Lurbinectedin + Berzosertib for Small Cell Lung Cancer
Recruiting in Palo Alto (17 mi)
Overseen byAnish Thomas, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: CYP3A inhibitors/inducers
Disqualifiers: Symptomatic brain metastases, HIV, others
No Placebo Group
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.
12345What 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.
23467Eligibility 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.
+5 more
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.
+6 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: 2/ Phase IIExperimental Treatment2 Interventions
Berzosertib + lurbinectedin at MTD
Group II: 1/ Phase IExperimental Treatment2 Interventions
Dose escalation of Berzosertib + lurbinectedin
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
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]Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored.
Treatment of Small Cell Lung Cancer with Lurbinectedin: A Review. [2022]Lurbinectedin was approved on June 15, 2020 by the Food and Drug Administration with the brand name ZEPZELCA as the first systematic approved therapy for patients having Small Cell Lung Cancer (SCLC).
Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. [2023]Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours.
Lurbinectedin: First Approval. [2021]The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.
ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer. [2023]Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.
Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma. [2022]Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet.
Lurbinectedin in the treatment of relapsed small cell lung cancer. [2021]Lurbinectedin is a marine-derived drug that inhibits transcription, a process that is frequently dysregulated in small cell lung cancer. The activity of lurbinectedin has been studied in many solid tumors, showing not only promising results but also a favorable safety profile. In relapsed small cell lung cancer, the drug has shown encouraging activity both as a single agent and in combination with doxorubicin, paclitaxel or irinotecan. The USA FDA has recently granted accelerated approval to lurbinectedin monotherapy in this setting. This article provides an update on available data and ongoing studies of lurbinectedin in small cell lung cancer, including Phase I combination trials, the basket Phase II trial and the ATLANTIS Phase III trial.