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Extensive Stage Lung Small Cell CarcinomaPhase 2NCT03896503

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

A Phase 2 study testing Berzosertib, Biopsy Procedure and Biospecimen Collection in people with Extensive Stage Lung Small Cell Carcinoma and Extrapulmonary Small Cell Neuroendocrine Carcinoma, run by National Cancer Institute (NCI) at 33 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Berzosertib, Biopsy Procedure and Biospecimen Collection
Could I receive a placebo?
No, everyone receives an active treatment
How many people
104 participants
Where
33 sitesUnited States
Study dates
30 Dec 2019to 13 May 2027
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

33 sites in 1 country.

33 sites in 1 country

United States33 sites

  • UCHealth University of Colorado Hospital

    Aurora, Colorado, 80045

  • NCI - Center for Cancer Research

    Bethesda, Maryland, 20892

  • Wake Forest University at Clemmons

    Clemmons, North Carolina, 27012

  • Parkland Memorial Hospital

    Dallas, Texas, 75235

  • UT Southwestern/Simmons Cancer Center-Dallas

    Dallas, Texas, 75390

  • Wayne State University/Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • University of Kansas Clinical Research Center

    Fairway, Kansas, 66205

  • Weisberg Cancer Treatment Center

    Farmington Hills, Michigan, 48334

  • HaysMed

    Hays, Kansas, 67601

  • University of Kansas Cancer Center

    Kansas City, Kansas, 66160

  • University Health Truman Medical Center

    Kansas City, Missouri, 64108

  • University of Kansas Cancer Center - North

    Kansas City, Missouri, 64154

  • Lawrence Memorial Hospital

    Lawrence, Kansas, 66044

  • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

    Lebanon, New Hampshire, 03756

  • University of Kansas Cancer Center - Lee's Summit

    Lee's Summit, Missouri, 64064

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • Laura and Isaac Perlmutter Cancer Center at NYU Langone

    New York, New York, 10016

  • USC Norris Oncology/Hematology-Newport Beach

    Newport Beach, California, 92663

  • University of Kansas Cancer Center at North Kansas City Hospital

    North Kansas City, Missouri, 64116

  • The University of Kansas Cancer Center - Olathe

    Olathe, Kansas, 66061

  • University of Kansas Cancer Center-Overland Park

    Overland Park, Kansas, 66210

  • University of Kansas Hospital-Indian Creek Campus

    Overland Park, Kansas, 66211

  • Mercy Hospital Pittsburg

    Pittsburg, Kansas, 66762

  • UPMC Hillman Cancer Center

    Pittsburgh, Pennsylvania, 15232

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

  • Salina Regional Health Center

    Salina, Kansas, 67401

  • Wake Forest Baptist Health - Hematology Oncology - Statesville

    Statesville, North Carolina, 28677

  • University of Kansas Health System Saint Francis Campus

    Topeka, Kansas, 66606

  • University of Kansas Hospital-Westwood Cancer Center

    Westwood, Kansas, 66205

  • Wake Forest Baptist Health - Wilkes Medical Center

    Wilkesboro, North Carolina, 28659

  • Wake Forest University Health Sciences

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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:

  1. 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.

  1. 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: Patients 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.

Being tested
Berzosertib, Biopsy Procedure, Biospecimen Collection, Computed Tomography, Topotecan Hydrochloride
Medical subject headings
Small Cell Lung Carcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BerzosertibDrug

    Also called 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970

    Given IV

  • Biopsy ProcedureProcedure or surgery

    Also called Biopsy, BIOPSY_TYPE, Bx

    Undergo a tumor biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo blood sample collection

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo a CT scan

  • Topotecan HydrochlorideDrug

    Also called Evotopin, Hycamptamine, Hycamtin, Nogitecan Hydrochloride

    Given IV

Study groups in NCT03896503
Study groupRoleWhat they receive
Cohort I Arm I (topotecan hydrochloride)Active comparatorParticipants 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.
Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Topotecan Hydrochloride
Cohort I Arm II (topotecan hydrochloride, berzosertib (M6620))ExperimentalParticipants 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.
Receives: Drug: Berzosertib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Topotecan Hydrochloride
Cohort II (exploratory cohort: topotecan, berzosertib (M6620))ExperimentalCohort 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.
Receives: Drug: Berzosertib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Topotecan Hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free Survival (PFS) Reported With 80% Confidence Interval

    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.

    Measured: 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.

  2. Progression-free Survival (PFS) Reported With 95% Confidence Interval

    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.

    Measured: 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.

Secondary outcomes (3)

  1. Objective Response Rate (ORR)

    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.

    Measured: Up to 2 years

  2. Overall Survival (OS) Reported With 80% Confidence Interval

    OS is defined as time from randomization to death, regardless of cause.

    Measured: Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort.

  3. Overall Survival (OS) Reported With 95% Confidence Interval

    OS is defined as time from randomization to death, regardless of cause.

    Measured: Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Apr 2019
  2. Study start30 Dec 2019
  3. Primary completion19 Dec 2022
  4. Study completion13 May 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
104 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03896503
Sponsor's protocol ID
NCI-2019-01769
Other IDs
NCI-2019-01769, 20-C-0009, 10268, 10268, ZIABC011078
Status last verified
Jun 2026
First submitted
27 Mar 2019
Last updated
31 Jul 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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

Publications

  • Fialkoff G, Takahashi N, Sharkia I, Gutin J, Hermoni N, Nirula M, Kumar R, Pongor L, Nichols S, Sciuto L, Parmar K, Desai P, Suresh P, Abel M, El Meskini R, Maoz M, Rottenberg Y, Nevo S, Nechushtan H, Peretz T, Roame D, Hubert A, Cohen JE, Salah A, Temper M, Grinshpun A, Weaver-Ohler Z, Rajan A, Figg WD Sr, Zick A, Sadeh R, Friedman N, Thomas A. Plasma nucleosome profiling reports on tumor burden and molecular subtypes in small cell lung cancer. J Clin Invest. 2026 Oct 1;136(19):e202151. doi: 10.1172/JCI202151. eCollection 2026 Oct 1.

    PubMed 42820295

  • Takahashi N, Hao Z, Villaruz LC, Zhang J, Ruiz J, Petty WJ, Mamdani H, Riess JW, Nieva J, Pachecho JM, Fuld AD, Shum E, Chauhan A, Nichols S, Shimellis H, McGlone J, Sciuto L, Pinkiert D, Graham C, Shelat M, Kattappuram R, Abel M, Schroeder B, Upadhyay D, Krishnamurthy M, Sharma AK, Kumar R, Malin J, Schultz CW, Goyal S, Redon CE, Pommier Y, Aladjem MI, Gore SD, Steinberg SM, Vilimas R, Desai P, Thomas A. Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. 2023 Dec 1;9(12):1669-1677. doi: 10.1001/jamaoncol.2023.4025.

    PubMed 37824137

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