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
4 other identifiers
interventional
104
1 country
33
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2
Started Dec 2019
Longer than P75 for phase_2
33 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 27, 2019
CompletedFirst Posted
Study publicly available on registry
April 1, 2019
CompletedStudy Start
First participant enrolled
December 30, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 19, 2022
CompletedResults Posted
Study results publicly available
November 13, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
June 23, 2026
ExpectedApril 13, 2026
January 1, 2026
3 years
March 27, 2019
August 8, 2024
April 9, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
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.
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.
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.
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)
Objective Response Rate (ORR)
Up to 2 years
Overall Survival (OS) Reported With 80% Confidence Interval
Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort.
Overall Survival (OS) Reported With 95% Confidence Interval
Up to 2 years for pulmonary cohort and up 31.5 for Exploratory Cohort
Other Outcomes (1)
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Date treatment consent signed to date off study, an average of 801.3 days.
Study Arms (3)
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.
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.
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.
Interventions
Undergo a tumor biopsy
Undergo a CT scan
Given IV
Given IV
Undergo blood sample collection
Eligibility Criteria
You may qualify if:
- 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
- +4 more criteria
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (33)
Los Angeles General Medical Center
Los Angeles, California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, 92663, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045, United States
University of Kansas Clinical Research Center
Fairway, Kansas, 66205, United States
HaysMed
Hays, Kansas, 67601, United States
University of Kansas Cancer Center
Kansas City, Kansas, 66160, United States
Lawrence Memorial Hospital
Lawrence, Kansas, 66044, United States
The University of Kansas Cancer Center - Olathe
Olathe, Kansas, 66061, United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211, United States
Mercy Hospital Pittsburg
Pittsburg, Kansas, 66762, United States
Salina Regional Health Center
Salina, Kansas, 67401, United States
University of Kansas Health System Saint Francis Campus
Topeka, Kansas, 66606, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536, United States
NCI - Center for Cancer Research
Bethesda, Maryland, 20892, United States
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201, United States
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, 48334, United States
University Health Truman Medical Center
Kansas City, Missouri, 64108, United States
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154, United States
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064, United States
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
Wake Forest University at Clemmons
Clemmons, North Carolina, 27012, United States
Wake Forest Baptist Health - Hematology Oncology - Statesville
Statesville, North Carolina, 28677, United States
Wake Forest Baptist Health - Wilkes Medical Center
Wilkesboro, North Carolina, 28659, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
Parkland Memorial Hospital
Dallas, Texas, 75235, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
Related Publications (1)
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.
PMID: 37824137DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Anish Thomas
- Organization
- National Cancer Institute
Study Officials
- PRINCIPAL INVESTIGATOR
Anish Thomas
National Cancer Institute LAO
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- LTE60
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 27, 2019
First Posted
April 1, 2019
Study Start
December 30, 2019
Primary Completion
December 19, 2022
Study Completion (Estimated)
June 23, 2026
Last Updated
April 13, 2026
Results First Posted
November 13, 2024
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
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