaxel showed an overall response rate of 27.5%, indicating some effectiveness in treating this aggressive cancer.

The treatment was generally well-tolerated, with modest toxicity levels; only 5% of patients experienced severe nonhematologic side effects, suggesting that this combination therapy could be a safe option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel plus carboplatin for advanced lung cancer: preliminary results of a Vanderbilt University phase II trial--LUN-46. Johnson, DH., Paul, DM., Hande, KR., et al.[2015]

In a multicenter study involving 130 patients with advanced non-small cell lung cancer (NSCLC), the combination of paclitaxel and carboplatin resulted in a moderate response rate of 23.8%, indicating its efficacy as a treatment option.

Both high-dose (200 mg/m2) and low-dose (175 mg/m2) paclitaxel regimens were well tolerated, with myelosuppression being the most significant side effect, but differences in toxicity between the two doses were minimal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-center study of two dose levels of paclitaxel with carboplatin in locally advanced and metastatic non-small cell lung cancer (NSCLC). Glorieux, P., Ortmanns, P., Marien, S., et al.[2015]

In a phase II study involving 155 patients with advanced non-small-cell lung cancer, the combination of paclitaxel and carboplatin resulted in a 34% objective response rate, indicating significant efficacy in treating this cancer type.

The treatment was generally safe, with manageable side effects like leukopenia and peripheral neuropathy, and a median survival of 8 months, along with a 1-year survival rate of 42%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-hour paclitaxel plus carboplatin for advanced non-small-cell lung cancer. Greco, FA., Hainsworth, JD.[2015]

In a study involving 180 patients with advanced non-small cell lung cancer (NSCLC), pemetrexed-carboplatin did not show superior efficacy compared to paclitaxel-carboplatin, with similar progression-free survival (PFS) rates and overall survival after a median follow-up of 17 months.

While both treatment regimens had comparable overall toxicities, the paclitaxel-carboplatin group experienced higher rates of alopecia and peripheral neuropathy, indicating a difference in side effects between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Yadav, A., Malik, PS., Khurana, S., et al.[2021]

In a meta-analysis of 486 patients with advanced non-squamous non-small cell lung cancer, the pemetrexed plus carboplatin regimen at 5 mg/min•mL (PCb5) showed a significantly lower incidence of treatment-emergent adverse events (TEAEs) compared to the 6 mg/min•mL (PCb6) regimen, including less thrombocytopenia, anemia, and fatigue.

Despite the differences in safety profiles, both PCb5 and PCb6 regimens demonstrated similar efficacy outcomes in terms of overall survival and progression-free survival, indicating that PCb5 may be a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. Okamoto, I., Schuette, WH., Stinchcombe, TE., et al.[2018]

The combination of paclitaxel and carboplatin has shown promising results in treating advanced non-small-cell lung cancer (NSCLC), with reported 1-year survival rates as high as 54%, making it a widely used regimen in clinical practice.

This combination therapy has been effective without additional toxicity, allowing for full doses of both drugs to be administered, and is currently being evaluated in ongoing studies for earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. Belani, CP.[2015]

Citations

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A Phase II Trial of Pevonedistat and Docetaxel in Patients ...

Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results ...

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A phase II trial of pevonedistat plus docetaxel in patients ...

In pre-clinical studies, pevonedistat, a first-in-class small molecule NAE inhibitor, exerts anti-tumor effects when combined with docetaxel.

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P2.02-02 A Phase 2 Study of MLN4924 (Pevonedistat) in ...

This is a phase 2, single arm, multicenter study of pevonedistat 20mg/m2 IV Days (D) 1, 3, 5 + carboplatin (AUC=5) D1 and paclitaxel 175mg/m2 D1 every 21 days ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT03228186

Trial of Pevonedistat Plus Docetaxel in Patients With ...

This study is a single institution Phase II single arm trial to assess the efficacy of the combination of pevonedistat plus docetaxel in patients with ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1525730423002243

A Phase II Trial of Pevonedistat and Docetaxel in Patients ...

The prognosis of patients with stage IV non–small-cell lung cancer (NSCLC) remains poor, with a 5-year survival rate of approximately 10% despite the advent of ...

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Study Results | Testing the Combination of MLN4924 ...

An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

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P2.02-02 A Phase 2 Study of MLN4924 (Pevonedistat) in ...

Results. From 4/2020 to 7/2021, 28 patients ... Safety data will be reported (NCT03965689). Keywords. Non-small cell lung cancer, Pevonedistat, Chemotherapy.