Lurbinectedin + Berzosertib for Small Cell Lung Cancer

Overseen By Danielle F Pinkiert, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Symptomatic brain metastases, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 21 days per cycle

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive neuroendocrine cancers. At first, SCLC and HGNEC respond to chemotherapy. But then they relapse quickly and become resistant to treatment. Researchers want to see if a combination of drugs can help. Objective: To see if the combination of lurbinectedin and berzosertib may be effective to shrink SCLC and HGNEC tumors, and to find the best dose of the combination. Eligibility: Adults ages 18 and older with a solid tumor, SCLC, or HGNEC. Design: Participants will get lurbinectedin by intravenous (IV) catheter on Day 1 of each cycle (1 cycle = 21 days). They will get berzosertib by IV on Days 1 and 2 of each cycle. Participants will continue to receive treatment as long as they are benefiting from treatment. Participants will have physical exams and blood tests. Their symptoms, medicines, and ability to perform their normal activities will be reviewed. Participants will have electrocardiograms to test heart function. Sticky pads will be placed on their chest, arms, and legs. Participants will give blood and hair samples for research. They may have optional tumor biopsies. Participants will have computed tomography (CT) scans to see if the treatment is effective. Participants will have a follow-up visit 1 month after treatment ends. Then they will be followed by email or phone for the rest of their life.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot take medications that strongly affect CYP3A enzymes. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Lurbinectedin and Berzosertib for treating Small Cell Lung Cancer?

Lurbinectedin is approved for treating Small Cell Lung Cancer (SCLC) and has shown effectiveness in patients with this condition. Research indicates that combining Lurbinectedin with Berzosertib, an ATR inhibitor, enhances its effectiveness, particularly in certain resistant types of SCLC, by promoting cancer cell death. ^{1 2 3 4 5}

What makes the drug combination of Lurbinectedin and Berzosertib unique for treating small cell lung cancer?

The combination of Lurbinectedin and Berzosertib is unique because Lurbinectedin is a marine-derived drug that inhibits transcription (the process of copying DNA to RNA), which is often abnormal in small cell lung cancer, while Berzosertib is a first-in-class inhibitor targeting ATR, a protein involved in DNA repair. This combination targets cancer cells in a novel way by disrupting both transcription and DNA repair mechanisms. ^{2 3 4 6 7}

Research Team

Anish Thomas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults 18+ with solid tumors, SCLC, or HGNEC who understand the study and consent to participate. They must use contraception if of child-bearing potential, have an ECOG performance status ≤2 (indicating a level of functioning), measurable disease per RECIST 1.1 criteria, and adequate organ function. Excluded are those with symptomatic brain metastases not stabilized by treatment, HIV-positive individuals on antiretroviral therapy, anyone eligible for curative therapy elsewhere, participants in other trials or allergic to similar compounds.

Inclusion Criteria

My blood tests show normal organ function.

I have advanced cancer and have had at least one chemotherapy treatment.

I agree to use birth control during the study.

Exclusion Criteria

I am not taking any strong medication that affects liver enzymes during the study.

Pregnant women are excluded from this study

I am not HIV-positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lurbinectedin on Day 1 and berzosertib on Days 1 and 2 of each 21-day cycle, continuing until disease progression or intolerable side effects

21 days per cycle

1 visit (in-person) per cycle

Follow-up

Participants have a follow-up visit 1 month after treatment ends and are then followed by email or phone for the rest of their life

1 month

1 visit (in-person), followed by remote follow-up

Open-label extension (optional)

Participants may continue treatment as long as they are benefiting

Indefinite

Treatment Details

Interventions

• Berzosertib
• Lurbinectedin

Trial Overview The trial is testing the effectiveness of combining lurbinectedin and berzosertib to shrink tumors in patients with SCLC and HGNEC. Participants receive lurbinectedin via IV on day one and berzosertib on days one and two every three weeks (21-day cycle). The best dose will be determined based on response which is monitored through physical exams, blood tests including heart function checks via electrocardiograms, CT scans for tumor assessment.

Participant Groups

Group I: 2/ Phase II Experimental Treatment 2 Interventions

Berzosertib + lurbinectedin at MTD

Group II: 1/ Phase I Experimental Treatment 2 Interventions

Dose escalation of Berzosertib + lurbinectedin

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving 38 patients with advanced non-small cell lung cancer (NSCLC), the combination of berzosertib and gemcitabine was found to be well tolerated, with common side effects including fatigue (55.3%) and anemia (52.6%).

The objective response rate (ORR) was 10.5% overall, but higher response rates were observed in patients with specific genomic features: 30.0% in those with high loss of heterozygosity and 33.0% in those with high tumor mutational burden, suggesting that genomic selection may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer. Plummer, R., Dean, E., Arkenau, HT., et al.[2022]

Lurbinectedin, approved by the FDA in June 2020 as ZEPZELCA, is the first systemic therapy specifically for Small Cell Lung Cancer (SCLC), highlighting its significance in cancer treatment.

The drug works by inhibiting the transcription of genes related to tumor growth, which helps to suppress tumor-associated macrophages and alter the tumor environment, making it a promising option for SCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Small Cell Lung Cancer with Lurbinectedin: A Review. Rajput, PS., Khan, SR., Singh, P., et al.[2022]

In a study involving 60 patients with advanced solid tumors, the combination of berzosertib and gemcitabine was found to be well tolerated, with a recommended Phase 2 dose established for this combination.

The treatment showed preliminary signs of efficacy, with many patients achieving either a partial response or stable disease, indicating potential benefits for those with resistant or refractory tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Middleton, MR., Dean, E., Evans, TRJ., et al.[2023]

Lurbinectedin (ZEPZELCA™) has been approved in the USA for treating adult patients with metastatic small cell lung cancer (SCLC) who have progressed after platinum-based chemotherapy, highlighting its efficacy in a challenging cancer type.

The drug has received orphan drug status in multiple countries, indicating its potential importance in treating rare cancers, and ongoing clinical investigations are exploring its use in other solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lurbinectedin: First Approval. Markham, A.[2021]

The combination of the ATR inhibitor berzosertib with lurbinectedin has shown promising results in enhancing the effectiveness of treatment for MYC-driven non-neuroendocrine small-cell lung cancer (SCLC), which is typically resistant to standard therapies.

Mechanistically, berzosertib helps overcome the cell cycle arrest caused by lurbinectedin, leading to increased cell death in cancer models, and the combination is currently being evaluated in a clinical trial (NCT04802174).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer. Schultz, CW., Zhang, Y., Elmeskini, R., et al.[2023]

In a study of 95 patients with small cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM) treated with lurbinectedin, the drug demonstrated a manageable safety profile and showed clinical activity, with median overall survival of 7.0 months for SCLC and 7.2 months for MPM.

Lurbinectedin was associated with immune system changes, including the depletion of classical monocytes and increased proliferation of T cells, suggesting its potential as a platform for future immunotherapy combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma. Dumoulin, DW., Cantini, L., Cornelissen, R., et al.[2022]

Lurbinectedin, a marine-derived drug, has shown promising efficacy in treating relapsed small cell lung cancer, both as a standalone treatment and in combination with other chemotherapy agents like doxorubicin and paclitaxel.

The drug has received accelerated approval from the FDA for monotherapy in relapsed small cell lung cancer, highlighting its favorable safety profile and potential as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lurbinectedin in the treatment of relapsed small cell lung cancer. Baena, J., Modrego, A., Zeaiter, A., et al.[2021]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of Small Cell Lung Cancer with Lurbinectedin: A Review. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Lurbinectedin: First Approval. [2021]

5. England pubmed.ncbi.nlm.nih.gov

ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Lurbinectedin in the treatment of relapsed small cell lung cancer. [2021]