Neoplasms

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Carcinoma, Small Cell

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Bronchial Neoplasms

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Lung Diseases

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Small Cell Lung Cancer

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Antineoplastic Agents

All Drugs and Chemicals

Topotecan

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may crossover to Arm II at disease progression. Patients undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Patients may also undergo blood sample collection during screening and on study.

Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 and M6620 IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Patients may also undergo blood sample collection during screening and on study.

Berzosertib

Biopsy

Biospecimen Collection

Computed Tomography

Topotecan Hydrochloride

Anish Thomas

This phase II trial studies how well berzosertib (M6620) works when given in combination with topotecan hydrochloride (topotecan) compared with topotecan alone in treating patients with small cell lung cancer that has come back (relapsed), or small cell cancer that arises from a site other than the lung (extrapulmonary). Drugs used in chemotherapy, such as topotecan hydrochloride, work by damaging the DNA (deoxyribonucleic acid) in tumor cells, causing those cells to die and the tumor to shrink. However, some tumor cells can become less affected by chemotherapy because they have ways to repair the damaged DNA. The addition of M6620 could help topotecan hydrochloride shrink the cancer and prevent it from returning by blocking enzymes needed for DNA repair.

PRIMARY OBJECTIVE:

I. To determine if the combination of berzosertib (M6620) with topotecan hydrochloride (topotecan) will result in an improvement in progression-free survival (PFS) compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC).

SECONDARY OBJECTIVE:

I. To determine the objective response rate (ORR) and overall survival (OS) with the combination of M6220 and topotecan in patients with relapsed SCLC and extrapulmonary small cell cancers.

EXPLORATORY OBJECTIVES:

I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to ribonucleic acid (RNA) sequencing (RNA-Seq):

Ia. To assess expression of genes Schlafen family member 11 (SLFN11), MYC, and ataxia-telangiesctasia mutated (ATM) among others.

Ib. To identify potential predictive biomarkers of response to a combination of M6620 with topotecan.

Ic. Identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.

II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Early-Phase and Experimental Clinical Trials (EET) Biobank at Nationwide Children's Hospital.

IV. To characterize circulating cell-free DNA (cfDNA) and circulating tumor cells in patients with relapsed SCLC and extrapulmonary small cell cancers.

V. To identify potential predictive biomarkers of response to a combination of M6620 with topotecan in patients with extrapulmonary small cell cancers.

OUTLINE: Patients are randomized to 1 of 2 arms. Patients with extrapulmonary small cell cancer are assigned to Arm II while patients with relapsed small cell lung cancer are assigned to both arms.

ARM I: Patients receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may crossover to Arm II at disease progression. Patients undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Patients may also undergo blood sample collection during screening and on study.

ARM II: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 and M6620 IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Patients may also undergo blood sample collection during screening and on study.

After completion of study treatment, patients are followed up at 4 weeks and then every 12 weeks thereafter.

Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs

Randomized Phase II Trial of Topotecan Plus M6620 (VX-970, Berzosertib) vs. Topotecan Alone in Patients With Relapsed Small-Cell Lung Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

The combination of M6620 with topotecan will be compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC). Kaplan-Meier curves and a one-tailed log-rank test will be the primary analysis methods.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs	NCT03896503	Bladder Small C... Extensive Stage... Extrapulmonary ... Limited Stage L... Platinum-Resist... Platinum-Sensit... Prostate Small ... Recurrent Lung ...	Berzosertib Biopsy Biospecimen Col... Computed Tomogr... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)
Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs	NCT03896503	Bladder Small C... Extensive Stage... Extrapulmonary ... Limited Stage L... Platinum-Resist... Platinum-Sensit... Prostate Small ... Recurrent Lung ...	Berzosertib Biopsy Biospecimen Col... Computed Tomogr... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for extrapulmonary small cell neuroendocrine carcinoma