RECRUITING

A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer, Extra-Pulmonary Small Cell Neuroendocrine Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors

Conditions

HRD Cancer SCLC Advanced Solid Tumors PARPi resistance ATR inhibition targeted DNA-damaging chemotherapy Antibody-Drug Conjugate topoisomerase-I inhibiting camptothecin

Quick Navigation

Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

Background: Small cell lung cancer and PARP inhibitor resistant tumors are aggressive cancers. Current treatments for people with these tumors yield little benefit. Researchers want to see if a combination of drugs can help. Objective: To find a safe combination of sacituzumab govitecan and berzosertib and to see if this will cause small cell lung cancer and PARP inhibitor resistant tumors to shrink. Eligibility: People ages 18 and older with a solid tumor, small cell lung cancer, or a homologous recombination-deficient cancer that is resistant to PARP inhibitors Design: Participants will be screened with: Standard clinical exams and tests EKG to test the heart Medical documentation to confirm cancer diagnosis Participants will get sacituzumab govitecan by vein on days 1 and 8 of each 21-day cycle. They will get berzosertib by vein on days 2 and 9. Treatment will continue as long as they can tolerate the drugs and their tumors are either stable or getting better. Before treatment and at least once per cycle, participants will have a physical exam and blood tests. Before treatment and every 2 or 3 cycles, they will have a CT scan. They will have a contrast agent injected into a vein for the scan. Participants will give blood and hair samples and tumor biopsies for research. Biopsies will be taken with a small needle under imaging guidance. After they stop treatment, participants will have a visit 1 month later. They will then be contacted by phone or email every 3 months for the rest of their lives....

Official Title

A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer, Extra-Pulmonary Small Cell Neuroendocrine Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors

Quick Facts

Study Start:2021-09-20

Study Completion:2027-03-01

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04826341

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 120 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* Age \>=18 years. Because no dosing or adverse event data are currently available on the use of sacituzumab govitecan in combination with and berzosertib in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. * ECOG performance status \<=2 * Participants must have adequate organ and marrow function as defined below: * leukocytes \>=3,000/mcL * Hemoglobin \>=9.0g/dL * absolute neutrophil count \>=1,500/mcL * platelets \>=100,000/mcL * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) \<=2.5 X institutional upper limit of normal * creatinine within normal institutional limits * Participants with neurologically stable brain metastases defined as asymptomatic metastasis, or treated metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment (including brain radiotherapy) may be included. Participants must be off any systemic corticosteroids for the treatment of brain metastases for at least 7 days prior to enrollment. * Participants with previously treated with topoisomerase 1/2 inhibitors can be enrolled. * The effects of the combined study drugs on the developing human fetus are unknown. For this reason and because study agents as well as other therapeutic agents used in this trial are known to be teratogenic, individuals of child-bearing potential and individuals who can father children must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, while taking the study drugs and for 6 months after the administered study drug (berzosertib or sacituzumab govitecan). * Ability of subject to understand and the willingness to sign a written informed consent document. * If this alteration is identified in a circulating tumor deoxyribonucleic acid (ctDNA) assay, the variant-allele fraction must be \> 20% to indicate relevance to predominant tumor clone * Mutation in one or more other genes involved in homologous DNA recombination repair in the tumor may be included at investigator's * Participants must have measurable disease, per RECIST 1.1. * Participants must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies (Pre-treatment, On-Treatment, PD). Up to 10 participants with non-biopsiable disease may be enrolled. * Participants should have demonstrated progressive disease while taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy. Response to prior PARPi is not required. * Participants may have received chemotherapy in the interval between PARPi and enrollment. * Recurrent histologically or cytologically confirmed SCLC or EP-SCNC after at least one prior platinum-based therapy. * Participants must have measurable disease, per RECIST 1.1. * Participants must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies (Pre-Treatment, On-Treatment, PD). Up to 10 participants with non-biopsiable disease may be enrolled.	* Participants who are receiving any other investigational agents or concurrent systemic anti-cancer therapies. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs or other agents used in study. * Participants with symptomatic brain metastasis. * Participants who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with sacituzumab govitecan. * Participants known to be homozygous for the UGT1A1\28 variant allele with severely reduced UGT1A1 activity. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant individuals are excluded from this study because study drugs have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study drugs, breastfeeding should be discontinued if the mother is treated with the study drugs. These potential risks may also apply to other agents used in this study. * Participants with myelosuppressive disorders or acute myeloid leukemia. * HIV positive participants with the following exception: Patients with long-standing (\>5 years) HIV on antiretroviral therapy \> 1 month (undetectable HIV viral load and CD4 count \> 150 cells/microL) may be eligible if the principal investigator determines no anticipated clinically significant drug-drug interactions. * Participants with evidence of chronic hepatitis B virus (HBV) infection, unless the HBV viral load is undetectable and participant is on suppressive therapy, if indicated. * HCV infected participants with the following exceptions: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

Inclusion Criteria

Exclusion Criteria

* Age \>=18 years. Because no dosing or adverse event data are currently available on the use of sacituzumab govitecan in combination with and berzosertib in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* ECOG performance status \<=2
* Participants must have adequate organ and marrow function as defined below:
* leukocytes \>=3,000/mcL
* Hemoglobin \>=9.0g/dL
* absolute neutrophil count \>=1,500/mcL
* platelets \>=100,000/mcL
* total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) \<=2.5 X institutional upper limit of normal
* creatinine within normal institutional limits
* Participants with neurologically stable brain metastases defined as asymptomatic metastasis, or treated metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment (including brain radiotherapy) may be included. Participants must be off any systemic corticosteroids for the treatment of brain metastases for at least 7 days prior to enrollment.
* Participants with previously treated with topoisomerase 1/2 inhibitors can be enrolled.
* The effects of the combined study drugs on the developing human fetus are unknown. For this reason and because study agents as well as other therapeutic agents used in this trial are known to be teratogenic, individuals of child-bearing potential and individuals who can father children must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, while taking the study drugs and for 6 months after the administered study drug (berzosertib or sacituzumab govitecan).
* Ability of subject to understand and the willingness to sign a written informed consent document.
* If this alteration is identified in a circulating tumor deoxyribonucleic acid (ctDNA) assay, the variant-allele fraction must be \> 20% to indicate relevance to predominant tumor clone
* Mutation in one or more other genes involved in homologous DNA recombination repair in the tumor may be included at investigator's
* Participants must have measurable disease, per RECIST 1.1.
* Participants must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies (Pre-treatment, On-Treatment, PD). Up to 10 participants with non-biopsiable disease may be enrolled.
* Participants should have demonstrated progressive disease while taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy. Response to prior PARPi is not required.
* Participants may have received chemotherapy in the interval between PARPi and enrollment.
* Recurrent histologically or cytologically confirmed SCLC or EP-SCNC after at least one prior platinum-based therapy.
* Participants must have measurable disease, per RECIST 1.1.
* Participants must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies (Pre-Treatment, On-Treatment, PD). Up to 10 participants with non-biopsiable disease may be enrolled.

* Participants who are receiving any other investigational agents or concurrent systemic anti-cancer therapies.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs or other agents used in study.
* Participants with symptomatic brain metastasis.
* Participants who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with sacituzumab govitecan.
* Participants known to be homozygous for the UGT1A1\*28 variant allele with severely reduced UGT1A1 activity.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant individuals are excluded from this study because study drugs have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study drugs, breastfeeding should be discontinued if the mother is treated with the study drugs. These potential risks may also apply to other agents used in this study.
* Participants with myelosuppressive disorders or acute myeloid leukemia.
* HIV positive participants with the following exception: Patients with long-standing (\>5 years) HIV on antiretroviral therapy \> 1 month (undetectable HIV viral load and CD4 count \> 150 cells/microL) may be eligible if the principal investigator determines no anticipated clinically significant drug-drug interactions.
* Participants with evidence of chronic hepatitis B virus (HBV) infection, unless the HBV viral load is undetectable and participant is on suppressive therapy, if indicated.
* HCV infected participants with the following exceptions: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

Contacts and Locations

Study Contact

Linda C Sciuto, R.N.

CONTACT

(240) 760-6117

linda.sciuto@nih.gov

Anish Thomas, M.D.

CONTACT

(240) 760-7343

anish.thomas@nih.gov

Principal Investigator

Anish Thomas, M.D.

PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Study Locations (Sites)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

United States

Collaborators and Investigators

Sponsor: National Cancer Institute (NCI)

Anish Thomas, M.D., PRINCIPAL_INVESTIGATOR, National Cancer Institute (NCI)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-09-20

Study Completion Date2027-03-01

Study Record Updates

Study Start Date2021-09-20

Study Completion Date2027-03-01

Terms related to this study

Keywords Provided by Researchers

PARPi resistance
ATR inhibition
targeted DNA-damaging chemotherapy
Antibody-Drug Conjugate
topoisomerase-I inhibiting camptothecin

Additional Relevant MeSH Terms

HRD Cancer
SCLC
Advanced Solid Tumors