Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High-Grade Neuroendocrine Cancers
- Conditions
- SCLCAdvanced Solid TumorHigh Grade Neuroendocrine CancersSmall Cell Cancer
- Interventions
- Registration Number
- NCT04802174
- Lead Sponsor
- National Cancer Institute (NCI)
- 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.
- Detailed Description
Background:
Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive neuroendocrine cancers with poor prognosis. Although responsive to chemotherapy initially, both tumor types relapse quickly and become refractory to treatment within a few months.
Replication stress is an SCLC hallmark, driven by oncogenes that drive rapid and unscheduled proliferation (TP53 and RB1 inactivation, MYC amplification, etc.). HGNECs share similarities in morphology, biologic behavior with SCLC. Treatment paradigms have largely paralleled those established for SCLC.
ATR is the master regulator of replication stress response. Upon activation, the ATR CHK1 signaling leads to cell cycle arrest and promotes replication fork stabilization and restart.
ATR inhibition generates replication stress and disables cell cycle checkpoints to ultimately cause mitotic catastrophe and cell death. Many genotoxic agents currently used in cancer therapy are also potent inducers of replication stress.
Berzosertib is a potent and selective kinase inhibitor of ATR, with demonstrated safety and anti-tumor activity as monotherapy and combination with multiple chemotherapeutics (including platinum, gemcitabine, and topoisomerase inhibitors) in high replication stress tumors.
Lurbinectedin is a recently approved second-line SCLC treatment which forms DNA adducts by covalently binding to the minor groove of DNA that kills cancer cells by inhibiting Pol-II and causing DNA damage
We hypothesize that a combination of ATR kinase inhibition with lurbinectedin will provide an attractive synergistic therapeutic option for SCLC and HGNEC.
Primary objectives:
Phase I: To identify the maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib.
Phase II: To assess the efficacy with respect to clinical response rate of a combination of lurbinectedin and berzosertib in previously treated participants with SCLC and HGNECs.
Eligibility:
All phases: Participants must be greater than or equal to 18 years of age and have a performance status (ECOG) less than or equal to 2. Participants must not have received chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior to enrollment.
Phase I: Participants with histologically confirmed solid tumors and progression on standard therapies. Participants with evaluable, but not measurable disease will be eligible for Phase I.
Phase II: Participants with histological confirmation of SCLC or HGNEC. Participants must have measurable disease to be eligible for Phase II.
Design:
This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib in a phase I trial, and assessing the efficacy with respect to clinical response rate of a combination of lurbinectedin and berzosertib as treatment of participants with recurrent SCLC and HGNEC.
Participants will receive lurbinectedin on day 1 and berzosertib on days 1 and 2, administered every 21 days (1 cycle), until disease progression or development of intolerable side effects.
Blood, hair follicles, and tumor will be collected at various time points to support the exploratory objectives.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 120
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/ Phase I Berzosertib Dose escalation of Berzosertib + lurbinectedin 2/ Phase II Lurbinectedin Berzosertib + lurbinectedin at MTD 2/ Phase II Berzosertib Berzosertib + lurbinectedin at MTD 1/ Phase I Lurbinectedin Dose escalation of Berzosertib + lurbinectedin
- Primary Outcome Measures
Name Time Method MTD Phase I Maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib.
Clinical response rate Phase II - 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.
- Secondary Outcome Measures
Name Time Method Safety and tolerability Phase I Dose level Adverse Events (AE) per CTCAE v5.0, by type and grade of toxicity.
Pharmacodynamic markers of response Phase I GammaH2ax and POLII as possible markers for pharmacodynamic activity and evaluation of changes in the markers between baseline and end of treatment vs. response
Pharmacokinetic profile of Berzosertib and Lurbinectedin Phase I This will be evaluated using descriptive methods and reported as exploratory results. If any statistical tests are performed in these analyses, the results will be presented without adjustment for multiple comparisons but reported in the context of the number of tests performed.
Progression-free survival (PFS) Phase II - Progression free survival will be determined from the on-study date until date of progression or death without progression, separately by cohort.
Overall survival (OS) Phase II - Overall survival determined from the on-study date until date of death or last follow-up, separately by phase II cohort.
Duration of response Phase II Duration of response to the combination in both platinum sensitive and refractory participants
Safety and tolerability of the MTD Phase II Grades and types of toxicity will be reported for all patients treated at the DLT.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States