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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, lurbinectedin and berzosertib, to determine if they can shrink tumors in people with small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC). These cancers often initially respond to chemotherapy but tend to recur and become resistant. The trial aims to find the most effective dose of this drug combination. People diagnosed with SCLC or HGNEC, whose cancer has not responded well to other treatments, might be suitable for this trial. Participants will receive the drugs via IV and undergo regular health check-ups and scans to monitor progress. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

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.

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

Research shows that combining lurbinectedin and berzosertib may help treat small cell lung cancer. Lurbinectedin has proven effective and generally safe for patients with this cancer type, especially when initial treatments fail.

Berzosertib has demonstrated safety when used alone or with other drugs to treat tumors. Combined with lurbinectedin, it effectively targets cancer cells.

Although both drugs have been tested separately, using them together is a new approach. These studies aim to understand patient tolerance for this combination and to determine the optimal dose. Researchers will closely monitor participants' safety throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Lurbinectedin and Berzosertib for Small Cell Lung Cancer because it introduces a novel way of tackling the disease. Unlike traditional treatments like chemotherapy that target dividing cells broadly, Lurbinectedin specifically inhibits transcription in cancer cells, while Berzosertib blocks a crucial DNA repair pathway. This dual-action strategy could potentially enhance the effectiveness of treatment by directly targeting cancer cell survival mechanisms, offering hope for better outcomes compared to current options.

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

Research has shown that the drug lurbinectedin may help treat small cell lung cancer (SCLC). In studies, 66.7% of patients who had already tried other treatments experienced tumor shrinkage with lurbinectedin. Berzosertib, used alone or with other drugs, has also demonstrated tumor-fighting capabilities and is considered safe. This trial will evaluate the combination of lurbinectedin and berzosertib, which might enhance their effectiveness against challenging cancers like SCLC and high-grade neuroendocrine cancers (HGNEC). These findings suggest that this drug combination could help shrink tumors unresponsive to standard treatments. ^{1 2 4 6 7}

Who Is on the Research Team?

Anish Thomas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9469650/

Lurbinectedin in small cell lung cancer - PMC - PubMed Central For roughly 30 years, outcomes for patients with extensive-stage ES-SCLC have remained substantially unchanged (8–12), and only recently the combination of ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04802174

NCT04802174 | Lurbinectedin With Berzosertib, an ATR ... Berzosertib is a potent and selective kinase inhibitor of ATR, with demonstrated safety and anti-tumor activity as monotherapy and combination with multiple ...

3. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-024-13104-w

Efficacy and toxicity of lurbinectedin in subsequent systemic ... As a promising alternative for second-line treatment for ES-SCLC, lurbinectedin has a certain level of efficacy and a favorable safety profile.

4. physiciansweekly.com physiciansweekly.com/post/second-line-later-therapies-show-promising-outcomes-in-small-cell-lung-cancer

Lurbinectedin Shows 66.7% Response Rate in 4th-Line ... Study shows lurbinectedin achieved 66.7% response rate in fourth-line SCLC therapy, with improved outcomes following prior immunotherapy ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT506206

Lurbinectedin for small cell lung cancer (SCLC) This study aimed to analyze line-dependent outcomes and response patterns of lurbinectedin in SCLC patients. ... small cell lung cancer: Preliminary results of a ...

6. embopress.org embopress.org/doi/10.15252/emmm.202217313

ATR inhibition augments the efficacy of lurbinectedin in ... We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in SCLC.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10405061/

ATR inhibition augments the efficacy of lurbinectedin in ... We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in small cell lung cancer. This synergy ...