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

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ClinicalTrials.gov Identifier: NCT04826341
Recruitment Status : Recruiting
First Posted : April 1, 2021
Last Update Posted : September 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
HRD Cancer SCLC Advanced Solid Tumors Drug: Berzosertib Drug: Sacituzumab Govitecan Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors
Actual Study Start Date : September 20, 2021
Estimated Primary Completion Date : March 1, 2026
Estimated Study Completion Date : March 1, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/Phase I
Dose escalated Sacituzumab Govitecan and Berzosertib
Drug: Berzosertib
Berzosertib will be supplied as 20 mg/mL M6620 to be diluted with 5% dextrose in water solution before intravenous infusion.

Drug: Sacituzumab Govitecan
Sacituzumab Govitecan will be administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles.

Experimental: 2/Phase II
Sacituzumab Govitecan and Berzosertib treatment with identified MTD based on phase I.
Drug: Berzosertib
Berzosertib will be supplied as 20 mg/mL M6620 to be diluted with 5% dextrose in water solution before intravenous infusion.

Drug: Sacituzumab Govitecan
Sacituzumab Govitecan will be administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles.




Primary Outcome Measures :
  1. Phase II: ORR [ Time Frame: Disease progression ]
    In phase II, in each cohort, the fraction of participants who experience a PR or CR will be reported along with a 95% confidence interval.

  2. Phase I: MTD [ Time Frame: Phase I ]
    In phase I, the toxicities identified at each dose level will be reported, by dose level, type, and grade.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Disease progression ]
    Progression free survival (PFS) will be calculated from on-study date until date of progression or death without progression, using the Kaplan-Meier method accompanied by determination of the median and its 95% confidence interval.

  2. Overall survival (OS) [ Time Frame: Death ]
    Overall survival (OS) will be calculated from the on-study date until date of death.

  3. Toxicity grade and type [ Time Frame: during treatment ]
    To assess safety and tolerability in phase II cohort in PARP inhibitor-resistant HRD tumors and previously treated SCLC, the toxicity grade and type will be reported for all patients treated on the two cohorts.

  4. Duration of response [ Time Frame: Disease progression ]
    Duration of response will be calculated by the Kaplan-Meier method (accompanied by determination of the median and its 95% confidence interval), starting at date response was identified until progression or the response is declared to have ended, if the participants have a PR or CR.

  5. Safety and tolerability [ Time Frame: during treatment ]
    Safety and tolerability of the combination will be reported by describing Adverse Events (AE) per CTCAE v5.0, by dose level, and type and grade of toxicity. This will be focused on phase I but also reported in phase II.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

All phases and cohorts

  • Subjects must not have received chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior to cycle 1 day 1.
  • Age greater than or equal to 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 less than or equal to 2
  • Participants must have adequate organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL
    • Hemoglobin greater than or equal to 9.0g/dL
    • absolute neutrophil count greater than or equal to 1,500/mcL
    • platelets greater than or equal to 100,000/mcL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal
    • creatinine within normal institutional limits

OR

--creatinine clearance greater than or equal to 30 mL/min/1.73 m2 for participants with creatinine levels above institutional normal

(calculated by Cockcroft-Gault formula).

  • 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, 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, while taking the study drugs and for 6 months after the administered study drug (berzosertib or sacituzumab govitecan). 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.
  • Ability of subject to understand and the willingness to sign a written informed consent document.

Phase I

  • Participants with histologically or cytologically confirmed advanced solid tumors with progression on at least one prior chemotherapy.
  • Known HRD cancer and documented evidence of at least ONE or MORE of the following:

    • Pathogenic or likely pathogenic somatic mutation or inactivating alteration of a gene involved in homologous recombination (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) repair in the tumor. Local testing in Clinical Laboratory Improvement Act (CLIA)-certified laboratory will be accepted. No

variants of uncertain significance (VUS) will be allowed.

  • 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

discretion

---Homologous recombination repair deficiency by genomic signature in the tumor by BROCA-HR, Foundation One or equivalent assay

--Presence of pathogenic or likely pathogenic germline mutation/variant in BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L. Germline mutations in other HR genes will be considered at investigator's discretion. Local testing in Clinical Laboratory Improvement Act (CLIA)-certified laboratory will be accepted. No variants of uncertain significance (VUS) will be allowed.

  • 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-Tumor, 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.

Phase II SCLC

  • Recurrent histologically or cytologically confirmed SCLC 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-Tumor, On-Treatment, PD). Up to 10 participants with non-biopsiable disease may be enrolled.

EXCLUSION CRITERIA:

  • 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 women 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 must be undetectable 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04826341


Contacts
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Contact: Rasa Vilimas, R.N. (240) 858-3158 rasa.vilimas@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04826341    
Other Study ID Numbers: 10000144
000144-C
First Posted: April 1, 2021    Key Record Dates
Last Update Posted: September 24, 2021
Last Verified: September 15, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
PARPi resistance
ATR inhibition
targeted DNA-damaging chemotherapy
Antibody-Drug Conjugate
topoisomerase-I inhibiting camptothecin
Additional relevant MeSH terms:
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Small Cell Lung Carcinoma
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases