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

Phase 2

Active, not recruiting

Conditions: Limited Stage Lung Small Cell Carcinoma
Platinum-Resistant Lung Small Cell Carcinoma
Platinum-Sensitive Lung Small Cell Carcinoma
Extensive Stage Lung Small Cell Carcinoma
Extrapulmonary Small Cell Neuroendocrine Carcinoma
Recurrent Lung Small Cell Carcinoma

Interventions: Procedure: Biopsy Procedure
Drug: Berzosertib
Procedure: Biospecimen Collection
Procedure: Computed Tomography
Drug: Topotecan Hydrochloride

Registration Number: NCT03896503

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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-telangiectasia 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 assigned to 1 of 2 cohorts.

COHORT I: Patient with SCLC are randomized to 1 of 2 arms.

ARM I: Participants 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. Participants may crossover to Arm II at disease progression. Participants undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.

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

COHORT II (Patients with extrapulmonary small cell cancer): Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 104

Inclusion Criteria

Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at diagnosis, with relapse at study entry with measurable disease at random assignment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Both platinum-sensitive and platinum-resistant patients will be included
Patients with extrapulmonary small cell cancers (cancers with small cell morphology and arising outside the lung, such as small cell prostate, bladder, etc.) will be eligible for the exploratory cohort
Patients must be >= 18 years of age because no dosing or adverse event data are currently available on the use of M6620 in combination with topotecan in patients <18 years of age
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Hemoglobin >= 9.0 g/dL - patients may receive transfusion to meet the hemoglobin (Hb) eligibility
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin =< 2 mg/dL
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (ULN)
Creatinine =< institutional ULN OR
Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are eligible as long as they are on effective anti-retroviral therapy with undetectable viral load within 6 months and there is no drug-drug interaction with M6220
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
The effects of M6620 on the developing human fetus are unknown. For this reason and because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completion of M6620 administration. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after completion of M6620 administration
Patients with treated brain metastases are eligible if they are symptomatically stable while off steroid therapy for a minimum of 21 days
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients with symptomatic brain metastasis are not eligible due to their extremely poor prognosis and since it is unclear whether the investigational agent penetrates the blood-brain barrier. However, subjects who have had treatment for their brain metastasis and are symptomatically stable while off steroid therapy for a minimum of 21 days may be enrolled
Patients who have received prior topotecan therapy
Patients who have had chemotherapy or radiotherapy within 3 weeks prior to enrollment.
- Note: Patients who have had palliative radiotherapy may be included as long as they have recovered from any radiotherapy related adverse events (allow at least a week between radiotherapy completion and study treatment)
Patients who have not recovered from adverse events due to prior anti-cancer therapy except hair loss and peripheral neuropathy (i.e., have residual toxicities > grade 1)
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 or topotecan used in study
M6620 is primarily metabolized by cytochrome P450 3A4 (CYP3A4); therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided. Patients requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or of which to minimize use. The Patient Drug Interactions Handout and Wallet Card should be provided to patients. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Patients with uncontrolled intercurrent illness
Pregnant women are excluded from this study because M6620 as a DDR inhibitor may 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 M6620, breastfeeding should be discontinued if the mother is treated with M6620. These potential risks may also apply to topotecan used in this study
Patients with high grade neuroendocrine cancers, but with no small cell morphology will not be eligible
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Patients with Li-Fraumeni syndrome will not be eligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort I Arm I (topotecan hydrochloride)	Biopsy Procedure	Participants 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. Participants may crossover to Arm II at disease progression. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm I (topotecan hydrochloride)	Biospecimen Collection	Participants 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. Participants may crossover to Arm II at disease progression. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm I (topotecan hydrochloride)	Computed Tomography	Participants 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. Participants may crossover to Arm II at disease progression. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm I (topotecan hydrochloride)	Topotecan Hydrochloride	Participants 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. Participants may crossover to Arm II at disease progression. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))	Berzosertib	Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))	Biopsy Procedure	Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))	Biospecimen Collection	Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))	Computed Tomography	Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))	Topotecan Hydrochloride	Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))	Berzosertib	Cohort II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))	Biopsy Procedure	Cohort II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))	Biospecimen Collection	Cohort II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))	Computed Tomography	Cohort II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))	Topotecan Hydrochloride	Cohort II: Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5 and berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a CT scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) Reported With 80% Confidence Interval	From start of treatment to time of progression or death, whichever occurs first, assessed at 6 months after last participant has enrolled; up to 2 years for pulmonary cohort and up 31.5 months for Exploratory Cohort.	The combination of M6620 with topotecan will be compared to topotecan alone in participants with relapsed small cell lung cancer (SCLC). Kaplan-Meier curves and a one-tailed log-rank test will be the primary analysis methods. PFS is defined as the duration of time from start of treatment to time of progression or death. whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and/or the appearance of one or more new lesions.
Progression-free Survival (PFS) Reported With 95% Confidence Interval	From start of treatment to time of progression or death, whichever occurs first, assessed at 6 months after last participant has enrolled; up to 2 years for pulmonary cohort and up 31.5 months for Exploratory Cohort.	The combination of M6620 with topotecan will be compared to topotecan alone in participants with relapsed small cell lung cancer (SCLC). Kaplan-Meier curves and a one-tailed log-rank test will be the primary analysis methods. PFS is defined as the duration of time from start of treatment to time of progression or death. whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and/or the appearance of one or more new lesions.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to 2 years	ORR is defined as percentage of participants who achieved either complete response (CR) or partial response (PR) as best response assessed using the revised Response Evaluation Criteria in Solid Tumors guideline (v 1.1). ORR percentage is calculated as the sum of the PR and CR rates, divided by the total number of participants who are evaluable for a response, multiplied by 100%. All participants included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions.
Overall Survival (OS) Reported With 80% Confidence Interval	Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort.	OS is defined as time from randomization to death, regardless of cause.
Overall Survival (OS) Reported With 95% Confidence Interval	Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort	OS is defined as time from randomization to death, regardless of cause.

Trial Locations

Locations (33): Los Angeles General Medical Center
🇺🇸
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
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Los Angeles, California, United States
USC Norris Oncology/Hematology-Newport Beach
🇺🇸
Newport Beach, California, United States
University of California Davis Comprehensive Cancer Center
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Sacramento, California, United States
UCHealth University of Colorado Hospital
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Aurora, Colorado, United States
University of Kansas Clinical Research Center
🇺🇸
Fairway, Kansas, United States
HaysMed
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Hays, Kansas, United States
University of Kansas Cancer Center
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Kansas City, Kansas, United States
Lawrence Memorial Hospital
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Lawrence, Kansas, United States
The University of Kansas Cancer Center - Olathe
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Olathe, Kansas, United States
University of Kansas Cancer Center-Overland Park
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Overland Park, Kansas, United States
University of Kansas Hospital-Indian Creek Campus
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Overland Park, Kansas, United States
Mercy Hospital Pittsburg
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Pittsburg, Kansas, United States
Salina Regional Health Center
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Salina, Kansas, United States
University of Kansas Health System Saint Francis Campus
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Topeka, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
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Westwood, Kansas, United States
University of Kentucky/Markey Cancer Center
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Lexington, Kentucky, United States
NCI - Center for Cancer Research
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Bethesda, Maryland, United States
Wayne State University/Karmanos Cancer Institute
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Detroit, Michigan, United States
Weisberg Cancer Treatment Center
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Farmington Hills, Michigan, United States
University Health Truman Medical Center
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Kansas City, Missouri, United States
University of Kansas Cancer Center - North
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Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit
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Lee's Summit, Missouri, United States
University of Kansas Cancer Center at North Kansas City Hospital
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North Kansas City, Missouri, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
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Lebanon, New Hampshire, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
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New York, New York, United States
Wake Forest University at Clemmons
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Clemmons, North Carolina, United States
Wake Forest Baptist Health - Hematology Oncology - Statesville
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Statesville, North Carolina, United States
Wake Forest Baptist Health - Wilkes Medical Center
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Wilkesboro, North Carolina, United States
Wake Forest University Health Sciences
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Winston-Salem, North Carolina, United States
University of Pittsburgh Cancer Institute (UPCI)
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Pittsburgh, Pennsylvania, United States
Parkland Memorial Hospital
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Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States