Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High-Grade Neuroendocrine Cancers

NCT04802174 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10000176000176-C
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

SCLC; Small Cell Cancer; Advanced Solid Tumor; High Grade Neuroendocrine Cancers

Keywords

SCLC; HGNC; M6620

Outcome Measures

Primary Outcomes (2)

• MTD

  Maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib.

  Phase I

• Clinical response rate

  \- Fraction of participants who experience a PR or CR in each cohort reported along with a 95% confidence interval. - Overall response rate for both cohorts combined, along with a 95% confidence interval.

  Phase II

Secondary Outcomes (7)

• Safety and tolerability

  Phase I

• Pharmacodynamic markers of response

  Phase I

• Pharmacokinetic profile of Berzosertib and Lurbinectedin

  Phase I

• Progression-free survival (PFS)

  Phase II

• Overall survival (OS)

  Phase II

Study Arms (2)

1/ Phase I

EXPERIMENTAL

Dose escalation of Berzosertib + lurbinectedin

Drug: Lurbinectedin; Drug: Berzosertib

2/ Phase II

EXPERIMENTAL

Berzosertib + lurbinectedin at MTD

Drug: Lurbinectedin; Drug: Berzosertib

Interventions

Lurbinectedin DRUG

Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.

1/ Phase I; 2/ Phase II

Berzosertib DRUG

Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.

1/ Phase I; 2/ Phase II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Both Phase I and Phase II:
• \>= 18 years of age.
• ECOG performance status \<= 2
• Measurable disease, per RECIST 1.1. Individuals with evaluable, but not measurable disease will be eligible for Phase I.
• Adequate organ functions
• Hemoglobin \>= 9.0 g/dL
• Absolute neutrophil count \>= 1.5x10\^9/L
• Platelets \>= 100x10\^9/L
• Total Bilirubin \<= 2.0 mg/dL
• Transaminases \<= 2 x ULN or if liver metastases were present, \<= 3 x ULN
• Creatinine \<= 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula \>= 60 mL/min
• Ability to understand and the willingness to sign a written informed consent document.
• Individuals of child-bearing potential (IOCBP) and individuals able to father a child must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study participation and for 6 months after the last dose of berzosertib/lurbinectedin for IOCBP and for 4 months after lurbinectedin or 3 months after berzosertib for individuals able to father children.
• Phase I:
• Histologically confirmed advanced solid cancers will be eligible.

You may not qualify if:

• Individuals with tumor amenable to potentially curative therapy.
• Currently receiving any other investigational agents.
• Received chemotherapy, or undergone major surgery within the prior 2 weeks and radiotherapy within the last 24 hours.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
• Symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, individuals who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
• Requirement for any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible.
• Evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
• HIV-positive on or off combination antiretroviral therapy are ineligible.
• Pregnant individuals are excluded from this study.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Schultz CW, Zhang Y, Elmeskini R, Zimmermann A, Fu H, Murai Y, Wangsa D, Kumar S, Takahashi N, Atkinson D, Saha LK, Lee CF, Elenbaas B, Desai P, Sebastian R, Sharma AK, Abel M, Schroeder B, Krishnamurthy M, Kumar R, Roper N, Aladjem M, Zenke FT, Ohler ZW, Pommier Y, Thomas A. ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer. EMBO Mol Med. 2023 Aug 7;15(8):e17313. doi: 10.15252/emmm.202217313. Epub 2023 Jul 25.

  PMID: 37491889 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Small Cell Lung Carcinoma

Interventions

PM 01183; berzosertib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Anish Thomas, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2021
• First Posted: March 17, 2021
• Study Start: June 1, 2021
• Primary Completion: December 17, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-03-13

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)