Advanced Solid Tumor Clinical Trial
Official title:
A Phase I/II Trial of Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High Grade Neuroendocrine Cancers
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.
Status | Recruiting |
Enrollment | 120 |
Est. completion date | December 1, 2027 |
Est. primary completion date | August 1, 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | - INCLUSION CRITERIA: - Both Phase I and Phase II: - Male and female, greater than or equal to 18 years of age. - ECOG performance status less than or equal to 2 - Measurable disease, per RECIST 1.1. Individuals with evaluable, but not measurable disease will be eligible for Phase I. - Adequate organ functions - Hemoglobin greater than or equal to 9.0 g/dL - Absolute neutrophil count greater than or equal to 1.5x10(9)/L - Platelets greater than or equal to 100x10(9)/L - Total Bilirubin less than or equal to 2.0 mg/dL - Transaminases less than or equal to 2 x ULN or if liver metastases were present, less than or equal to 3 x ULN - Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula greater than or equal to 60 mL/min - Ability to understand and the willingness to sign a written informed consent document. - Women of child-bearing potential and men 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 women and for 4 months after lurbinectedin or 3 months after berzosertib for men. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Phase I: - Histologically confirmed advanced solid cancers will be eligible. - At least one prior chemotherapy Phase II: - Histological confirmation of SCLC or HGNEC. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist. EXCLUSION CRITERIA: - 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 women are excluded from this study. |
Country | Name | City | State |
---|---|---|---|
United States | National Institutes of Health Clinical Center | Bethesda | Maryland |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | MTD | Maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib. | Phase I | |
Primary | 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 | Safety and tolerability | Dose level Adverse Events (AE) per CTCAE v5.0, by type and grade of toxicity. | Phase I | |
Secondary | Pharmacodynamic markers of response | GammaH2ax and POLII as possible markers for pharmacodynamic activity and evaluation of changes in the markers between baseline and end of treatment vs. response | Phase I | |
Secondary | Pharmacokinetic profile of Berzosertib and Lurbinectedin | 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. | Phase I | |
Secondary | Progression-free survival (PFS) | - Progression free survival will be determined from the on-study date until date of progression or death without progression, separately by cohort. | Phase II | |
Secondary | Overall survival (OS) | - Overall survival determined from the on-study date until date of death or last follow-up, separately by phase II cohort. | Phase II | |
Secondary | Duration of response | Duration of response to the combination in both platinum sensitive and refractory participants | Phase II | |
Secondary | Safety and tolerability of the MTD | Grades and types of toxicity will be reported for all patients treated at the DLT. | Phase II |
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