Description:
Background:
Several small molecule poly-(ADP)-ribose polymerase inhibitors (PARPi) have been approved by
the FDA for multiple cancers with homologous recombination (HR) deficiencies. Despite their
measurable initial benefit, PARPi resistance is a major problem in the clinic. There are no
established standards for care of patients who have disease progression after PARPi.
Small cell lung cancer (SCLC) is an aggressive cancer with poor prognosis. Despite being
chemo-sensitive initially, the tumors are invariably chemo-resistant at recurrence. Currently
available therapies for patients who have disease progression after chemotherapy yield
limited benefit, and most patients die within months of relapse.
In preclinical studies, ataxia telangiectasia and Rad3-related protein (ATR) inhibition can
overcome PARPi/chemotherapy-resistance in tumors with restored HR or restored fork
protection. However, combinations of DNA damage response inhibitors and chemotherapy may be
challenging in clinic due to overlapping toxicities, specifically myelosuppression.
To mitigate some of the overlapping toxicities relating to myelosuppression, we have proposed
a strategy that incorporates tumor targeted DNA-damaging chemotherapy delivery (using
approaches such as antibody drug conjugates) and dose scheduling of ATR inhibitors.
Sacituzumab govitecan is an antibody-drug conjugate, comprising a topoisomerase-I inhibiting
camptothecin, SN-38, linked to a humanized antibody targeting trophoblastic cell-surface
antigen 2 (Trop-2), and is FDA approved as Trodelvy for triple-negative breast cancer
patients who have received at least two prior therapies for metastatic disease.
Berzosertib is a potent and selective kinase inhibitor of ATR in phase I and II clinical
trials as a single agent and in combination with chemotherapy, radiation and other anticancer
agents.
We hypothesize that a combination of berzosertib with sacituzumab govitecan will provide an
effective therapeutic option for patients with PARPi resistant tumors and
chemotherapy-resistant SCLCs.
Primary objectives:
Phase I: To identify the maximum tolerated dose (MTD) of sacituzumab govitecan in combination
with berzosertib.
Phase II HRD cohort: To assess the efficacy with respect to objective response rate (ORR) of
the combination of sacituzumab govitecan and berzosertib in previously treated participants
with HRD.
Phase II SCLC cohort: To assess the efficacy with respect to ORR of the combination of
sacituzumab govitecan and berzosertib in previously treated participants with SCLC.
Eligibility:
All phases: Subjects must be greater than or equal to 18 years of age and have a performance
status (ECOG) less than or equal to 2.
Phase I: Adult participants with advanced solid tumors with progression on at least one prior
chemotherapy.
Phase II HRD cohort: Known HRD cancer and documented evidence of germline or somatic BRCA
mutation or other HRD germline mutation, or tumor is HRD positive; progressive disease while
taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy.
Phase II SCLC cohort: Recurrent SCLC after at least one prior platinum-based therapy.
Design:
This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD)
of sacituzumab govitecan in combination with berzosertib in a phase I trial, and assessing
the efficacy with respect to clinical response rate of a combination of sacituzumab govitecan
and berzosertib as treatment of subjects with recurrent SCLC and HRD positive tumors in a
phase II trial. The accrual ceiling will be set to 70 for this study.
Participants will receive sacituzumab govitecan on days 1 and 8 and berzosertib on days 2 and
9, 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.
The Phase I will follow a 3+3 design: dose will be escalated in cohorts of 3-6 participants
each with the individual dose of berzosertib and sacituzumab govitecan increased in
successive dose levels.
The phase II HRD cohort and phase II SCLC cohort will be conducted using a Simon two-stage
Minimax design in order to rule out an unacceptably low 5% response rate (p0=0.05) for HRD
and 10% (p=0.10) response rate for SCLC in favor of a targeted response rate of 20% (p1=0.20)
and 30% (p1=0.30), respectively.
Title
- Brief 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
- 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
Clinical Trial IDs
- ORG STUDY ID:
10000144
- SECONDARY ID:
000144-C
- NCT ID:
NCT04826341
Conditions
- HRD Cancer
- SCLC
- Advanced Solid Tumors
Interventions
Drug | Synonyms | Arms |
---|
Berzosertib | | 1/Phase I |
Sacituzumab Govitecan | | 1/Phase I |
Purpose
Background:
Several small molecule poly-(ADP)-ribose polymerase inhibitors (PARPi) have been approved by
the FDA for multiple cancers with homologous recombination (HR) deficiencies. Despite their
measurable initial benefit, PARPi resistance is a major problem in the clinic. There are no
established standards for care of patients who have disease progression after PARPi.
Small cell lung cancer (SCLC) is an aggressive cancer with poor prognosis. Despite being
chemo-sensitive initially, the tumors are invariably chemo-resistant at recurrence. Currently
available therapies for patients who have disease progression after chemotherapy yield
limited benefit, and most patients die within months of relapse.
In preclinical studies, ataxia telangiectasia and Rad3-related protein (ATR) inhibition can
overcome PARPi/chemotherapy-resistance in tumors with restored HR or restored fork
protection. However, combinations of DNA damage response inhibitors and chemotherapy may be
challenging in clinic due to overlapping toxicities, specifically myelosuppression.
To mitigate some of the overlapping toxicities relating to myelosuppression, we have proposed
a strategy that incorporates tumor targeted DNA-damaging chemotherapy delivery (using
approaches such as antibody drug conjugates) and dose scheduling of ATR inhibitors.
Sacituzumab govitecan is an antibody-drug conjugate, comprising a topoisomerase-I inhibiting
camptothecin, SN-38, linked to a humanized antibody targeting trophoblastic cell-surface
antigen 2 (Trop-2), and is FDA approved as Trodelvy for triple-negative breast cancer
patients who have received at least two prior therapies for metastatic disease.
Berzosertib is a potent and selective kinase inhibitor of ATR in phase I and II clinical
trials as a single agent and in combination with chemotherapy, radiation and other anticancer
agents.
We hypothesize that a combination of berzosertib with sacituzumab govitecan will provide an
effective therapeutic option for patients with PARPi resistant tumors and
chemotherapy-resistant SCLCs.
Primary objectives:
Phase I: To identify the maximum tolerated dose (MTD) of sacituzumab govitecan in combination
with berzosertib.
Phase II HRD cohort: To assess the efficacy with respect to objective response rate (ORR) of
the combination of sacituzumab govitecan and berzosertib in previously treated participants
with HRD.
Phase II SCLC cohort: To assess the efficacy with respect to ORR of the combination of
sacituzumab govitecan and berzosertib in previously treated participants with SCLC.
Eligibility:
All phases: Subjects must be greater than or equal to 18 years of age and have a performance
status (ECOG) less than or equal to 2.
Phase I: Adult participants with advanced solid tumors with progression on at least one prior
chemotherapy.
Phase II HRD cohort: Known HRD cancer and documented evidence of germline or somatic BRCA
mutation or other HRD germline mutation, or tumor is HRD positive; progressive disease while
taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy.
Phase II SCLC cohort: Recurrent SCLC after at least one prior platinum-based therapy.
Design:
This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD)
of sacituzumab govitecan in combination with berzosertib in a phase I trial, and assessing
the efficacy with respect to clinical response rate of a combination of sacituzumab govitecan
and berzosertib as treatment of subjects with recurrent SCLC and HRD positive tumors in a
phase II trial. The accrual ceiling will be set to 70 for this study.
Participants will receive sacituzumab govitecan on days 1 and 8 and berzosertib on days 2 and
9, 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.
The Phase I will follow a 3+3 design: dose will be escalated in cohorts of 3-6 participants
each with the individual dose of berzosertib and sacituzumab govitecan increased in
successive dose levels.
The phase II HRD cohort and phase II SCLC cohort will be conducted using a Simon two-stage
Minimax design in order to rule out an unacceptably low 5% response rate (p0=0.05) for HRD
and 10% (p=0.10) response rate for SCLC in favor of a targeted response rate of 20% (p1=0.20)
and 30% (p1=0.30), respectively.
Detailed Description
Background:
Several small molecule poly-(ADP)-ribose polymerase inhibitors (PARPi) have been approved by
the FDA for multiple cancers with homologous recombination (HR) deficiencies. Despite their
measurable initial benefit, PARPi resistance is a major problem in the clinic. There are no
established standards for care of patients who have disease progression after PARPi.
Small cell lung cancer (SCLC) is an aggressive cancer with poor prognosis. Despite being
chemo-sensitive initially, the tumors are invariably chemo-resistant at recurrence. Currently
available therapies for patients who have disease progression after chemotherapy yield
limited benefit, and most patients die within months of relapse.
In preclinical studies, ataxia telangiectasia and Rad3-related protein (ATR) inhibition can
overcome PARPi/chemotherapy-resistance in tumors with restored HR or restored fork
protection. However, combinations of DNA damage response inhibitors and chemotherapy may be
challenging in clinic due to overlapping toxicities, specifically myelosuppression.
To mitigate some of the overlapping toxicities relating to myelosuppression, we have proposed
a strategy that incorporates tumor targeted DNA-damaging chemotherapy delivery (using
approaches such as antibody drug conjugates) and dose scheduling of ATR inhibitors.
Sacituzumab govitecan is an antibody-drug conjugate, comprising a topoisomerase-I inhibiting
camptothecin, SN-38, linked to a humanized antibody targeting trophoblastic cell-surface
antigen 2 (Trop-2), and is FDA approved as Trodelvy (Trademark) for triple-negative breast
cancer patients who have received at least two prior therapies for metastatic disease.
Berzosertib is a potent and selective kinase inhibitor of ATR in phase I and II clinical
trials as a single agent and in combination with chemotherapy, radiation and other anticancer
agents.
We hypothesize that a combination of berzosertib with sacituzumab govitecan will provide an
effective therapeutic option for patients with PARPi resistant tumors and
chemotherapy-resistant SCLCs.
Primary objectives:
Phase I: To identify the maximum tolerated dose (MTD) of sacituzumab govitecan in combination
with berzosertib.
Phase II HRD cohort: To assess the efficacy with respect to objective response rate (ORR) of
the combination of sacituzumab govitecan and berzosertib in previously treated participants
with HRD.
Phase II SCLC cohort: To assess the efficacy with respect to ORR of the combination of
sacituzumab govitecan and berzosertib in previously treated participants with SCLC.
Eligibility:
All phases: Subjects must be greater than or equal to 18 years of age and have a performance
status (ECOG) less than or equal to 2.
Phase I: Adult participants with advanced solid tumors with progression on at least one prior
chemotherapy.
Phase II HRD cohort: Known HRD cancer and documented evidence of germline or somatic BRCA
mutation or other HRD germline mutation, or tumor is HRD positive; progressive disease while
taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy.
Phase II SCLC cohort: Recurrent SCLC after at least one prior platinum-based therapy.
Design:
This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD)
of sacituzumab govitecan in combination with berzosertib in a phase I trial, and assessing
the efficacy with respect to clinical response rate of a combination of sacituzumab govitecan
and berzosertib as treatment of subjects with recurrent SCLC and HRD positive tumors in a
phase II trial. The accrual ceiling will be set to 70 for this study.
Participants will receive sacituzumab govitecan on days 1 and 8 and berzosertib on days 2 and
9, 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.
The Phase I will follow a 3+3 design: dose will be escalated in cohorts of 3-6 participants
each with the individual dose of berzosertib and sacituzumab govitecan increased in
successive dose levels.
The phase II HRD cohort and phase II SCLC cohort will be conducted using a Simon two-stage
Minimax design in order to rule out an unacceptably low 5% response rate (p0=0.05) for HRD
and 10% (p=0.10) response rate for SCLC in favor of a targeted response rate of 20% (p1=0.20)
and 30% (p1=0.30), respectively.
Trial Arms
Name | Type | Description | Interventions |
---|
1/Phase I | Experimental | Dose escalated Sacituzumab Govitecan and Berzosertib | - Berzosertib
- Sacituzumab Govitecan
|
2/Phase II | Experimental | Sacituzumab Govitecan and Berzosertib treatment with identified MTD based on phase I. | - Berzosertib
- Sacituzumab Govitecan
|
Eligibility 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Phase II: ORR |
Time Frame: | Disease progression |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Progression free survival (PFS) |
Time Frame: | Disease progression |
Safety Issue: | |
Description: | 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. |
Measure: | Overall survival (OS) |
Time Frame: | Death |
Safety Issue: | |
Description: | Overall survival (OS) will be calculated from the on-study date until date of death. |
Measure: | Toxicity grade and type |
Time Frame: | during treatment |
Safety Issue: | |
Description: | 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. |
Measure: | Duration of response |
Time Frame: | Disease progression |
Safety Issue: | |
Description: | 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. |
Measure: | Safety and tolerability |
Time Frame: | during treatment |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- PARPi resistance
- ATR inhibition
- targeted DNA-damaging chemotherapy
- Antibody-Drug Conjugate
- topoisomerase-I inhibiting camptothecin
Last Updated
September 1, 2021