Sacituzumab Govitecan + Berzosertib for Small Cell Lung Cancer

Overseen By Anish Thomas, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, UGT1A1 inhibitors

Disqualifiers: Symptomatic brain metastasis, Myelosuppressive disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: Until disease progression or intolerable side effects

120 Participants Needed

Trial Summary

What is the purpose of this trial?

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....

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other investigational drugs or certain medications that affect liver enzymes. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Sacituzumab Govitecan + Berzosertib for Small Cell Lung Cancer?

Sacituzumab Govitecan has shown effectiveness in heavily pretreated small cell lung cancer patients, with 60% of patients experiencing tumor shrinkage and a median overall survival of 7.5 months. Additionally, Sacituzumab Govitecan has been effective in treating metastatic triple-negative breast cancer, suggesting its potential in other cancers. ^{1 2 3 4 5}

What safety data exists for Sacituzumab Govitecan and Berzosertib in humans?

Sacituzumab Govitecan has been associated with side effects like neutropenia (low white blood cell count), diarrhea, colitis (inflammation of the colon), and sepsis (a severe infection), and these need close monitoring. Berzosertib has been studied in combination with other drugs for advanced solid tumors, but specific safety data for its use with Sacituzumab Govitecan in small cell lung cancer is not detailed in the available research. ^{1 2 4 6 7}

What makes the drug Sacituzumab Govitecan + Berzosertib unique for treating small cell lung cancer?

This drug combination is unique because it includes Sacituzumab Govitecan, an antibody-drug conjugate that targets a specific protein (Trop-2) on cancer cells to deliver a chemotherapy agent directly to them, potentially improving effectiveness and reducing side effects compared to traditional chemotherapy. ^{1 2 5 8 9}

Research Team

Anish Thomas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with certain advanced cancers, including small cell lung cancer and solid tumors resistant to PARP inhibitors. Participants must have a lesion safe for biopsy, measurable disease, stable brain metastases if present, good organ function, and no major treatments within specific time frames before the trial. They should not have severe genetic disorders affecting drug processing or uncontrolled illnesses that could hinder compliance.

Inclusion Criteria

I can take care of myself and perform daily activities.

My brain metastases are stable and not causing new symptoms.

I am willing to have a biopsy and have at least one lesion that can safely be biopsied.

Exclusion Criteria

I have a blood disorder affecting my bone marrow or acute myeloid leukemia.

I have a specific genetic variant that affects drug processing.

I am infected with Hepatitis C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive sacituzumab govitecan on days 1 and 8 and berzosertib on days 2 and 9 of each 21-day cycle

Until disease progression or intolerable side effects

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month after treatment, then every 3 months for life

1 visit (in-person), then contact by phone or email

Treatment Details

Interventions

• Berzosertib
• Sacituzumab Govitecan

Trial Overview The study is testing a combination of two drugs: Sacituzumab Govitecan and Berzosertib in patients with aggressive cancers like small cell lung cancer. The goal is to find a safe dosage that can shrink these tumors. Patients will receive the drugs intravenously on set days over 21-day cycles as long as they benefit without intolerable side effects.

Participant Groups

Group I: 2/Phase II Experimental Treatment 2 Interventions

Sacituzumab Govitecan and Berzosertib treatment with identified MTD based on phase I.

Group II: 1/Phase I Experimental Treatment 2 Interventions

Dose escalated Sacituzumab Govitecan and Berzosertib

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 50 patients with metastatic small cell lung cancer (mSCLC) who had been heavily pretreated, sacituzumab govitecan demonstrated a 14% objective response rate, with 60% of patients showing tumor shrinkage, indicating its potential efficacy as a treatment option.

The treatment was found to be generally safe, with manageable side effects; however, significant adverse events included neutropenia (34%) and fatigue (13%). This suggests that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan. Gray, JE., Heist, RS., Starodub, AN., et al.[2022]

Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 and has shown a 33.3% overall response rate in patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies, based on a phase I/II study with 108 participants.

The treatment has a median duration of response of 7.7 months, and while it is generally well-tolerated, common side effects include nausea, neutropenia, and fatigue, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer. Seligson, JM., Patron, AM., Berger, MJ., et al.[2021]

In a phase 1/2 trial involving 108 patients with heavily pretreated metastatic triple-negative breast cancer, sacituzumab govitecan-hziy demonstrated a response rate of 33.3%, with a median duration of response of 7.7 months, indicating its efficacy in this challenging patient population.

The treatment was associated with significant myelotoxic effects, including anemia and neutropenia, but overall survival was promising at a median of 13.0 months, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia, A., Mayer, IA., Vahdat, LT., et al.[2019]

In a study involving 60 patients with advanced solid tumors, the combination of berzosertib and gemcitabine was found to be well tolerated, with a recommended Phase 2 dose established for this combination.

The treatment showed preliminary signs of efficacy, with many patients achieving either a partial response or stable disease, indicating potential benefits for those with resistant or refractory tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Middleton, MR., Dean, E., Evans, TRJ., et al.[2023]

Sacituzumab govitecan (SG) demonstrated effectiveness in treating relapsed or refractory metastatic triple-negative breast cancer (RM-TNBC), with a median overall survival of 12.9 months and an objective response rate of 34% based on an analysis of 412 patients across three trials.

The treatment was associated with significant adverse effects, particularly myelosuppression, with 46% of patients experiencing grade ≥3 neutropenia, and there were four treatment-related deaths reported, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An integrated analysis of Sacituzumab govitecan in relapsed or refractory metastatic triple-negative breast cancer. Cheng, SX., Chen, QC., Lin, GH., et al.[2023]

A total of 1,884 adverse event reports related to sacituzumab govitecan were analyzed, identifying 114 adverse event signals, with most occurring within 30 days of treatment initiation, highlighting the importance of monitoring for early reactions.

Risk factors for hospitalization due to adverse events included being male and experiencing conditions like colitis, febrile neutropenia, and sepsis, indicating specific patient profiles that may require closer observation during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postmarketing safety of Sacituzumab govitecan: a pharmacovigilance study based on FDA adverse event reporting system (FAERS). Li, X., Zhang, L., Hu, S., et al.[2023]

Sacituzumab govitecan-hziy (TRODELVY) received accelerated FDA approval for treating metastatic triple-negative breast cancer (mTNBC) based on a trial involving 108 patients, showing an objective response rate of 33.3% and a median duration of response of 7.7 months.

The safety profile was assessed in a larger group of 408 patients, with common side effects including nausea, neutropenia, and fatigue, occurring in 25% or more of patients, indicating that while effective, the treatment can have significant adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer. Wahby, S., Fashoyin-Aje, L., Osgood, CL., et al.[2022]

Sacituzumab govitecan (SG) showed a clinically significant advantage over chemotherapy for treating HR+/HER2- metastatic breast cancer, providing an increase of 0.284 life years and 0.217 quality-adjusted life years (QALYs).

However, SG was not considered cost-effective at the current pricing, with an incremental cost-effectiveness ratio (ICER) of $612,772/QALY, indicating that substantial price reductions would be necessary for it to be deemed cost-effective from a third-party payer perspective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Shi, D., Li, Y., Liang, X., et al.[2023]

Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 and delivers a topoisomerase I inhibitor, showing promise in treating metastatic triple-negative breast cancer (mTNBC) after at least two prior therapies.

In April 2020, it received accelerated approval in the USA for mTNBC, and it is currently undergoing further clinical trials for various cancers, indicating its potential as a versatile treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan: First Approval. Syed, YY.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

An integrated analysis of Sacituzumab govitecan in relapsed or refractory metastatic triple-negative breast cancer. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Postmarketing safety of Sacituzumab govitecan: a pharmacovigilance study based on FDA adverse event reporting system (FAERS). [2023]

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan: First Approval. [2021]